Copper and silicon mediated, HMPA-free, n+3 ring expansions for the construction of medium sized lactones and lactams: short synthesis of (+)-cis-lauthisan

Article abstract of DOI:10.1016/j.tet.2016.05.063

In this report, several new epoxide examples were united with β-silyl ketone enolates for the construction, after oxidative fragmentation, of ring expanded lactones, n+3 atoms in size. Importantly, azido lactones were found to be valuable in an extension of this protocol involving the n+3+p expansion into a series of hydroxyolefinic lactams. We also document a short, stereoselective total synthesis of (+)-cis-lauthisan and a new, cuprate-mediated and HMPA-free procedure for the generation of β-silyl silylenol ethers, useful in the environmentally-friendly construction of medium sized lactones.

Full text of DOI:10.1016/j.tet.2016.05.063

Tetrahedron xxx (2016) 1e6
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper and silicon mediated, HMPA-free, nþ3 ring expansions for
the construction of medium sized lactones and lactams: short
synthesis of (þ)-cis-lauthisan
,
Gary H. Posner a, Mark A. Hatcher b, William A. Maio c
*
a Department of Chemistry, Johns Hopkins University, Baltimore, MD 21210, USA
b GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
c Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In this report, several new epoxide examples were united with
b-silyl ketone enolates for the con-
Received 22 April 2016
Received in revised form 11 May 2016
Accepted 23 May 2016
Available online xxx
struction, after oxidative fragmentation, of ring expanded lactones, nþ3 atoms in size. Importantly, azido
lactones were found to be valuable in an extension of this protocol involving the nþ3þp expansion into
a series of hydroxyolefinic lactams. We also document a short, stereoselective total synthesis of (þ)-cis-
lauthisan and a new, cuprate-mediated and HMPA-free procedure for the generation of
ethers, useful in the environmentally-friendly construction of medium sized lactones.
b-silyl silylenol
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Medium sized lactones
Ketone enolates
Epoxide ring opening
Ring expansion
Total synthesis
1. Introduction
2. Mechanistic investigations
Pursuing our interest in epoxide ring opening reactions for the
construction of medium sized lactones1 and lactams,2 we initiated
a detailed investigation into our three-step, silicon-mediated nþ3
ring expansion process with respect to substrate scope and overall
efficiency. For example, the major advantage of this method over
our previously reported two-step procedure3 was the replacement
of toxic tin and lead reagents [LiSnBu3 and Pb(OAc)4, respectively]
with environmentally-friendly sources of silicon (Me3SiLi) and
hypervalent iodine [PhI(OAc)2, I2]. Unfortunately, however, in or-
As mentioned above, the success of our nþ3 ring expansion
method relies upon the use of hypervalent iodine to fragment
silyl hemiketal intermediates (cf.1, Scheme 1), formed via the union
b
-
R
R
O
O
O
R
HO
PhI(OAc)2
I2, CH2Cl2
O
O
6
5
SiMe3
rac-1
2
trans-2
der to generate the requisite b-silyl enolate, it was necessary to
not formed
employ hexamethylphosphoramide (HMPA); a polar aprotic sol-
vent which is known to be highly toxic. Also of note, a compre-
hensive substrate scope, in terms of reactive functionality on the
epoxide sidechain, was not undertaken in either of our initial re-
ports. Herein, we address both of these deficiencies and also
provide a showcase for this method with the synthesis of ring
expanded lactams and the stereoselective construction of (þ)-cis-
lauthisan.
OTBS
Me
O
!
O
2a
Scheme 1. Hemiketal oxidative fragmentation and lactone ORTEP.
* Corresponding author. E-mail address: wmaio@nmsu.edu (W.A. Maio).
http://dx.doi.org/10.1016/j.tet.2016.05.063
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Posner, G. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.063

2
G.H. Posner et al. / Tetrahedron xxx (2016) 1e6
of
b-silyl ketone enolates with epoxides, into lactones (cf. 2) with
exclusively C(5)eC(6) cis-alkene geometry (n¼5 and 6). Said dif-
ferently, when utilizing either cyclopent- or cyclohex-enone as
starting material, despite the trans-orientation between the hy-
drogens of their corresponding
b-silyl hemiketals, we have not
observed any trans-alkene containing lactone products.
The observed stereochemical preference for this reaction was
initially somewhat of a mystery, especially when one considers the
anionic fragmentation mechanism that was operative in our earlier
work3 and led to trans-alkenes as major products. Importantly, the
cis-geometry was unambiguously confirmed in two ways: (1) via
calculation of the alkene proton coupling constant (J¼w10 Hz) of
the resultant acyclic diols obtained after DIBAl-H reduction, and (2)
the X-ray crystal structure of lactone 2a which is representative of
the nine-membered ring series (Scheme 1). On a related note, to the
best of our knowledge, there have been no other literature reports
4
ꢀ
that exploit the Suarez reaction conditions [PhI(OAc)2, I2] for the
oxidative fragmentation of a b-silyl hemiketal such as 1.
Scheme 3. 5þ3 Ring expansion for the construction of eight-membered rings.
After considering these data, as well as several literature reports
concerning similar fragmentation reactions,5 we now propose the
following, nonconcerted, fragmentation mechanism to account for
cis-alkene formation (Scheme 2). In the absence of photochemical
irradiation, hypoiodite 3, formed upon the sequential addition of
PhI(OAc)2 and I2 to a solution of 1 in CH2Cl2 at 0 ꢀC, homolytically
cleaves to form oxygen-centered radical 4 which subsequently
Several epoxide examples7 in Scheme 3 are noteworthy. In ad-
dition to chiral, non racemic epoxides (cf. 9a),8 masked amine
functionality, notably terminal nitriles (9b), aromatic nitro groups
(9c), and azides (9dee) are exceedingly competent. Two step yields
for these lactones are generally good with the notable exception
being allyl cyanide oxide, where the poor yield may be attributed to
undergoes bond scission to generate a lactone carbonyl and
carbon centered radical 5. Previously, Kochi and co-workers ob-
served that -silyl radicals of this nature can be stabilized through
hyperconjugation between the half filled radical p-orbital and the
filled carbonesilicon
-orbital.6 For this to occur in our system,
b-silyl
epoxide volatility and/or a-proton acidity.
Related to this study, we also united two new epoxide examples
with the enolate corresponding to six-membered enol ether 10
(Scheme 4).1 Not surprisingly, 4-azidobutene oxide produced the
desired lactone in comparable yield to 7 (cf. 2b vs 9d), while a ter-
b
s
carbonecarbon bond rotation must occur, resulting in an eclipsed
conformation (6) before final fragmentation and olefin formation,
orienting the C(5)eC(6) hydrogens cis to one another in the product
(Scheme 2).
minal aliphatic nitro group with acidic
a-protons was also sur-
prisingly able to withstand the reaction conditions.
Scheme 4. 6þ3 Ring expansion for the construction of nine-membered rings.
4. Lactone to lactam ring expansions
In 2005, we published a short report regarding the sequential
ring expansions of n-sized cycloalkenones into hydroxyolefinic
nþ3þp sized lactones,1b where translactonization was efficiently
triggered by fluoride mediated silyl ether cleavage. After the suc-
cess of this work, we sought to develop an analogous protocol for
the conversion of lactones into ring expanded lactams, especially in
Scheme 2. Proposed hemiketal oxidative fragmentation mechanism.
light of our related studies on the synthesis of d-lactams via lactone
ring contraction.2 In a similar way, we had hoped that azido lac-
tones 9dee and 2b would serve as suitable substrates for this
purpose.9
3. Construction of novel eight-membered lactones
Initially, relying on the Corey method for azide reduction,10
lactone 2b was treated with hydrogen over the Lindlar catalyst
(Scheme 5). While the desired chemoselective reduction did occur,
concomitant intramolecular reorganization was not observed;
primary amine 11 was isolated as the major organic product (80%).
This result is surprising, especially when one considers the transi-
tion state required for lactam formation is six atoms in size. A va-
riety of subsequent reaction conditions were screened, for
example: heat, microwave irradiation, base treatment (Et3N and
K2CO3), and the addition of Lewis acids (e.g., TiCl4, CeCl3, Me3Al, and
In addition to cyclohexenone, we have also reported that the b-
silyl silylenol ether of cyclopentenone (7) can be exploited for the
synthesis of eight-membered (5þ3) lactones (cf. 9, Scheme 3).1
However, while reexamining our initial work, the substrate scope
seemed somewhat limited, with silyl and benzyl protected alcohols
the only reported functional groups tolerant of the two-step pro-
cedure. We now wish to report several additional reactive moieties
that can survive both the epoxide opening step and subsequent
oxidative fragmentation conditions (Scheme 3).
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G.H. Posner et al. / Tetrahedron xxx (2016) 1e6
3
Al2O3), but unfortunately, this intermediate could not be driven to
the desired 11-membered lactam product.
lactone (þ)-9a, made in two steps (59%) from enol ether 7, was first
saturated and then converted, using the Lawesson reagent, to thi-
onolactone (þ)-14. In only two additional steps involving: (1)
treatment with ethyllithium, followed by iodomethane, and (2)
reductive removal of sulfur, (þ)-cis-lauthisan could be accessed in
good overall yield (21% from 7) and high enantioselectivity. Im-
portantly, as determined by 1H NMR, no trace of the undesired
trans-oxocane was observed, with all data in good agreement with
previous literature reports for this compound.
6. Copper-mediated conjugate addition studies
According to the original report by Still, the addition of Me3Si-
Liegenerated via the addition of MeLi to Me3SiSiMe3 in HMPAeto
cyclohexenone occurs smoothly (Scheme 7), with HMPA acting to
stabilize the silyl anion and facilitate the 1,4-addition process.15
Wanting to find a more environmentally-friendly alternative, the
use of comparable additives was explored. For example, tetrame-
thylethylenediamine (TMEDA) and dimethyltetrahydropyr-
imidinone (DMPU) were separately substituted into the reaction,
however, neither gave any evidence of the desired conjugate ad-
dition. In support of these findings, Fleming has reported that,
trimethylsilyl lithium is difficult to generate in the absence of
HMPA.16
Scheme 5. nþ3þp Lactone to lactam ring expansion.
Undeterred by these results, we next sought to exploit eight-
membered azido lactones 9d and 9e in a similar process. Pleasingly,
by switching to the Staudinger conditions (PPh3 and H2O), azide
reduction was directly followed by lactone to lactam ring expansion
(cf. 9de12 and 9ee13) in good overall yield (Scheme 5). Un-
fortunately, when 2b was treated with these same conditions,
lactone 11 was again isolated as the major organic product. While it
is still unclear why amine 11 does not undergo ring expansion, one
may argue that it could be due to the thermodynamic stability of
a nine-membered lactone compared to the 11-membered lactam.11
Further investigations into the scope and limitations of this new,
four-step, synthesis of medium-sized lactams is ongoing, and will
be reported in due course.
5. Stereoselective synthesis of (D)-cis-lauthisan
Previously, we have exploited our ring expansion protocol for
the short and efficient syntheses of medium sized lactones and
piperidines.1,2 As an extension of these studies, we now wish to
report the use of a 5þ3 expansion as the key step in the total
synthesis of (þ)-cis-lauthisan [(þ)-16], an easier to access saturated
derivative of the marine derived cyclic ether (þ)-laurencin.12 Pre-
vious syntheses have suffered from long synthetic sequences (up to
18 steps), have been racemic, or proceeded with poor stereo-
induction.13 A notable exception is a recent study by Urbano and
~
Carreno which produced the optical enantiomer, (ꢁ)-cis-lauthisan,
in only four steps with high enantioselectivity via a reductive cy-
clization cascade.13j
Scheme 7. Copper-mediated, HMPA-free nþ3 ring expansion.
By uniting our ring expansion method with the elegant study by
Since the trimethylsilyl anion proved troublesome to generate
differently, it became necessary to explore complementary condi-
tions that would allow for the necessary 1,4-addition of a silyl an-
ion. Pleasingly, a search of the literature would prove useful in
finding the appropriate anion and a method to perform the nec-
essary conjugate addition.16 Of note, this method was also in-
dependently utilized by Hwu during a recent report regarding the
Nicolaou regarding carbanion addition to thionolactones,14 we have
affected
a
stereoselective total synthesis of (þ)-cis-lauthisan
[(þ)-16] in only six linear operations (Scheme 6). (þ)-Hexenyl
conversion of enolates to b
-silyl enones.17 Utilizing this procedure,
we found that chlorodimethylphenylsilane could be treated with
excess lithium metal, leading to a dark red solution of PhMe2SiLi.
After stirring ca. 18 h, the anion could be transferred, via cannula, to
a flame dried flask containing copper (I) iodide suspended in THF at
ꢁ25 ꢀC. After stirring for an additional 4 h, cyclohexenone could be
added dropwise to the solution of silyl cuprate followed by Me3SiCl
and triethylamine after 30 min, forming the desired b-silyl silylenol
ether (17, Scheme 7). Importantly, this compound was stable to
routine aqueous work-up and flash column chromatography using
florisil as stationary phase.
Several aspects of this new protocol are noteworthy. In order to
achieve reproducibly high yields, it was necessary to wash the CuI
Scheme 6. Stereoselective total synthesis of (þ)-cis-lauthisan.
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4
G.H. Posner et al. / Tetrahedron xxx (2016) 1e6
every two weeks using a soxhlet extractor (THF as solvent). As an
alternative, CuI$SMe2 could be substituted in place of CuI, however,
the product enol ether retained an unpleasant odor, even after
vacuum distillation. Comparable yields could also be achieved us-
ing diethylzinc (Et2Zn) either in place of CuI, or with a catalytic
amount of CuI added. Yields for this process were typically high
(75e80%) and proceeded with the main advantage being a shorter
reaction time overall, compared to the cuprate method. Also of
to 0 ꢀC. To this was added MeLi (0.63 mL, 1.0 mmol, 1.6 M in Et2O)
dropwise, turning the solution a bright yellow color. After 5 min,
the flask was then cooled to ꢁ78 ꢀC before a solution of epoxide
(0.5 mmol) in THF (1.5 mL) was added via cannula. The mixture was
allowed to stir for 5 min before BF3$Et2O (60 mL, 0.5 mmol, neat)
was added (1 drop every 4 s) while cooling the needle with a piece
of dry ice. After 30 min, the reaction was quenched with the ad-
dition of phosphate buffer (3.0 mL, pH 7.0) and allowed to warm to
rt. The crude reaction mixture was then extracted with Et2O
(3ꢂ25 mL) and the combined organic layers dried over MgSO4 and
concentrated in vacuo. The crude product was purified by silica gel
chromatography (90% hexanes, 10% ethyl acetate, w1% Et3N) to
yield the desired hemiketal as a colorless oil which was taken di-
rectly on to the next step without further purification.
In a second step, an oven dried 25 mL roundbottomed flask was
charged with hemiketal (0.1 mmol), dissolved in CH2Cl2 (8 mL) and
cooled to 0 ꢀC. To this solution was added, sequentially, PhI(OAc)2
(0.048 g, 0.15 mmol) and then I2 (0.033 g, 0.13 mmol), turning the
solution a dark purple color. The reaction was stirred for 5 h at 0 ꢀC
before being quenched with a saturated aqueous solution of so-
dium thiosulfate, turning the solution a light pink color. The crude
mixture was then extracted with CH2Cl2 (3ꢂ25 mL), and the
combined organic layers were dried over MgSO4 and concentrated
in vacuo. The crude product was purified by silica gel chromatog-
raphy (90% hexanes, 10% ethyl acetate) to afford the desired lactone
as a colorless (often volatile) oil.
note,
b
-silyl silylenol ether 17 is stable at ꢁ20 ꢀC under nitrogen for
at least several months and large quantities can be generated and
stored allowing one to consider it a stock reagent, utilized in small
quantities, as needed.
When compared to the previously studied
10,1,2 the steric and electronic environment surrounding the
esilicon group of 17 is markedly different (Scheme 7). At the onset
b-silyl silylenol ether
b
of this work, we were not sure that a lithium enolate derived from
17 could productively interact with a mono substituted epoxide.
Pleasingly, when 17 was treated with MeLi at 0 ꢀC, followed by
cooling to ꢁ78 ꢀC and the addition of 4-phenyl-butene oxide and
BF3$Et2O, a hemiketal was produced in high yield (77%). Impor-
tantly, when this intermediate was subsequently treated with
PhI(OAc)2 and I2 at 0 ꢀC in CH2Cl2, cis-alkene-containing lactone 2e
was isolated as the sole reaction product, in good overall yield (51%
from 17, Scheme 7). Encouraged by this result, two additional ep-
oxides were screened in this new HMPA-free nþ3 reaction se-
quence (Scheme 7, 2a and 2d), with yields being comparable, if not
better than those observed using
parentheses).
b-silyl silylenol ether 10 (yields in
8.2. Lactone 2a
1H NMR (CDCl3)
d 5.50e5.46 (m, 2H), 4.95e4.89 (m, 1H),
7. Conclusion
3.90e3.86 (m, 1H), 2.47e2.42 (m, 1H), 2.34e2.23 (m, 3H),
2.06e2.01 (m, 3H), 1.85e1.59 (m, 3H), 1.15 (d, J¼8.0 Hz, 3H), 0.88 (s,
In this study, several new epoxide examples were united with b-
9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3)
d 174.2, 134.4, 124.9,
silyl ketone enolates for the construction, after oxidative frag-
mentation, of ring expanded nþ3 lactones. As an extension of this
work, lactone to lactam ring expansion was investigated, as was the
stereoselective total synthesis of (þ)-cis-lauthisan. In a final note,
a new, cuprate-mediated and HMPA-free protocol for the genera-
70.9, 65.7, 45.0, 34.8, 33.6, 26.4, 25.9, 24.5,18.0, ꢁ4.2, ꢁ4.8; IR (neat)
3011, 2953, 2930, 2857,1743, 1448,1359,1257,1139,1107, 836 cmꢁ1
;
HRMS (EI), m/z (MþNa) calcd 335.2013 for C17H32O3SiNaþ, found
335.2016 (note: unfortunately, the optical rotation for this com-
pound was not obtained).
tion of a b-silyl silylenol ether is described, advancing this process
even more towards a robust and environmentally-friendly pro-
cedure for the construction of medium sized lactones. Additional
investigations by the Maio Laboratory are currently ongoing and
will be reported in due course.
8.3. Lactone 2b
1H NMR (CDCl3)
3.41e3.33 (m, 2H), 2.48e2.24 (m, 5H), 2.08e2.01 (m, 3H), 1.92e1.77
(m, 2H); 13C NMR (CDCl3)
174.2, 134.8, 124.3, 70.6, 40.0, 34.0, 33.7,
d 5.52e5.44 (m, 2H), 4.89e4.83 (m, 1H),
8. Experimental section
d
33.5, 26.4, 25.3; IR (neat) 2949, 2099, 1742, 1448, 1261, 1213, 1138,
727 cmꢁ1; HRMS (FAB) m/z (MþH) calcd 210.1243 for C10H15N3Oþ2 ,
found 210.1244.
Unless otherwise noted, reactions were performed in flame or
oven dried glassware under an atmosphere of dry argon. Reaction
solvents (CH2Cl2, THF, and Et2O) were purified before use via dis-
tillation. All other solvents and reagents were purchased from
SigmaeAldrich and used as received, unless otherwise specified.
8.4. Lactone 2c
Thin-layer chromatography (TLC) was performed using plates
1H NMR (CDCl3)
J¼6.8 Hz, 2H), 2.49e2.21 (m, 4H), 2.80e1.97 (m, 4H), 1.82e1.42 (m,
6H); 13C NMR (CDCl3)
174.5, 134.6, 124.5, 75.4, 72.6, 34.0, 33.6,
d 5.50e5.46 (m, 2H), 4.78e4.72 (m, 1H), 4.38 (t,
ꢁ
precoated with silica gel 60 A F-254 (250
m
m) and visualized by UV
light, KMnO4, or anisaldehyde stains, followed by heating. 1H and
13C NMR spectra were recorded on a Bruker 400 (operating at
400 MHz and 100 MHz, respectively) or Varian XL-400 operating at
the same frequencies, and are reported relative to residual solvent
d
26.9, 26.5, 25.3, 22.5 (note: one carbon resonance is missing due to
accidental overlap); IR (neat) 2951, 1737, 1552, 1448, 1356, 1215,
1139, 730 cmꢁ1; HRMS (EI), m/z (MþNa) calcd 264.1206 for
peak (
d
7.26 and
d
77.0 for 1H and 13C in CDCl3. Data for 1H NMR
ppm) (multiplicity,
C
12H19NO4Naþ, found 264.1200.
spectra are reported as follows: chemical shift (
d
coupling constant (Hz), integration). Spectra obtained are described
using the following abbreviations: br¼broad, s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet.
8.5. Lactone 2d
Has been reported previously by our laboratory. See Ref. 1b.
8.1. General procedure
8.6. Lactone 2e
An oven dried 25 mL roundbottomed flask was charged with
b-
silyl silylenol ether (1.0 mmol), dissolved in THF (1.5 mL) and cooled
Has been reported previously by our laboratory. See Ref. 1a.
Please cite this article in press as: Posner, G. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.063

G.H. Posner et al. / Tetrahedron xxx (2016) 1e6
5
8.7. Lactone 9a
evacuated using a vacuum pump, replacing the inner atmosphere
with a blanket of hydrogen using a balloon. After 5 h, the reaction
mixture was diluted with CH2Cl2 (1 mL), passed over Celite, and
concentrated in vacuo. The crude product was purified by silica gel
chromatography (70% hexanes, 30% ethyl acetate) to afford the
desired BOC-protected lactone as a colorless oil (0.036 g, 92%). 1H
½
a D
ꢃ
23þ22.5ꢀ (c¼0.53, CHCl3); 1H NMR (CDCl3)
d 5.81e5.70 (m,
2H), 4.58e4.52 (m, 1H), 2.88e2.77 (m, 1H), 2.71 (ddd, J¼13.2, 6.0,
2.8 Hz, 1H), 2.46e2.38 (m, 1H), 2.29 (ddd, J¼13.6, 11.6, 4.8 Hz, 1H),
2.13e2.05 (m, 2H), 1.67e1.59 (m, 1H), 1.55e1.47 (m, 1H), 1.43e1.22
(m, 8H), 0.86 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d
177.3, 132.5, 128.4,
NMR (CDCl3) d 5.49e5.46 (m, 2H), 4.82e4.76 (m,1H), 3.38e3.32 (m,
78.4, 37.8, 34.7, 34.4, 31.7, 28.9, 25.7, 24.3, 22.5, 14.0; IR (neat) 3018,
2932, 2858, 1749, 1454, 1323, 1215, 1149, 1053 cmꢁ1; HRMS (CI), m/z
(MþNa) calcd 233.1512 for C13H22O2Naþ, found 233.1517.
1H), 3.08e3.03 (m, 1H), 2.48e2.21 (m, 4H), 2.07e1.97 (m, 3H),
1.82e1.73 (m, 3H), 1.42 (s, 9H) (note: the NH proton is likely over-
laping with the chloro-form peak at 7.26); 13C NMR (CDCl3)
d 174.6,
155.8, 134.6, 124.5, 79.2, 71.2, 37.1, 34.5, 33.9, 33.5, 28.3, 26.5, 25.3;
IR (neat) 3413, 2981, 1811, 1742, 1716, 1512, 1371 cmꢁ1; HRMS (EI),
m/z (MþNa) calcd 306.16757 for C15H25NO4Naþ, found 306.16750.
8.8. Lactone 9b
1H NMR (CDCl3)
2.87e2.62 (m, 6H), 2.38e2.31 (m, 1H), 2.25e2.14 (m, 1H); 13C NMR
d 5.90e5.72 (m, 2H), 4.83e4.77 (m, 1H),
8.13. Lactam 12
(CDCl3)
d 175.6, 134.0, 126.5, 116.1, 71.6, 37.6, 33.3, 24.3, 23.6; IR
(neat) 2928, 2866, 2291, 1751, 1461 cmꢁ1; HRMS (EI), m/z (MþNa)
A 10 mL roundbottomed flask was charged with lactone 9d
(0.03 g, 0.2 mmol) and dissolved in THF (3 mL). To this was added
PPh3 (0.081 g, 0.23 mmol) and H2O (0.1 mL) before the contents of
the flask were heated to 50 ꢀC in an oil bath. After 18 h, the reaction
was concentrated in vacuo and columned directly without workup
(92% CH2Cl2, 7% MeOH, 1% NH4OH) to afford the desired lactam as
calcd 188.0682 for C9H11NO2Naþ, found 188.0691.
8.9. Lactone 9c
1H NMR (CDCl3)
d 7.93e7.91 (m, 1H), 7.55e7.35 (m, 3H),
5.84e5.73 (m, 2H), 4.92e4.86 (m, 1H), 3.29e3.14 (m, 2H),
2.87e2.78 (m, 1H), 2.72e2.66 (m,1H), 2.61e2.53 (m,1H), 2.30e2.21
a colorless oil (0.018 g, 69%). 1H NMR (CDCl3)
d 5.60e5.53 (m, 3H),
4.13e4.04 (m, 1H), 3.49e3.40 (m, 1H), 3.19 (br s, 1H), 2.74 (br s, 1H),
(m, 2H), 2.16e2.09 (m, 1H); 13C NMR (CDCl3)
d 176.6, 149.6, 133.0,
2.38e1.99 (m, 5H), 1.85e1.61 (m, 2H), 1.26e1.07 (m, 1H); 13C NMR
132.9, 132.6, 132.5, 127.8, 127.7, 124.7, 77.2, 37.6, 37.4, 34.4, 24.3; IR
(neat) 2938, 1747, 1526, 1348, 1215, 1055 cmꢁ1; HRMS (CI) m/z
(MþNa) calcd 284.0893 for C14H15NO4SiNaþ, found 284.0890.
(CDCl3) d 173.0, 129.7, 127.5, 69.4, 36.1, 34.2, 24.1 (note: two carbon
resonances are missing due to accidental overlap.); IR (neat) 3300,
2927, 2853, 1640, 1547, 1444 cmꢁ1; HRMS (EI), m/z (MþNa) calcd
192.0995 for C9H15NO2Naþ, found 192.0993.
8.10. Lactone 9d
8.14. Lactam 13
1H NMR (CDCl3)
d 5.82e5.69 (m, 2H), 4.66e4.60 (m, 1H),
3.44e3.33 (m, 2H), 2.83e2.68 (m, 2H), 2.50e2.43 (m, 1H),
Was prepared in a similar manner to lactam 12. 1H NMR (CDCl3)
2.34e2.27 (m, 1H), 2.14e2.05 (m, 2H), 1.91e1.75 (m, 2H); 13C NMR
d
5.77 (s, 1H), 5.63e5.53 (m, 2H), 3.88e3.87 (m, 1H), 3.23e3.14 (m,
(CDCl3)
d
176.7, 132.8,127.7, 75.1, 47.9, 37.6, 34.2, 33.8, 24.2; IR (neat)
2H), 2.38e2.04 (m, 6H),1.66e1.24 (m, 4H); 13C NMR (CDCl3)
d
173.2,
2939, 2100, 1748, 1215, 1057 cmꢁ1; HRMS (EI), m/z (MþNa) calcd
129.6, 128.0, 77.2, 70.4, 39.8, 37.1, 31.5, 29.9, 25.2; IR (neat) 3300,
2927, 2862, 1640, 1556, 1454 cmꢁ1; HRMS (FAB), m/z (MþH) calcd
184.1338 for C10H18NOþ2 , found 184.1346.
218.0899 for C9H13N3O2Naþ, found 218.0913.
8.11. Lactone 9e
8.15. Thionolactone 14
1H NMR (CDCl3)
d 5.82e5.69 (m, 2H), 4.57e4.52 (m, 1H),
3.35e3.30 (m, 2H), 2.87e2.68 (m, 2H), 2.50e2.42 (m, 1H),
Lactone (þ)-9a (0.128 g, 0.61 mmol) was placed in a 25 mL
roundbottomed flask with THF (7 mL) along with palladium on
carbon (w0.020 g, 20% by weight). The flask was then covered with
a septa and evacuated using a vacuum pump, replacing the inner
atmosphere with a blanket of hydrogen using a balloon. The re-
action was monitored by GC and found to be complete after 15 h.
The solution was then concentrated in vacuo to dryness and passed
over a plug of silica using hexanes to afford the saturated lactone as
2.33e2.26 (m, 1H), 2.13e2.02 (m, 2H), 1.80e1.59 (m, 4H); 13C NMR
(CDCl3)
(neat) 3030, 2946, 2872, 2097, 1743, 1454, 1314, 1211, 1146, 1053,
726 cmꢁ1
HRMS (EI), m/z (MþNa) calcd 232.1056 for
10H15N3O2Naþ, found 232.1048.
d 177.2, 132.8, 128.0, 77.5, 50.8, 37.7, 34.4, 31.5, 25.2, 24.3; IR
;
C
8.12. Lactone 11
a colorless oil (0.088 g, 70%). ½a D
ꢃ
25þ26.15ꢀ (c¼0.325, CHCl3); 1H
A 10 mL roundbottomed flask was charged with lactone 2b
(0.006 g, 0.03 mmol) and the Lindlar catalyst (w0.002 g, 30% by
weight) before being dissolved in ethanol (2 mL). The flask was
then covered with a septa and evacuated using a vacuum pump,
replacing the inner atmosphere with a blanket of hydrogen using
a balloon. After 2 h the reaction mixture was diluted with CH2Cl2
(1 mL), passed over Celite, and then concentrated in vacuo to afford
the desired lactone as a colorless oil (0.004 g, 80%). 1H NMR (CDCl3)
NMR (CDCl3) d 4.57e4.50 (m, 1H), 2.57e2.43 (m, 2H), 1.95e1.87 (m,
1H), 1.85e1.79 (m, 1H), 1.78e1.55 (m, 4H), 1.54e1.40 (m, 4H),
1.34e1.22 (m, 8H), 0.88 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d 177.0,
78.7, 37.3, 35.6, 32.4, 31.7, 29.1, 28.9, 26.4, 25.7, 23.9, 22.5, 14.0; IR
(neat) 2929, 2858, 1732, 1456, 1232, 1119, 1006 cmꢁ1; HRMS (CI), m/
z (M) calcd 212.1770 for C13H24Oþ2 , found 212.1785.
In a second step, the saturated lactone (0.084 g, 0.40 mmol) was
placed in a 25 mL roundbottom flask with toluene (2.5 mL, anhy-
drous) before the Lawesson reagent (0.160 g, 0.40 mmol) was added
in one portion. The contents of the flask were then heated to reflux
for 1 h and then allowed to slowly cool to rt. The cooled solution
was then purified directly without workup (98% hexanes, 2% ethyl
acetate) to afford the desired lactone as a colorless oil (0.064 g,
d
5.49e5.47 (m, 2H), 4.89e4.84 (m, 1H), 2.49e2.22 (m, 5H),
2.08e1.88 (m, 3H), 1.83e1.73 (m, 2H), 1.43 (s, 2H). Because of the
polar nature of this compound, it was protected as its BOC-
derivative for further characterization.
A 15 mL roundbottomed flask was charged with 11 (0.029 g,
0.14 mmol) and dissolved in ethyl acetate (2 mL). To this was added
the Lindlar catalyst (w0.005 g, 30% by weight) and BOC anhydride
(0.036 g, 0.17 mmol). The flask was then covered with a septa and
71%). ½a D
ꢃ
25þ17.22ꢀ (c¼1.15, CHCl3); 1H NMR (CDCl3)
d 4.80e4.84
(m, 1H), 3.18e3.12 (m, 1H), 3.00e2.93 (m, 1H), 2.02e1.67 (m, 6H),
1.66e1.55 (m, 2H), 1.54e1.40 (m, 2H), 1.38e1.22 (m, 8H), 0.87 (t,
Please cite this article in press as: Posner, G. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.063

6
G.H. Posner et al. / Tetrahedron xxx (2016) 1e6
J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d
229.1, 85.2, 44.1, 37.5, 35.6, 32.4,
chromatography (70% hexanes, 30% ethyl acetate) to yield the de-
sired -silyl silylenol ether (2) as a slightly yellow oil (1.34 g, 85%).
1H NMR (CDCl3)
7.59e7.54 (m, 2H), 7.44e7.37 (m, 3H), 4.89e4.88
31.6, 29.0, 26.2, 25.8, 24.0, 22.5, 14.0; IR (neat) 2926, 2360, 1458,
b
1302, 1232, 1081 cmꢁ1; HRMS (CI), m/z (M) calcd 228.1542 for
d
C
13H24OSþ, found 228.1554.
(m, 1H), 2.02e1.98 (m, 2H), 1.81e1.71 (m, 3H), 1.59e1.55 (m, 1H),
1.39e1.34 (m, 1H), 0.35 (s, 3H), 0.34 (s, 3H), 0.23 (s, 9H); 13C NMR
8.16. (D)-cis-Lauthisan (16)
(CDCl3) d 149.6,138.2,133.9, 128.9, 127.7, 104.7, 29.9, 23.7, 23.6, 23.5,
0.4, ꢁ4.8, ꢁ4.9. IR (neat) 3068, 2956, 2930, 2856, 1655, 1427, 1365,
1251, 1187, 1113, 1029, 987 cmꢁ1; HRMS (EI) m/z (M) calcd 304.1679
for C17H28OSiþ2 , found 304.1643.
Thionolactone 14 (0.060 g, 0.26 mmol) was placed in a 25 mL
roundbottomed flask with THF (3 mL) and then cooled to ꢁ78 ꢀC. To
this solution was added ethyllithium (0.788 mL, 0.394 mmol, 0.5 M
in cyclohexane/benzene) slowly via syringe. The reaction was
allowed to stir for 10 min at ꢁ78 ꢀC before iodomethane (0.033 mL,
0.53 mmol) was added in one portion. After warming to rt, the
reaction mixture was quenced with water and extracted with ether
(3ꢂ25 mL). The combined organic layers were then dried over
MgSO4 and concentrated in vacuo. The crude material was purified
by silica gel chromatography (95% hexanes, 5% ethyl acetate) to
yield the desired cyclic ether as a colorless oil (0.055 g, 77%). This
material was found to be unstable and taken directly on to the next
step without characterization.
Acknowledgements
The authors would like to thank the National Science Founda-
tion for seed support for this project, as well as Drs. Amy Sarjeant
(JHU), Susan Hatcher (OSU), and Phil Mortimer (JHU) for providing
analytical data services (X-ray and mass analysis). We would also
like to thank Drs. Maxime Siegler (JHU) for data handling, Ryan
Conyers (JHU) for coordinating data retrieval, and Alvin Kalinda
(JHU) for his efforts regarding the reproducibility of our copper-
mediated conditions. WAM dedicates this manuscript to his col-
league and friend, Dr. James P. Bacci (1979e2015), with deep ad-
miration and great respect.
In a second step, this cyclic ether (0.045 g, 0.17 mmol) was
placed in a 25 mL roundbottomed flask with toluene (5 mL, anhy-
drous) and treated with tributyltin hydride (0.111 mL, 0.41 mmol)
and a catalytic amount of AIBN (0.005 g). The contents of the flask
were then heated to reflux for 1.5 h after which the solution was
cooled to rt, passed over a plug of silica gel using hexanes, and
concentrated in vacuo. The crude reaction mixture was then puri-
fied by silica gel chromatography (95% hexanes, 5% ethyl acetate) to
yield the desired compound as a colorless oil (0.035 g, 95%).
References and notes
1. (a) Hatcher, M.; Borstnik, K.; Posner, G. H. Tetrahedron Lett. 2003, 44, 5407; (b)
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~
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½
a D
ꢃ
24þ14.6ꢀ (c¼0.15, CHCl3); 1H NMR (CDCl3)
d 3.44e3.38 (m, 1H),
3.36e3.30 (m, 1H), 1.82e1.56 (m, 5H), 1.55e1.33 (m, 9H), 1.32e1.20
5. For example, see: (a) Kaino, M.; Naruse, Y.; Ishihara, K.; Yamamoto, H. J. Org.
(m, 8H), 0.93 (t, J¼7.6 Hz, 3H), 0.88 (t, J¼7.2 Hz, 3H); 13C NMR
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7. Epoxides utilized in this study were synthesized according to known literature
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(CDCl3) d 81.1, 79.6, 37.0, 33.6, 33.3, 31.9, 29.8, 29.5, 27.0, 26.3, 24.0,
22.6, 14.11, 10.9 (note: similar to known literature reports, two
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;
8. The non-racemic (S)-1,2-epoxyoctane used to prepare lactone 9a in high en-
antiomeric excess was generated by kinetic resolution using the Jacobsen
HRMS (CI), m/z (M) calcd 226.2291 for C15H30Oþ, found 226.2284.
CoIII(AcOH) catalyst, ½a D
ꢃ
24e8.9ꢀ (c¼2.05, CHCl3 ), lit. ½a D
ꢃ
24e8.9ꢀ (c¼1.8, CHCl3
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8.17. -Silyl silylenol ether 17
b
In an oxygen purged, nitrogen filled glove bag, lithium ribbon
(0.51 g, 73.0 mmol) was carefully cut and added to a flame dried
100 mL flask. To this, was added chlorodimethylphenylsilane
(1.78 g, 10.4 mmol) and THF (17 mL), which produced a dark red
solution. After being allowed to stir at rt overnight (ca. 18 h), the
silyl anion was transferred, via cannula, to a 50 mL roundbottom
flask at ꢁ25 ꢀC containing freshly purified CuI (0.99 g, 5.2 mmol).
After an additional 4 h of stirring, cyclohexenone (0.50 g, 5.2 mmol)
in THF (3 mL) was added dropwise, followed by triethylamine
(1.4 mL, 16.0 mmol) and trimethylsilyl chloride (2.0 mL, 16.0 mmol)
after 30 min. Finally, after one additional hour of stirring, the re-
action was warmed to 0 ꢀC and poured into a separatory funnel
containing 100 mL of ice chilled hexanes. The organic layer was
quickly washed, successively, with a saturated aqueous solution of
NH4Cl (2ꢂ40 mL), brine (30 mL) and deionized water (2ꢂ30 mL).
The organic layer was then dried over MgSO4, filtered, and con-
centrated in vacuo. The crude product was purified by Florisil
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Please cite this article in press as: Posner, G. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.063