Fragmentation of bicyclic γ-silyloxy-β-hydroxy-α- diazolactones as an approach to ynolides

Article abstract of DOI:10.1021/jo500634d

Medium-sized ynolides were prepared by the Lewis acid-mediated fragmentation of bicyclic γ-silyloxy-β-hydroxy-α-diazolactones in which the Cβ-Cγ bond is the ring fusion bond. Although these lactone fragmentation substrates reacted somewhat less efficientl

Full text of DOI:10.1021/jo500634d

Article
pubs.acs.org/joc
Open Access on 06/12/2015
Fragmentation of Bicyclic γ‑Silyloxy-β-hydroxy-α-diazolactones as an
Approach to Ynolides
Ali Bayir and Matthias Brewer*
Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, United States
S
* Supporting Information
ABSTRACT: Medium-sized ynolides were prepared by the Lewis acid-
mediated fragmentation of bicyclic γ-silyloxy-β-hydroxy-α-diazolactones
in which the Cβ−Cγ bond is the ring fusion bond. Although these
lactone fragmentation substrates reacted somewhat less efficiently than
their carbocyclic counterparts, the fragmentation provided 11-
membered ynolides in up to 84% yield. Unlike prior fragmentations
of similar substrates, elevated temperatures were required to obtain optimum yields of the ynolide products. The ynolides
reported herein have ring sizes of 10 or 11, which are the smallest reported to date.
Scheme 1. Formation of Medium- and Large-Ring Ynones
INTRODUCTION
■
Medium and large rings are common scaffolds in biologically
active compounds, and there is growing interest in exploring
macrocycles in therapeutic drug discovery programs.1−4 Thus,
the development of methods to prepare these structures is an
important and ongoing area of research.2,3 Large-ring lactones
that contain an alkyne within the ring (i.e., ynolides5,6) are not
common species but have proven to be useful synthetic
intermediates in a number of macrolide natural product
syntheses. For example, Smith and Malamas7 subjected an
ynolide intermediate to partial reduction as a way to
stereoselectively form a cis-alkene in their synthesis of cis-
normethyljatropholactone. Macrolactonization of alkynoates
followed by partial reduction has also been used in the
syntheses of phorboxazole B8−10 and laulimalide11−20 as a way
to circumvent isomerization of the requisite cis-enoate during
the macrolactonization step. In addition, Danishefsky and co-
workers took advantage of ynolides as Diels−Alder dienophiles
in their approach to resorcinylic fused macrolides.5,6 These
useful synthetic intermediates have been typically prepared
through conventional macrocycle formation techniques,
namely, macrolactonization and alkene or alkyne ring-closing
metathesis.21 In addition, Ogasawara and co-workers22 reported
a Pd-catalyzed carbomacrolactonization procedure that pro-
vides moderate yields of ynolides that are 15-membered or
larger. Unfortunately, all of these strategies suffer from the
common limitation of macrocyclization strategies, namely, the
requirement of high-dilution conditions. To the best of our
knowledge, no ynolides having a ring size smaller than 14 have
been reported.
preparation of the corresponding medium- and large-ring
ynoates by fragmentation of bicyclic diazo lactones. While
ultimately successful in delivering 10- and 11-membered
ynolides, the fragmentation of these bicyclic lactones was not
as straightforward as the fragmentation of the corresponding
ketone species, and we describe our results herein.
RESULTS AND DISCUSSION
■
Our initial target for these studies was 10-membered ynolide 9
that we envisioned would come from fragmentation of diazo
lactone 8, which we prepared as shown in Scheme 2.
Formylation of cyclohexanone with the Vilsmeier reagent26
followed by reduction with sodium borohydride27 gave allylic
alcohol 4 in 75% yield over the two steps. Subsequent
dihydroxylation with osmium tetroxide provided 1,2-ketodiol 5
in an unoptimized yield of 34%. Reaction of 5 with p-
toluenesulfonylhydrazone glyoxylic acid chloride (6)28 pro-
vided diazoester 7, which was then treated with DBU to effect
an intramolecular aldol addition providing the requisite bicyclic
diazo lactone 8 in 37% yield over two steps.29 Unfortunately,
subjecting diazo 8 to the standard fragmentation conditions led
only to the formation of an insoluble precipitate; none of the
desired fragmentation product was observed. All of the
We recently disclosed that bicyclic γ-silyloxy-β-hydroxy-α-
diazoketones in which the Cβ-Cγ bond is the ring fusion bond
fragment in the presence of a Lewis acid to provide 10-, 11-,
and 12-membered cyclic 2-alkynones in good to excellent yields
(Scheme 1).23 In view of the fact that γ-silyloxy-β-hydroxy-α-
diazoesters fragment as efficiently as their ketone ana-
logues,24,25 we sought to extend this methodology to the
Received: March 18, 2014
Published: June 12, 2014
© 2014 American Chemical Society
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Scheme 2. Synthetic Route to Bicyclic β,γ-Dihydroxy-α-diazolactone 8
Scheme 3. Synthesis of Bicyclic Diazo Lactone Fragmentation Precursors 16
fragmentation substrates we previously studied had the γ-
oxygen protected as a silyl ether, and with this in mind we
attempted to convert diol 5 into the bis(tert-butyldimethylsilyl)
ether and then selectively deprotect the primary alcohol.
Unfortunately, these attempts were not successful.
improve the reaction outcome. We next assessed the ability of
other Lewis acids to mediate the fragmentation and found that
zinc chloride provided no reaction while indium triflate gave a
mixture of epoxide 17 in 5% yield and diene 18 in 31% yield
(Figure 1). Treating the fragmentation precursor with BF3·
OEt2 in acetonitrile at 0 °C provided the desired product 9 in
only 6% isolated yield. To buffer against any acid that might be
formed over the course of the BF3·OEt2-mediated reaction, we
included a proton sponge in the mixture, but this did not
provide an increase in the yield. Interestingly, when BF3·OEt2
was added to a −78 °C solution of the fragmentation precursor
in dichloromethane, none of the desired product was formed.
Instead, desilylated diene 19, which had not been observed
previously, was formed as the major product. With this in mind,
we attempted the fragmentation with SnCl4 at both −78 °C
and room temperature. At low temperature the desired product
was formed only as a minor component of a complex mixture,
but treating the cis-fused fragmentation precursor 16-cis with 1
equiv of SnCl4 at room temperature provided the desired
lactone product in 21% yield. Ultimately, we discovered that
adding 16-trans or 16-cis to a refluxing solution of SnCl4 in
dichloromethane provided the desired product in 17% or 33%
yield, respectively. Crystallization of 9 from cold methanol
provided crystalline material, and the structure of 9 was further
confirmed by single-crystal X-ray diffraction, which showed the
alkyne to be distorted from linearity by approximately 10°.33
This distortion is consistent with values computed for
cyclodecyne.34
Ultimately, we prepared γ-silyloxy-β-hydroxy-α-diazolactone
16 by the route shown in Scheme 3. Pd-mediated α-
oxygenation30 of commercially available ethyl 2-oxocyclohex-
anecarboxylate (10) gave α-hydroxy-β-keto ester 11, which was
converted into bis(silyl ether) 12 in which the ketone is
conveniently protected as the silyl enol ether. Reduction of the
ester with DIBAL-H and subsequent selective cleavage of the
silyl enol ether with CsF in acetic acid provided keto alcohol
14, and acylation of the primary alcohol with bromoacetyl
bromide gave bromoacetate 15. Treatment of 15 with N,N′-
ditosylhydrazine31 in the presence of DBU provided the
corresponding diazo ester, which spontaneously cyclized to give
diazo lactones 16-trans and 16-cis as separable diastereomers.32
In view of the high yields we observed for the fragmentation
of bicyclic diazo ketones (Scheme 1) and acyclic diazo esters,25
we were surprised to observe that subjecting diazo lactones 16-
trans and 16-cis to the standard fragmentation conditions (i.e.,
1 equiv of SnCl4 at 0 °C) provided cyclic ynoate 9 (Figure 1) in
only 10% and 12% yield, respectively. We thought that
hydrolysis of the strained ynoate might be a facile reaction
that would complicate isolation, but carrying out the
fragmentation in the presence of molecular sieves did not
In considering why diazo lactone 16-cis fragmented in lower
yields than its carbocyclic counterpart 1a (Scheme 1), we
hypothesized that the proximity of the inductively electron-
withdrawing ester to the bond that breaks might slow the bond-
breaking step and increase the likelihood of competitive side
reactions. To evaluate this supposition, we prepared diazo-
acetate 21 (Scheme 4),35 which has the ester and the breaking
bond in the same relative position as in 16. Subjecting this
Figure 1. Products observed in various attempts to fragment diazo 16.
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Scheme 4. Preparation of Acetate Diazo Ester 21 and Its Fragmentation
Scheme 5. Preparation and Fragmentation of Diazo Lactone 29
Scheme 6. Preparation of Diazo Lactone 38a and Diazo Ester 37b
compound to the standard fragmentation conditions resulted in
a smooth transformation to give ynoate 22 in 70% isolated
yield. This result indicates that the low yields observed in the
fragmentation of 16 are most likely not due to the position of
the electron-withdrawing ester.
To see whether the ring size affected the outcome of the
fragmentation reaction, we envisioned preparing homologues of
diazo lactone 16 in which either the carbocyclic ring or the ring
containing the diazo ester was enlarged. With this in mind, we
prepared diazo lactone 29 (Scheme 5), in which the ring
bearing the diazo group has been enlarged by one methylene
unit. Addition of allylmagnesium bromide to the known 2-
silyloxycyclohex-2-enone 23 provided a tertiary alcohol that was
converted into ketone 24 via a base-catalyzed silyl transfer
reaction.36 Ozonolysis of alkene 24 provided aldehyde 25 in
high yield, and selective reduction of the aldehyde with Raney
nickel37 provided the primary alcohol as hemiacetal 26. The
hemiacetal was converted into diazo ester 28 by acylation and
subsequent diazotization as described for the preparation of 16
(Scheme 3), but in this case cyclization did not spontaneously
occur. However, treatment of 28 with LiHMDS under dilute
conditions at low temperatures effected the ring closure and
gave a single diastereomer (tentatively assigned as trans) of the
desired bicyclic fragmentation precursor 29 in 69% yield. Upon
treatment with 1 equiv of SnCl4 at 0 °C, diazo 29 fragmented
to provide the 11-membered cyclic ynoate 30 in 50% yield. The
yield of 30 increased to 63% when the reaction was run at reflux
temperature. The higher yields obtained for this enlarged ring
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Scheme 7. Base-Mediated Formation and Subsequent Reaction of Diazo Ester 39
system seem to indicate that ring size does indeed play a role in
the fragmentation outcome.
CONCLUSIONS
■
While bicyclo[5.4.0] and -[4.5.0] diazo systems 29 and 38a-cis
fragmented to provide the corresponding 11-membered
ynolides in 63% and 84% yield respectively, the bicyclo[4.4.0]
homologue 16-cis provided the 10-membered ynolide in at best
33% yield; as observed in our prior studies,23 the corresponding
trans-fused bicyclic diazo lactones consistently fragmented in
slightly lower yields. Attempts to form the bicyclo[4.6.0] diazo
lactone system failed because of an unexpected silyl migration
and translactonization event. At this point it is clear that the
fragmentation of bicyclic diazo lactones to provide ynolide
products is not as straightforward or high-yielding as the
fragmentation of their carbocyclic counterparts, which gives
large-ring ynones (Scheme 1). It is unclear why these systems
behave differently, and computational studies to shed light on
this interesting reactivity trend are planned. It is noteworthy
that the ynolides presented here have the smallest ring size
reported to date; all prior examples of this structural motif are
14-membered2 or larger.
We next focused on preparing homologues of 16 (Scheme 3)
in which the carbocyclic ring was expanded by one or two
methylene units by routes analogues to that used for the
preparation of 16. While diazotization of 36a (n = 2; Scheme 6)
led directly to the diastereomeric bicyclic fragmentation
precursors 38a-trans and 38a-cis, diazotization of 36b (n =
3) provided the linear diazo species 37b. Interestingly, in our
prior work with the carbocyclic derivatives of these diazo
compounds23 we noted a similar difficulty in forming the
bicyclo-[4.6.0] ring system (1c, Scheme 1) and observed that at
equilibrium the system exists predominantly in the ring-opened
form. Attempts to convert 37b to its ring-closed form by
treatment with DBU failed to yield any desired product.
In an attempt to drive the ring closure under more strongly
basic and nonequilibrating conditions, we treated 37b with
LiHMDS to provide a material we initially assigned as the
homologue of 38a-cis in 64% yield. However, attempts to
fragment this latter material did not provide any desired ynolide
product, which was surprising in view of the fact that the
carbocyclic variant 1c (Scheme 1) had fragmented in 93%
yield.23 Ultimately, full characterization of the cyclization
product revealed that it was in fact the spectroscopically similar
diazo lactone 39 (Scheme 7). Although the desired ring closure
had occurred, the initially formed alkoxide product apparently
underwent a subsequent silyl migration and translactonization.
We have never encountered silyl migration in any of our prior
work with similar substrates, and it is unclear why it occurred in
this case. However, considering that the ring-closure step itself
is unfavorable, it seems likely that in this case silyl migration is
promoted by unfavorable steric interactions in the ring-closed
form. This rearrangement is an unanticipated complication that
is not possible in the carbocyclic series. Unfortunately, attempts
to circumvent this rearrangement have not been fruitful.
Subjecting diazo lactone 39 to the standard ring-fragmentation
conditions returned cyclic ether 40 in 80% yield.
EXPERIMENTAL SECTION38
■
(2-Chlorocyclohex-1-en-1-yl)methanol (4). POCl3 (9.32 mL,
0.1 mmol) was added slowly to a 0 °C solution of DMF (10.84 mL,
0.14 mmol) in trichloroethylene (20 mL) at such a rate as to maintain
the reaction temperature below 10 °C. The mixture was allowed to
warm to room temperature, and cyclohexanone (11.4 mL, 0.11 mmol)
in trichloroethylene (25 mL) was added at such a rate as to maintain
the reaction temperature below 60 °C; the reaction mixture was then
maintained at 55−60 °C for 3 h. The mixture was cooled in an ice
bath, and a solution of NaOAc (40 g) in water (94 mL) was added
slowly over 1 h, keeping the reaction temperature below 35 °C. The
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 50 mL). The organic layers were combined, washed with
brine (2 × 200 mL) and water (200 mL), and dried over anhydrous
Na2SO4. Anhydrous NaOAc (1 g) was added to the dried organic
layer, and the solvent was reduced in vacuo. The residue was dissolved
in 50 mL of MeOH, and the pH was adjusted to 8 by addition of a
10% aqueous NaOH solution at ice-bath temperature. NaBH4 powder
(3.78 g, 0.1 mmol) was added in small portions, and the mixture was
stirred overnight at room temperature. The mixture was treated with
90 mL of water and extracted with EtOAc (3 × 90 mL). The organic
layers were combined, washed with brine, and dried over anhydrous
MgSO4. The solvent was evaporated, and the crude product was
purified via flash silica gel chromatography (hexanes/EtOAc 20:1 to
5:1; Rf = 0.62 in hexanes/EtOAc 2:1) to afford the title compound in
We were pleased to find that upon treatment with SnCl4 at 0
°C, diazo lactone 38a-cis productively fragmented to give 11-
membered cyclic ynoate 41 in 64% yield, while 38a-trans
provided the desired product in 57% yield. At 40 °C these
yields increased to 84% and 67%, respectively (Scheme 8).
These results further support the notion that ring size is an
important factor affecting the fragmentation outcome.
75% yield (10.99 g). The H and 13C NMR data for this material
1
matched previously reported values.26,27
2-Hydroxy-2-(hydroxymethyl)cyclohexanone (5). OsO4 (2.78
g, 0.27 mmol) was added to a room-temperature solution of (2-
chlorocyclohex-1-en-1-yl)methanol (4) (2 g, 13.67 mmol) and NMO
(3.20 g, 27.33 mmol) in a mixture of THF (46 mL) and water (23
mL), and the mixture was stirred for 48 h. Then Na2SO3 (10 g) was
added, and the mixture was stirred for an additional hour. The mixture
was filtered through a pad of silica gel, which was then washed with
EtOAc (150 mL). The solvents were removed in vacuo to provide an
oily residue that was purified by silica gel flash chromatography
(hexanes/EtOAc 2:1; Rf = 0.23 in hexanes/EtOAc 1:1) to afford the
known compound 2-hydroxy-2-(hydroxymethyl)cyclohexanone as a
Scheme 8. Reactions of Bicyclic Diazo Lactones 38a and 38b
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colorless oil (0.66 g, 34%). The 1H and 13C NMR data for this material
matched previously reported values.39,40
and bicyclic diazo lactone 16-cis (0.0818 g, 0.25 mmol) in dry CH2Cl2
(1 mL) was then added in one portion. The vial containing the bicyclic
diazo lactone was rinsed with 1.3 mL of CH2Cl2, and this too was
added to the refluxing reaction mixture. The mixture was held at reflux
for 10 min and then cooled in an ice bath, at which point 5% aqueous
NaHCO3 (8 mL) was added and the mixture was transferred with the
aid of CH2Cl2 (10 mL) into a separatory funnel. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The organic layers were combined and dried over anhydrous
Na2SO4. The solvents were removed in vacuo, and the residue was
subjected to flash column chromatography on Davisil (hexanes/EtOAc
10:1, 6:1, 1:1; Rf = 0.13 in hexanes/EtOAc 1:1) to afford pure cyclic
ynoate 9 in 33% yield (0.0134 g). According to the same procedure,
diazo lactone 16-trans provided the title compound in 17% yield as
determined by NMR analysis using mesitylene as an internal standard.
Ethyl 1-Hydroxy-2-oxocyclohexanecarboxylate (11). A mix-
ture of commercially available ethyl 2-oxocyclohexanecarboxylate (10)
(4.69 mL, 29.4 mmol), 10% Pd/carbon (1.5 g), and Et3N (4.5 mL,
32.3 mmol) in EtOH (150 mL) was attached to a balloon of O2 via a
three-way stopcock. The air in the reaction flask was evacuated via an
aspirator and replaced with oxygen three times, and the reaction
mixture was stirred under O2 overnight. The mixture was filtered
through Celite, and the solids were rinsed with EtOH (100 mL). The
filtrate was concentrated in vacuo, and the oily residue was purified by
silica gel flash column chromatography (hexanes/EtOAc 6:1; Rf = 0.35
in hexanes/EtOAc 5:1) to give the α-oxygenated product as a colorless
oil in 69% yield (3.77 g). The 1H and 13C NMR spectral data matched
previously reported values.30
(1-Hydroxy-2-oxocyclohexyl)methyl 2-Diazoacetate (7). 2-
Hydroxy-2-(hydroxymethyl)cyclohexanone (5) (0.15 g, 1.03 mmol) in
CH2Cl2 (1 mL) was added to a 0 °C solution of p-toluenesulfonylhy-
drazone glyoxylic acid chloride (6)28,41 (0.29 g, 1.14 mmol) in CH2Cl2
(10 mL) to provide a light-yellow solution. Et3N (0.35 mL, 2.30
mmol) in CH2Cl2 (0.7 mL) was added dropwise, causing the color of
the reaction mixture to become deep yellow. The reaction mixture was
allowed to warm in the ice bath to room temperature over a period of
4 h, at which point the solvent was removed in vacuo. The solid
residue was suspended in toluene (10 mL) and mixed with Florisil (1
g), and the solids were removed by filtration and rinsed with toluene
(75 mL). The filtrate was concentrated under reduced pressure, and
the crude product was used in the next step for the formation of 8
1
without further purification (Rf = 0.50 in hexanes/EtOAc 1:1). H
NMR (500 MHz, CDCl3) δ 4.76 (bs, 1H), 4.72 (d, J = 11.65 Hz, 1H),
4.21 (d, J = 11.72 Hz, 1H), 4.12 (s, 1H), 2.60−2.58 (m, 2H), 2.26−
2.22 (m, 1H), 2.16−2.12 (m, 1H), 1.85−1.84 (m, 1H), 1.71−1.65 (m,
3H); 13C NMR (125 MHz, CDCl3) δ 210.8, 166.6, 78.2, 67.9, 46.5,
38.4, 38.1, 27.7, 22.7; IR (film) 3500 (br), 2940.1, 2866.2, 2111.7,
1692.9, 1453.2, 1389.7, 1337.9, 1246.2, 1175.2, 1128.1, 1050.7, 1008.1,
851.2, 738.6 cm−1.
rel-(4aS,8aR)-4-Diazo-4a,8a-dihydroxyhexahydro-1H-iso-
chromen-3(4H)-one (8). DBU (0.15 mL, 0.97 mmol) was added
dropwise to a solution of diazoester 7 (0.14 g, 0.65 mmol) in CH2Cl2
(13 mL) at room temperature, and the mixture was stirred for 12 h, at
which point saturated aqueous NH4Cl (15 mL) was added. The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (3 ×
15 mL). The organic layers were combined, dried over anhydrous
MgSO4, and filtered. The filtrate was evaporated under reduced
pressure to give an orange-red oily residue. Flash column
chromatography (hexanes/EtOAc 3:1; Rf = 0.21 in hexanes/EtOAc
1:1) on a Davisil solid support provided the title bicyclic diazo lactone
as a yellow solid in 37% yield (0.081 g) over two steps starting from 5.
1H NMR (500 MHz, CDCl3) δ 4.29 (d, J = 11.4 Hz, 1H), 4.17 (bs,
Ethyl 1,2-Bis(tert-butyldimethylsilyloxy)cyclohex-2-enecar-
boxylate (12).42 2,5-Lutidine (0.35 g, 3.25 mmol) and TBSOTf
(0.86 g, 3.25 mmol) were added sequentially to a 0 °C solution of α-
hydroxy-β-ketoester 11 (0.20 g, 1.08 mmol) in CH2Cl2 (5 mL). The
mixture was allowed to warm to room temperature overnight and was
then cooled to 0 °C before the addition of saturated aqueous NaHCO3
(10 mL). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The organic layers were
combined, dried over anhydrous MgSO4, and filtered. Upon removal
of the solvent, the filtrate gave an oily residue that was purified by silica
gel flash column chromatography (hexanes/Et2O 40:1; Rf = 0.78 in
hexanes/EtOAc 5:1) to give the bis(silyl ether) as a colorless oil in
1H), 3.90 (d, J = 10.3 Hz, 1H), 3.15 (s, 1H), 1.96 (t, J = 11.6 Hz, 1H),
1.82−165 (m, 5H), 1.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
166.3, 71.5, 70.9, 68.2, 63.0, 32.6, 30.8, 22.4, 20.5; IR (film) 3371.6,
2935.9, 2106.1, 1659.4, 1392.3, 1298.60 cm−1; MS (ESI) calcd for
[C9H12N2O4H]+ 213.08698, found 213.08715.
1
99% yield (0.44 g). H NMR (500 MHz, CDCl3) δ 4.89 (dd, J = 4.9,
4-Oxacyclodecyne-3,6-dione (9). Representative Experimental
Procedure 1: Fragmentation Reactions Conducted at 0 °C and at
Room Temperature. A 1 M solution of SnCl4 in CH2Cl2 (0.25 mL,
0.25 mmol) was added in a steady stream to a solution of bicyclic
diazo lactone 16-cis (0.0826 g, 0.25 mmol) in dry CH2Cl2 (6.3 mL) at
0 °C. The yellow solution initially turned colorless and then became
deep yellow in color. After 30 min, 5% aqueous NaHCO3 (12 mL) was
added, and the mixture was transferred with the aid of CH2Cl2 (10
mL) into a separatory funnel. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic
layers were combined and dried over anhydrous NaSO4. The solvents
were removed in vacuo, and the residue was subjected to flash column
chromatography on Davisil (hexanes/EtOAc 10:1, 6:1, 1:1; Rf = 0.13
in hexanes/EtOAc 1:1) to afford pure cyclic ynoate 9 in 12% yield
(0.005 g). The yield increased to 21% (0.0089 g) when the same
procedure was followed at room temperature. According to the same
procedure at 0 °C, diazo lactone 16-trans provided the title compound
in 10% yield as determined via NMR analysis using mesitylene as an
internal standard. Crystallization from cold methanol provided crystals
3.2 Hz, 1H), 4.19 (qd, J = 10.8, 7.1 Hz, 1H), 4.09 (qd, J = 10.8, 7.2 Hz,
1H), 2.09 (m, 2H), 1.95 (dt, J = 13.2, 3.2 Hz, 1H), 1.85 (dt, J = 13.2,
3.4 Hz, 1H), 1.77−1.68 (m, 1H), 1.62−1.56 (m, 1H), 1.27 (t, J = 7.1
Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H), 0.12 (s,
3H), 0.11 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 174.5, 149.6,
105.9, 78.0, 61.0, 37.0, 26.1, 25.9, 24.1, 18.8, 18.3, 17.8, 14.3, −2.9,
−3.0, −4.4, −4.5; MS (ESI) calcd for [C21H42O4Si2Na]+ 437.25138,
found 437.25164.
(1,2-Bis(tert-butyldimethylsilyloxy)cyclohex-2-enyl)-
methanol (13).43 DIBAL-H (44.4 mL, 52.97 mmol) was added
dropwise to a −78 °C solution of 12 (9.98 g, 24.08 mmol) in toluene
(240 mL), and the resulting mixture was stirred for 1 h at −78 °C,
transferred to a 0 °C bath, and quenched with 150 mL of saturated
potassium sodium tartrate tetrahydrate. The mixture was allowed to
warm to room temperature overnight with efficient stirring. The
reaction mixture was extracted with EtOAc (3 × 150 mL), and the
organic layers were combined, washed with water and brine, and dried
over anhydrous MgSO4. The mixture was filtered and concentrated in
vacuo to give an oily residue that was purified via silica gel flash
column chromatography (hexanes/Et2O 20:1; Rf = 0.68 in hexanes/
EtOAc 5:1) to afford the title compound as a colorless oil in 69% yield
(6.19 g). 1H NMR (500 MHz, CDCl3) δ 4.91 (t, J = 3.7 Hz, 1H), 3.59
(dd, J = 10.4, 4.5 Hz, 1H), 3.51 (dd, J = 10.5, 8.6 Hz, 1H), 2.10−1.96
(m, 2H), 1.85−1.65 (m, 4H), 1.58−1.51 (m, 1H), 0.94 (s, 9H), 0.87
(s, 9H), 0.17 (s, 3H), 0.16 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 150.9, 107.5, 75.5, 68.1, 34.6, 26.13, 26.1,
24.5, 18.9, 18.6, 18.4, −2.78, −2.8, −4.2, −4.4; MS (ESI) calcd for
[C19H40O3Si2Na]+ 395.24082, found 395.24092.
1
suitable for X-ray crystallography (mp 95 °C). H NMR (500 MHz,
CDCl3) δ 4.85 (s, 2H), 2.53−2.50 (m, 2H), 2.39 (t, J = 6.0 Hz, 2H),
2.04−1.99 (m, 2H), 1.86−1.82 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 204.5, 153.5, 99.9, 74.7, 72.2, 41.0, 25.5, 24.6, 19.7; IR (film)
2923.3, 2854.8, 2229.8, 1734.1, 1558.6, 1454.4, 1376.3, 1280.8, 1194.9,
1124.6, 1078.3, 1037.7, 985.7, 922.0, 738.8 cm−1; MS (ESI) calcd for
[C9H10O3H]+ 167.07027, found 167.07016.
Representative Experimental Procedure 2: Fragmentation
Reactions Conducted at 40 °C. A 1 M solution of SnCl4 in
CH2Cl2 (0.25 mL, 0.25 mmol) was added to refluxing CH2Cl2 (4 mL),
6041
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2-(tert-Butyldimethylsilyloxy)-2-(hydroxymethyl)-
cyclohexanone (14).44 Acetic acid (0.45 g, 0.53 mL, 7.42 mmol) and
CsF (0.56 g, 3.7 mmol) were added sequentially to a 0 °C solution of
13 (0.55 g, 1.48 mmol) in a mixture of CH3CN (21.4 mL) and MeOH
(8.6 mL). The mixture was allowed to warm to room temperature
overnight and was then recooled to 0 °C and diluted with 20 mL of
EtOAc, and saturated NaHCO3 solution was added. The resulting
white precipitate was separated via vacuum filtration, and the layers in
the filtrate were separated. The aqueous layer was extracted with Et2O
(3 × 30 mL), and the organic layers were combined, washed with
saturated NaHCO3 and brine, and dried over anhydrous MgSO4. The
solvents were evaporated, and the oily residue was purified by silica gel
flash column chromatography (hexanes/EtOAc 8:1; Rf = 0.41 in
hexanes/EtOAc 5:1) to give the title compound as an oil in 86% yield
(0.33 g). 1H NMR (500 MHz, CDCl3) δ 3.67 (d, J = 7 Hz, 2H), 2.73
(ddd, J = 13.6, 8.8, 5.5 Hz, 1H), 2.36 (t, J = 7.4 Hz, 1H), 2.30 (dt, J =
7.2, 7.0 Hz, 1H), 1.98−1.87 (m, 3H), 1.85−1.73 (m, 2H), 1.66−1.59
(m, 1H), 0.90 (s, 9H), 0.18 (s, 3H), 0.04 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 212.7, 81.4, 67.4, 39.3, 37.8, 27.7, 26.1, 21.4, 18.7,
−2.4, −3.1; MS (ESI) calcd for [C13H26O3SiNa]+ 281.15434, found
281.15428.
J = 1.7 Hz, 1H), 1.94 (dt, J = 14.7, 4.4 Hz, 1H), 1.80−1.67 (m, 5H),
1.61−1.55 (m, 1H), 1.22−1.12 (m, 1H), 0.90 (s, 9H), 0.16 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 163.9, 75.2, 70.9, 68.4, 61.6, 32.4,
30.0, 25.9, 22.7, 19.5, 18.1, −2.7, −3.2; IR (film) 3538.6, 2952.2,
2859.6, 2103.5, 1699.4, 1465.0, 1388.8, 1302.9 cm−1; MS (ESI) calcd
for [C15H26N2O4SiH]+ 327.17346, found 327.17401.
Reaction of Diazo Lactone 16-cis with Indium Triflate To
Provide 17 and 18. A solution of diazo lactone 16-cis (0.100 g, 0.31
mmol) in CH2Cl2 (4 mL) was added to a −78 °C suspension of
In(OTf)3 (0.173 g, 0.31 mmol, dried in a vacuum oven at 180 °C for
16 h before use) in CH2Cl2 (4 mL). The mixture was allowed to warm
to room temperature over 2 h, at which point water (8 mL) was added.
The layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The organic layers were combined, dried over
anhydrous MgSO4, and filtered, and the solvent was evaporated to give
an oily residue that was purified by flash column chromatography on
Davisil (hexanes/EtOAc 8:1, 5:1, 3:1) to provide epoxide 17 (Rf =
0.46 in hexanes/EtOAc 5:1) in 5% yield (0.005 g) and diene 18 (Rf =
0.21 in hexanes/EtOAc 5:1) in 31% yield (0.027 g) with the following
spectral data:
rel-(11S,5aR,8aR)-5a-(tert-Butyldimethylsilyloxy)-
hexahydrooxireno[2,3-d]isochromen-8(8aH)-one (17). 1H NMR
(500 MHz, CDCl3) δ 4.30 (d, J = 12.3 Hz, 1H), 3.93 (d, J = 11.9
Hz, 1H), 3.43 (s, 1H), 2.38 (dt, J = 13.7, 4.2 Hz, 1H), 1.84−1.69 (m,
5H), 1.50−1.43 (m, 2H), 0.90 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 167.3, 72.6, 71.9, 64.6, 55.9, 32.5, 27.3,
25.9, 23.0, 20.1, 18.5, −2.5, −3.0; IR (film) 2950.3, 2933.9, 2848.9,
1753.4, 1635.7, 1462.1, 1295.3, 1263.4, 1179.5, 1074.4, 957.7, 909.5,
838.1, 778.3, 735.9 cm−1; MS (ESI) calcd for [C15H26O4SiH]+
299.16731, found 299.16731.
8a-(tert-Butyldimethylsilyloxy)-8,8a-dihydro-1H-isochromen-
3(7H)-one (18). 1H NMR (500 MHz, CDCl3) δ 6.38 (ddd, J = 9.7, 6.0,
1.9 Hz, 1H), 6.20 (dd, J = 9.9, 2.8 Hz, 1H), 5.69 (s, 1H), 4.31 (d, J =
12.1 Hz, 1H), 4.18 (d, J = 12.1 Hz, 1H), 2.59−2.51 (m, 1H), 2.27 (dt,
J = 18.9, 5.4 Hz, 1H), 1.87 (dd, J = 13.2, 4.6 Hz, 1H), 1.47 (ddd, J =
12.9, 11.6, 5.1 Hz, 1H), 0.84 (s, 9H), 0.11 (s, 3H), −0.02 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 164.9, 151.2, 140.0, 124.6, 113.9, 76.0,
66.4, 32.0, 25.6, 22.2, 18.5, −3.4, −3.9; IR (film) 2956.0, 2929.0,
2856.7, 1725.4, 1631.9, 1472.7, 1462.1, 1290.4, 1250.9, 1250.9, 1222.9,
1201.7, 1161.2, 1114.9, 1060.9, 1028.1, 892.1, 828.5, 777.4 cm−1; MS
(ESI) calcd for [C15H24O3SiH]+ 281.15675, found 281.15654.
8a-Hydroxy-8,8a-dihydro-1H-isochromen-3(7H)-one (19).
BF3·OEt2 (0.045 mL, 0.36 mmol) was added in a steady stream to a
solution of bicyclic diazo lactone 16-trans (0.12 g, 0.36 mmol) in dry
CH2Cl2 (7 mL) at −78 °C. After 1.5 h, distilled water (7 mL) was
added at 0 °C, and the mixture was transferred with the aid of CH2Cl2
(10 mL) into a separatory funnel. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The organic
layers were combined and dried over anhydrous MgSO4, and the
solvents were removed in vacuo. The residue was subjected to flash
column chromatography on Davisil (hexanes/EtOAc 2:1, 1:1; Rf1 =
0.45 in CH2Cl2/EtOAc 1:1) to afford 19 in 26% yield (0.0153 g). H
NMR (500 MHz, CDCl3) δ 6.44 (ddd, J = 11.3, 6.3, 2.2 Hz, 1H), 6.24
(dd, J = 10.3, 2.9 Hz, 1H), 5.71 (s, 1H), 4.34 (d, J = 11.9 Hz, 1H), 4.25
(d, J = 11.8 Hz, 1H), 2.65−2.57 (m, 1H), 2.53 (bs, 1H), 2.33 (dtt, J =
18.8, 5.8, 1.3 Hz, 1H), 1.93 (ddt, J = 13.4, 5.1, 0.8 Hz, 1H), 1.51 (ddd,
J = 13.4, 11.6, 5.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 165.2,
151.8, 140.7, 124.1, 113.3, 76.3, 64.5, 29.5, 21.9; IR (film) 3394.9 (b),
2920.4, 2854.8, 1720.6, 1694.5, 1681.0, 1624.1, 1455.4, 1288.5, 1248.9,
1229.7, 1101.4, 1057.1, 877.7, 734.9, 710.8 cm−1; MS (ESI) calcd for
[C9H10O3H]+ 167.07027, found 167.06980.
(1-(tert-Butyldimethylsilyloxy)-2-oxocyclohexyl)methyl 2-
Bromoacetate (15). Bromoacetyl bromide (0.57 mL, 6.51 mmol)
was added dropwise to a 0 °C solution of alcohol 14 (0.56 g, 2.17
mmol) and pyridine (0.44 mL, 5.43 mmol) in dry CH2Cl2 (21 mL),
and the resulting white suspension was stirred at room temperature for
5 h. The mixture was cooled to 0 °C, and MeOH (0.7 mL) was added,
at which point the white suspension became a clear solution. Saturated
aqueous NH4Cl (20 mL) was added, and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 × 20 mL), and the
organic layers were combined and dried over anhydrous MgSO4. The
solvents were removed in vacuo, and the resulting oily residue was
purified by flash silica gel column chromatography (hexanes/EtOAc
8:1; Rf = 0.47 in hexanes/EtOAc 5:1) to provide the desired
1
bromoacetate as an oil in 90% yield (0.74 g). H NMR (500 MHz,
CDCl3) δ 4.34 (d, J = 11.6 Hz, 1H), 4.31 (d, J = 11.7 Hz, 1H), 3.81 (s,
2H), 2.72 (ddd, J = 15.4, 9.9, 5.6 Hz, 1H), 2.32 (td, J = 13.5, 5.6 Hz,
1H), 1.98−1.86 (m, 3H), 1.80−1.74 (m, 2H), 1.68−1.62 (m, 1H),
0.88 (s, 9H), 0.13 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 209.1, 166.9, 79.5, 68.9, 38.9, 38.1, 27.6, 25.9, 25.6, 21.2, 18.6, −2.4,
−3.1; MS (ESI) calcd for [C15H27BrO4SiH]+ 379.09347, found
379.09340.
8a-(tert-Butyldimethylsilyloxy)-4-diazo-4a-hydroxyhexahy-
dro-1H-isochromen-3(4H)-one (16-cis and 16-trans).31 N,N′-
Ditosylhydrazine (3.81 g, 11.19 mmol) was added to a 0 °C solution of
bromoacetate 15 (2.12 g, 5.59 mmol) in THF (56 mL), at which point
DBU (5.19 mL, 34.6 mmol) was added dropwise. The mixture was
stirred at room temperature for 8 h and then cooled to 0 °C, and
saturated aqueous NaHCO3 (60 mL) was added. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2 (3 ×
60 mL). The organic layers were combined and dried over anhydrous
CaCl2, and the solvents were removed by evaporation to give a crude
solid product. The crude product was purified via flash column
chromatography (hexanes/EtOAc 8:1, 6:1, 4:1, 2:1, 1:1) on a Davisil
solid support to provide the bicyclic diazo lactone as two separated
diastereomers that had the following spectral data:
rel-(4aS,8aR)-8a-(tert-Butyldimethylsilyloxy)-4-diazo-4a-hydroxy-
hexahydro-1H-isochromen-3(4H)-one (16-cis). Yield 0.62 g, 34%; Rf
= 0.31 in hexanes/EtOAc 5:1; 1H NMR (500 MHz, CDCl3) δ 4.23 (d,
J = 10.2 Hz, 1H), 4.12 (bs, 1H), 2.95 (bs, 1H), 1.98 (bs, 1H), 1.91−
1.86 (m, 1H), 1.83−1.73 (m, 2H), 1.71−1.65 (m, 2H), 1.42 (bs, 2H),
0.92 (s, 9H), 0.20 (s, 3H), 0.18 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 164.7, 72.4, 72.1, 69.7, 63.1, 34.5 (b), 32.0, 25.9, 21.8 (b), 18.4, −2.2,
−2.5 (b); IR (film) 2928.1, 2857.7, 2102.5, 1690.7, 1471.7, 1391.7
cm−1; MS (ESI) calcd for [C15H26N2O4SiH]+ 327.17346, found
327.17385.
(1-(tert-Butyldimethylsilyloxy)-2-oxocyclohexyl)methyl Ace-
tate (20).45 Acetic anhydride (0.43 mL, 4.58 mmol), DMAP (0.0023
g, 0.02 mmol), and Et3N (0.71 mL, 5.08 mmol) were added
sequentially to a 0 °C solution of alcohol 14 (0.26 g, 1 mmol) in
CH2Cl2 (5 mL). The mixture was stirred for 2 h at 0 °C, and then
water (5 mL) was added. The organic layer was separated, the aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The organics were
combined, dried (Na2SO4), and concentrated. The product was
purified by silica gel flash column chromatography (hexanes/EtOAc
rel-(4aR,8aR)-8a-(tert-Butyldimethylsilyloxy)-4-diazo-4a-hydrox-
yhexahydro-1H-isochromen-3(4H)-one (16-trans). Yield 0.90 g,
49%; Rf = 0.45 in hexanes/EtOAc 5:1; 1H NMR (500 MHz,
CDCl3) δ 4.23 (d, J = 10.9 Hz, 1H), 3.76 (d, J = 10.9 Hz, 1H), 2.64 (d,
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10:1; Rf = 0.42 in hexanes/EtOAc 5:1) to give the keto acetate in 86%
yield (0.26 g). H NMR (500 MHz, CDCl3) δ 4.26 (d, J = 11.7 Hz,
Et2O (20 mL) was added dropwise to a 0 °C solution of 2-
silyloxycyclohex-2-enone (23) (3.0 g, 13.25 mmol) in Et2O (24 mL).
2-Silyloxycyclohex-2-enone36 was made according to the literature
procedure. During the addition the colorless solution became yellow in
color. After 3 h of stirring at 0 °C, the reaction mixture was quenched
with 50 mL of aqueous NH4Cl solution, and the resulting mixture was
warmed to room temperature. The organic layer was separated, and
the aqueous layer was extracted with Et2O (3 × 50 mL). The organic
layers were combined, washed with brine, dried over anhydrous
MgSO4, and concentrated to give an oily residue. This residue, which
contained the crude tertiary alcohol (2.72 g, 10.13 mmol), was
dissolved in 50 mL of dry MeOH and cooled to 0 °C. K2CO3 (0.07 g,
0.5 mmol) was added, and the mixture was stirred at room
temperature for 1 h. The mixture was concentrated to give an oily
residue, which was dissolved in 50 mL of Et2O and washed with brine.
The organic layer was dried over anhydrous MgSO4 and concentrated
down to an oily residue. Purification via flash silica gel chromatography
(hexanes/Et2O 50:1; Rf = 0.45 in hexanes/EtOAc 40:1) provided the
1
1H), 4.23 (d, J = 11.7 Hz, 1H), 2.72 (ddd, J = 13.7, 9.5, 5.4 Hz, 1H),
2.33 (ddd, J = 12.7, 6.8, 5.7 Hz, 1H), 2.06 (s, 3H), 1.96−1.85 (m, 3H),
1.82−1.74 (m, 2H), 1.68−1.61 (m, 1H), 0.89 (s, 9H), 0.14 (s, 3H),
0.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 209.3, 170.6, 79.7, 67.4,
38.9, 38.4, 27.6, 25.9, 21.3, 20.9, 18.6, −2.6, −3.2; MS (ESI) calcd for
[C15H28O4SiH]+ 301.18296, found 301.18300.
Ethyl 2-(2-(Acetoxymethyl)-2-(tert-butyldimethylsilyloxy)-1-
hydroxycyclohexyl)-2-diazoacetate (21). Lithium bis-
(trimethylsilyl)amide (1 M in THF/ethylbenzene, 0.75 mL, 0.75
mmol) was added dropwise over 1.5 h to a −78 °C solution of ketone
20 (0.20 g, 0.65 mmol) and ethyl diazoacetate (0.08 g, 0.72 mmol) in
THF (12 mL). After the mixture was stirred for 30 min at −78 °C,
saturated aqueous NH4Cl (12 mL) was added. The mixture was
allowed to warm to room temperature, and the layers were separated.
The aqueous layer was extracted with EtOAc (3 × 15 mL), and the
organic layers were combined, washed with brine, and dried over
anhydrous CaCl2. The solvents were evaporated, and the crude yellow
oily residue was purified via silica gel flash column chromatography
(hexanes/Et2O 7:1, 5:1, 3:1) on a Davisil support to provide the
acetate diazoester as two separate diastereomers. Both diastereomers
were isolated together with an inseparable unknown impurity. The
major diastereomer was obtained in 41% yield (0.14 g) as determined
by NMR analysis using mesitylene as an internal standard (Rf = 0.42 in
hexanes/EtOAc 5:1), and the minor diastereomer was obtained in 8%
yield (0.030 g) as determined by NMR analysis using mesitylene as an
internal standard (Rf = 0.26 in hexanes/EtOAc 5:1).
1
title compound in 83% yield (2.95 g). The H and 13C NMR spectral
data were identical to the reported values.46
2-(1-(tert-Butyldimethylsilyloxy)-2-oxocyclohexyl)-
acetaldehyde (25).47 A solution of allyl ketone 24 (1.27 g, 4.73
mmol) in CH2Cl2 (50 mL) was cooled to −78 °C, and ozonized
oxygen gas was passed through the solution at a rate of 1 L/min until
the solution became blue in color, at which point the solution was
purged with nitrogen until the blue color disappeared. Then
triphenylphosphine (2.48 g, 9.46 mmol) was added, and after 30
min the mixture was allowed to warm to room temperature over a
period of 2 h. The solvent was removed, and the crude product was
purified via flash column chromatography on a Davisil support
(hexanes/EtOAc 10:1, 2:1; Rf = 0.23 in hexanes/EtOAc 8:1) to afford
the title aldehyde in 93% yield (1.19 g). 1H NMR (500 MHz, CDCl3)
δ 9.73 (t, J = 2.4 Hz, 1H), 2.76 (dd, J = 15.4, 2.5 Hz, 1H), 2.78−2.73
(m, 1H, overlapped with dd at 2.76), 2.61 (dd, J = 15.4, 2.4 Hz, 1H),
2.36 (ddd, J = 13.6, 6.2, 5.7 Hz, 1H), 2.02−1.87 (m, 4H), 1.82−1.73
(m, 1H), 1.68−1.61 (m, 1H), 0.90 (s, 9H), 0.17 (s, 3H), 0.05 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 209.8, 200.6, 80.1, 50.5, 41.1, 38.7,
Data for the major diastereomer: 1H NMR (500 MHz, CDCl3) δ 4.46
(d, J = 12.2 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H, overlapped with peaks
from the impurity), 3.97 (d, J = 12.2 Hz, 1H), 2.24−2.17 (m, 1H),
2.09 (s, 3H), 1.93−1.89 (m, 2H), 1.71 (apparent tt, J = 13.3, 3.9 Hz,
3H), 1.62 (m, 2H), 1.54−1.51 (m, 1H), 1.26 (t, J = 7.11 Hz, 3H), 0.87
(s, 9H), 0.18 (s, 3H), 0.12 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
170.5, 166.6, 81.9, 73.3, 66.7, 62.2, 60.7, 32.8, 32.7, 26.2, 22.8, 21.1,
20.3, 18.6, 14.6, 1.9, 2.2; IR (film) 3505.8, 2930.9, 2893.4, 2094.8,
1747.6, 1693.6, 1471.7, 1464.0, 1388.8, 1367.6, 1297.2, 1251.9, 1234.5
cm−1; MS (ESI) calcd for [C19H34N2O6SiNa]+ 437.20783, found
437.20797.
27.5, 25.9, 21.5, 18.6, −2.1, −2.7; MS (ESI) calcd for
[C14H26O3SiNa]+ 293.15434, found 293.15429.
Data for the minor diastereomer: 1H NMR (500 MHz, CDCl3) δ 4.28
(d, J = 11.8 Hz, 1H), 4.21 (q, J = 7.0 Hz, 2H, overlapped with peaks
from the impurity), 4.08 (d, J = 11.8 Hz, 1H), 2.09 (s, 3H), 1.94−1.85
(m, 2H), 1.72−1.52 (m, 7H, overlapped with peaks from the
impurity), 1.27 (t, J = 7.1 Hz, 3H), 0.93 (s, 9H), 0.15 (s, 3H), 0.11 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 169.7, 79.1, 75.7, 68.9,
64.1, 61.2, 33.7, 30.4, 26.5, 26.2, 22.7, 21.0, 18.8, 14.6, −1.8, −1.9; IR
(film) 3481.7, 2954.1, 2860.6, 2096.7, 1746.6, 1696.5, 1471.7, 1389.8,
1367.6, 1293.3, 1253.8, 1111.1, 1033.9 cm−1; MS (ESI) calcd for
[C19H34N2O6SiNa]+ 437.20783, found 437.20810.
3a-(tert-Butyldimethylsilyloxy)octahydrobenzofuran-7a-ol
(26).37 An aqueous suspension of Raney nickel (5.67 g of the
suspension) was transferred with THF (20 mL) to a solution of
aldehyde 25 (0.87 g, 3.21 mmol) in THF (10 mL). The suspension
was stirred at room temperature for 30 min, diluted with Et2O (50
mL), and filtered through Celite, and the solvent was evaporated to
yield an oily residue. The crude product was purified via silica gel flash
column chromatography (hexanes/EtOAc 20:1, 10:1; 15:1; 5:1; Rf =
0.40 in hexanes/EtOAc 4:1) to afford the hemiacetal in 69% yield
1
(0.60 g). H NMR (500 MHz, CDCl3) δ 4.10 (ddd, J = 8.9, 8.5, 4.6
Ethyl 9-Acetoxy-8-oxonon-2-ynoate (22). According to
representative experimental procedure 1 that was used to prepare 9,
the major diastereomer of diazoester 21 (0.060 g, 0.14 mmol) reacted
at 0 °C to give tethered ketone ynoate 22 in 70% yield (0.024 g) after
purification via flash chromatography on Davisil (hexanes/EtOAc 10:1,
8:1, 6:1, 4:1, 3:1, 2:1, 1:1; Rf = 0.11 in hexanes/EtOAc 5:1); the yield
was determined to be 83% via NMR analysis using mesitylene as an
internal standard. Under the same experimental conditions, the minor
diastereomer of diazoester 21 (0.049 g, 0.12 mmol) provided the title
compound in 54% isolated yield (0.012 g); the yield was determined
to be 61% via NMR analysis using mesitylene as an internal standard.
1H NMR (500 MHz, CDCl3) δ 4.63 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H),
2.45 (t, J = 7.1 Hz, 2H), 2.34 (t, J = 7.1 Hz, 2H), 2.16 (s, 3H), 1.73 (tt,
J = 7.9, 7.0 Hz, 2H), 1.60 (tt, J = 7.6, 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 203.4, 170.4, 153.8, 88.5, 73.7,
68.1, 61.9, 38.1, 26.9, 22.4, 20.6, 18.6, 14.2; IR (film) 2900.1, 2233.7,
1751.4, 1730.2, 1705.2, 1419.7, 1367.6, 1251.9, 1234.5, 1076.3, 1026.2,
910.4, 858.4, 753.2, 735.9 cm−1; MS (ESI) calcd for [C13H18O5Na]+
277.10464, found 277.10486.
Hz, 1H), 3.84 (dt, J = 8.4, 6.9 Hz, 1H), 3.29 (s, 1H), 2.14 (ddd, J =
11.2, 10.0, 6.9 Hz, 1H), 1.91 (ddd, J = 12.4, 8.3, 4.1 Hz, 1H), 1.86 (dt,
J = 14.3, 4.4 Hz, 1H), 1.79−1.74 (m, 1H), 1.67−1.60 (m, 2H), 1.54−
1.47 (m, 2H), 1.44−1.37 (m, 2H), 0.91 (s, 9H), 0.15 (s, 3H), 0.14 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 102.7, 80.3, 64.3, 36.1, 35.5,
33.6, 25.9, 22.9, 21.7, 18.2, −2.5, −2.6; IR (film) 3438.2 (b), 2933.9,
2857.7, 1471.75, 1360.8, 1295.26, 1252.8 cm−1; MS (ESI) calcd for
[C14H28O3SiNa]+ 295.16999, found 295.17049.
2-(1-(tert-Butyldimethylsilyloxy)-2-oxocyclohexyl)ethyl 2-
Bromoacetate (27). Pyridine (0.47 mL, 5.81 mmol) and
bromoacetyl bromide (0.61 mL, 6.98 mmol) were added sequentially
to a 0 °C solution of hemiacetal 26 (0.63 g, 2.33 mmol) in CH2Cl2 (23
mL), and the resulting heterogeneous mixture was stirred overnight at
room temperature. The mixture was cooled to 0 °C, and then MeOH
(0.25 mL) was added, at which point the white suspension became a
clear solution. Saturated aqueous NH4Cl (25 mL) was added, and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(3 × 25 mL), and the organic layers were combined, dried over
anhydrous MgSO4, and filtered. The solvents were removed in vacuo,
and the resulting oily residue was purified by flash silica gel column
chromatography (hexanes/EtOAc 20:1; Rf = 0.48 in hexanes/EtOAc
2-Allyl-2-(tert-butyldimethylsilyloxy)cyclohexanone (24).
Freshly prepared allylmagnesium bromide (2.40 g, 19.88 mmol) in
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4:1) to provide the desired bromoacetate as an oil in 57% yield (0.52
g). H NMR (500 MHz, CDCl3) δ 4.26−4.23 (m, 2H), 3.77 (s, 2H),
2.56−2.45 (m, 2H), 2.30 (dt, J = 21.5, 7.2 Hz, 1H), 1.98−1.93 (m,
3H), 1.86−1.79 (m, 2H), 1.74−1.65 (m, 2H), 0.87 (s, 9H), 0.18 (s,
3H), 0.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 210.9, 167.1, 80.7,
62.3, 42.1, 39.6, 37.1, 27.7, 26.1, 25.8, 22.7, 18.7, −2.4, −2.7; MS (ESI)
calcd for [C16H29BrO4SiH]+ 393.10913, found 393.10952.
= 7.1 Hz, 2H), 3.05 (dd, J = 12.4, 3.9 Hz, 1H), 2.74−2.68 (m, 1H),
2.40−2.36 (m, 1H), 2.15 (dt, J = 15.3, 3.9 Hz, 1H), 1.98−1.93 (m,
1H), 1.82−1.63 (m, 4H), 1.47−1.32 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H),
0.90−0.86 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 213.1, 170.4,
83.0, 62.0, 36.8, 30.4, 30.1, 25.4, 24.1, 22.2, 13.9. MS (ESI) calcd for
[C11H18O4Na]+ 237.1103, found 237.1105.
1
Methyl 1,2-Bis(tert-butyldimethylsilyloxy)cyclohept-2-ene-
carboxylate (33a). Compound 33a was prepared from 32a (0.15
g, 0.79 mmol) by the method described for the preparation of 12.
Purification by silica gel flash column chromatography (hexanes/Et2O
50:1; Rf = 0.75 in hexanes/EtOAc 5:1) provided the title compound as
2-(1-(tert-Butyldimethylsilyloxy)-2-oxocyclohexyl)ethyl 2-
Diazoacetate (28). Diazo ester 28 was prepared from bromoacetate
27 by the same procedure used to make 16-cis. The product was
purified via filtration through a pad of Davisil using an 8:1 hexanes/
EtOAc mixture as the eluent to provide the title compound (Rf = 0.28
1
a colorless oil in 93% yield (0.30 g). H NMR (500 MHz, CDCl3) δ
1
in hexanes/EtOAc 4:1) in 85% yield (0.51 g). H NMR (500 MHz,
5.02 (dd, J = 6.9, 5.6 Hz, 1H), 3.68 (s, 3H), 2.14 (ddd, J = 14.5, 11.6,
4.7 Hz, 1H), 2.10−2.02 (m, 2H), 1.94−1.86 (m, 1H), 1.76 (td, J =
14.6, 3.9 Hz, 2H), 1.67−1.52 (m, 2H), 0.91 (s, 9H), 0.89 (s, 9H), 0.16
(s, 6H), 0.15 (s, 3H), 0.12 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
174.6, 152.9, 110.5, 83.0, 51.9, 35.7, 26.7, 26.3, 26.1, 23.3, 22.4, 19.2,
18.4, −2.7, −2.8, −4.3, −4.6; MS (ESI) calcd for [C21H42O4Si2H]+
415.26944, found 415.26939.
CDCl3) δ 4.57 (bs, 1H), 4.29−4.19 (m, 2H), 2.53−2.44 (m, 2H), 2.31
(ddd, J = 14.4, 7.3, 7.0 Hz, 1H), 1.99−1.93 (m, 2H), 1.91 (dd, J = 6.1,
5.3 Hz, 1H), 1.87−1.77 (m, 2H), 1.74−1.63 (m, 2H), 0.88 (s, 9H),
0.19 (s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 210.7,
166.3 (b), 80.6, 60.6, 45.9 (b), 42.2, 39.4, 37.5, 27.6, 25.9, 22.6, 18.5,
−2.6, −2.9; IR (film) 2928.1, 2855.73, 2112.14, 1724.4, 1697.4,
1472.7, 1394.6, 1394.6, 1359.8, 1248.0 cm−1; MS (ESI) calcd for
[C16H28N2O4SiNa]+ 363.17106, found 363.17147.
(E)-Ethyl 1,2-Bis(tert-butyldimethylsilyloxy)cyclooct-2-ene-
carboxylate (33b). Compound 33b was prepared from 32b (0.20
g, 0.91 mmol) by the method described for the preparation of 12.
Purification by silica gel flash column chromatography (hexanes/Et2O
30:1; Rf = 0.72 in hexanes/EtOAc 5:1) provided the title compound as
rel-(5aR,9aS)-5a-(tert-Butyldimethylsilyloxy)-1-diazo-9a-
hydroxyoctahydrobenzo[d]oxepin-2(1H)-one (29). A solution of
diazo ester 28 (0.05 g, 0.15 mmol) in THF (3 mL) was added
dropwise over 16 h by a syringe pump to a stirred −78 °C solution of
lithium bis(trimethylsilyl)amide (1 M in THF/ethylbenzene, 0.20 mL,
0.18 mmol) in THF (30 mL). After 1 h, saturated aqueous NH4Cl
solution (24 mL) was added to the reaction mixture at −78 °C, and
the mixture was allowed to warm to room temperature. The mixture
was extracted with EtOAc (3 × 70 mL), and the organic layers were
combined, washed with brine, dried over anhydrous CaCl2, filtered,
and concentrated to a solid residue. Flash column chromatography of
the crude product over Davisil (hexanes/EtOAc 4:1, 2:1, 1:1; Rf = 0.21
in hexanes/EtOAc 3:1) afforded a single diastereomer of the title
1
a colorless oil in 94% yield (0.38 g). H NMR (500 MHz, CDCl3) δ
4.74 (dd, J = 9.8, 8.5 Hz, 1H), 4.19 (qd, J = 10.8, 7.2 Hz, 1H), 4.05
(qd, J = 10.8, 7.1 Hz, 1H), 2.42 (tdd, J = 14.2, 9.7, 7.0 Hz, 1H), 2.21
(dt, J = 14.5, 7.3 Hz, 1H), 2.16−2.03 (m, 2H), 1.76−1.64 (m, 3H),
1.58−1.48 (m, 3H), 1.26 (t, J = 7.2 Hz, 3H), 0.89 (two s, 18H), 0.17
(s, 3H), 0.14 (s, 3H), 0.137 (s, 3H), 0.12 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 173.9, 152.7, 105.6, 82.7, 60.9, 37.0, 27.4, 26.3, 26.1,
23.7, 23.3, 22.6, 19.2, 18.5, 14.2, −2.5, −2.6, −4.3, −4.4; MS (ESI)
calcd for [C23H46O4Si2H]+ 443.30074, found 443.30074.
(1,2-Bis(tert-butyldimethylsilyloxy)cyclohept-2-enyl)-
methanol (34a). The title compound was prepared from 33a (2.84 g,
6.85 mmol) according to the same procedure as used to prepare 13.
Purification by silica gel flash column chromatography (hexanes/Et2O
40:1; Rf = 0.80 in hexanes/EtOAc 5:1) provided compound 34a as a
1
product in 69% yield (0.035 g). H NMR (500 MHz, CDCl3) δ 4.37
(ddd, J = 12.8, 9.8, 1.8 Hz, 1H), 4.26 (ddd, J = 12.8, 6.1, 2.8 Hz, 1H),
2.34 (ddd, J = 15.8, 9.8, 2.8 Hz, 1H), 1.97 (s, 1H), 1.93 (dt, J = 12.6,
4.9 Hz, 1H), 1.80 (dt, J = 13.9, 4.3 Hz, 1H), 1.72−1.55 (m, 6H),
1.52−1.48 (m, 1H), 0.92 (s, 9H), 0.16 (s, 3H), 0.09 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 171.6, 75.6, 74.0, 67.9, 65.4, 38.6, 35.3, 32.8,
26.1, 20.4, 20.2, 18.8, −1.7, −1.9; IR (film) 3358.2 (b), 2927.1, 2855.7,
2106.4, 1727.3, 1635.7, 1471.7, 1398.5, 1305.9, 1259.6 cm−1; MS
(ESI) calcd for [C16H28N2O4SiH]+ 341.18911, found 341.18924.
4-Oxacycloundecyne-3,7-dione (30). According to representa-
tive experimental procedure 1 or 2 used to prepare 9, diazo lactone 29
provided 11-membered cyclic ynoate 30 in 50% yield (0.022 g) at 0 °C
and 63% yield (0.0063 g) at 40 °C. The title compound was isolated
via flash column chromatography on Davisil (hexanes/EtOAc 4:1, 3:1,
2:1, 1:1; Rf = 0.16 in hexanes/EtOAc 2:1). 1H NMR (500 MHz,
CDCl3) δ 4.65−4.63 (m, 2H), 2.79−2.77 (m, 2H), 2.76−2.73 (m,
2H), 2.42−2.39 (m, 2H), 1.92 (tt, J = 5.9, 4.0 Hz, 2H), 1.76−1.72 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 207.8, 154.4, 97.9, 73.1, 65.5,
44.4, 41.7, 25.0, 20.9, 18.2; IR (film) 2922.3, 2851.9, 2229.8, 1714.8
(b), 1463.1, 1387.8, 1282.7, 1228.7, 1079.2, 740.7 cm−1; MS (ESI)
calcd for [C10H12O3H]+ 181.08592, found 181.08584.
1
colorless oil in 80% yield (2.13 g). H NMR (500 MHz, CDCl3) δ
5.06 (dd, J = 7.9, 5.6 Hz, 1H), 3.58 (s, 1H), 3.56 (d, J = 1.6 Hz, 1H),
2.20 (dqd, J = 16.2, 5.3, 2.5 Hz, 1H), 2.00 (dd, J = 7.4, 6.2 Hz, 1H),
1.94 (dq, J = 7.8, 2.3 Hz, 1H), 1.88−1.83 (m, 3H), 1.74−1.68 (m,
1H), 1.65−1.61 (m, 1H), 1.48−1.40 (m, 1H), 0.94 (s, 9H), 0.89 (s,
9H), 0.18 (s, 3H), 0.17 (s, 3H), 0.13 (s, 3H), 0.11 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 154.9, 111.1, 80.0, 68.8, 34.4, 26.9, 26.2, 26.19,
23.6, 23.1, 18.8, 18.5, −2.6, −2.7, −4.1, −4.4; MS (ESI) calcd for
[C20H42O3Si2Na]+ 409.25647, found 409.25635.
(E)-(1,2-Bis(tert-butyldimethylsilyloxy)cyclooct-2-enyl)-
methanol (34b). The title compound was prepared from 33b (0.27 g,
0.61 mmol) according to the same procedure as used to prepare 13.
Purification by silica gel flash column chromatography (hexanes/Et2O
40:1; Rf = 0.79 in hexanes/EtOAc 5:1) provided compound 34b as a
1
colorless oil in 64% yield (0.16 g). H NMR (500 MHz, CDCl3) δ
4.79 (dd, J = 9.9, 8.6 Hz, 1H), 3.76 (dd, J = 11.0, 3.9 Hz, 1H), 3.47
(dd, J = 10.9, 10.0 Hz, 1H), 2.84 (dddd, J = 14.0, 12.2, 9.9, 5.6 Hz,
1H), 2.18 (dd, J = 9.9, 3.8 Hz, 1H), 1.99−1.88 (m, 2H), 1.80−1.74
(m, 1H), 1.63−1.57 (m, 4H), 1.49−1.37 (m, 2H), 0.94 (s, 9H), 0.89
(s, 9H), 0.21 (s, 3H), 0.18 (s, 3H), 0.14 (s, 3H), 0.12 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 154.1, 107.5, 80.6, 68.8, 37.0, 28.1, 26.3,
26.1, 24.1, 22.8, 22.4, 18.8, 18.4, −2.6, −3.7, −4.6; MS (ESI) calcd for
[C21H44O3Si2H]+ 401.29017, found 401.29030.
Methyl 1-Hydroxy-2-oxocycloheptanecarboxylate (32a).
The title compound was prepared from commercially available methyl
2-oxocycloheptanecarboxylate (31a) (2.01 g, 11.8 mmol) by the
method described for the preparation of 11. Purification of the crude
product via flash silica gel chromatography (hexanes/EtOAc 8:1; Rf =
0.25 in hexanes/EtOAc 5:1) afforded the title compound in 66% yield
1
(1.44 g). The H and 13C NMR spectral data matched previously
2-(tert-Butyldimethylsilyloxy)-2-(hydroxymethyl)-
cycloheptanone (35a). Compound 35a was prepared from 34a
(0.15 g, 0.40 mmol) by the method described for the preparation of
14. The title compound was obtained in 87% yield (0.09 g) after
purification by silica gel flash column chromatography (hexanes/
reported values.48
Ethyl 1-Hydroxy-2-oxocyclooctanecarboxylate (32b). The
title compound was prepared from commercially available ethyl 2-
oxocyclooctanecarboxylate (31b) (4.88 g, 24.8 mmol) by the method
described for the preparation of 11. Purification of the crude product
via flash silica gel chromatography (hexanes/EtOAc 6:1; Rf = 0.27 in
hexanes/EtOAc 5:1) afforded the title compound in 99% yield (5.26
g). 1H NMR (500 MHz, CDCl3) δ 4.35 (d, J = 1.6 Hz, 1H), 4.19 (q, J
1
EtOAc 8:1; Rf = 0.36 in hexanes/EtOAc 5:1). H NMR (500 MHz,
CDCl3) δ 3.70 (dd, J = 11.4, 7.2 Hz, 1H), 3.60 (dd, J = 11.4, 6.4 Hz,
1H), 2.77−2.72 (m, 1H), 2.44 (ddd, J = 13.7, 12.5, 4.8 Hz, 1H), 2.29
(dd, J = 7.1, 6.5 Hz, 1H), 1.78−1.71 (m, 5H), 1.63−1.56 (m, 2H),
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1
1.47−1.38 (m, 1H), 0.90 (s, 9H), 0.21 (s, 3H), 0.09 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 214.5, 84.5, 68.5, 40.1, 36.0, 29.3, 26.1, 25.3,
23.9, 18.8, −2.3, −2.8; MS (ESI) calcd for [C14H28O3SiNa]+
295.16999, found 295.17004.
38a-cis: Yield 0.034 g, 25%; Rf = 0.19 in hexanes/EtOAc 5:1; H
NMR (500 MHz, CDCl3) δ 4.01 (d, J = 12.3 Hz, 1H), 3.96 (d, J =
12.3 Hz, 1H), 3.60 (d, J = 1.7 Hz, 1H), 2.02−1.90 (m, 3H), 1.87−1.73
(m, 3H), 1.59−1.46 (m, 3H), 1.37−1.28 (m, 1H), 0.92 (s, 9H), 0.20
(s, 3H), 0.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.5, 75.5,
75.2, 70.1, 65.9, 35.9, 34.7, 28.9, 25.9, 21.6, 20.2, 18.6, −2.6, −2.9; IR
(film) 3503.8, 2929.0, 2857.7, 2102.5, 1693.57, 1464.0, 1392.7, 1287.5,
1128.4 cm−1; MS (ESI) calcd for [C16H28N2O4SiH]+ 341.18911,
found 341.18928.
2-(tert-Butyldimethylsilyloxy)-2-(hydroxymethyl)-
cyclooctanone (35b). Compound 35b was prepared from 34b (0.16
g, 0.39 mmol) by the method described for the preparation of 14. The
title compound was obtained in 85% yield (0.10 g) after purification by
silica gel flash column chromatography (hexanes/EtOAc 8:1; Rf = 0.31
in hexanes/EtOAc 5:1). 1H NMR (500 MHz, CDCl3) δ 3.75 (dd, J =
11.4, 7.2 Hz, 1H), 3.57 (dd, J = 11.4, 6.4 Hz, 1H), 2.69 (ddd, J = 12.1,
7.9, 4.0 Hz, 1H), 2.39 (ddd, J = 12.3, 9.3, 4.2 Hz, 1H), 2.15 (dd, J =
6.5, 7.1 Hz, 1H), 2.04 (dd, J = 14.6, 3.4 Hz, 1H), 1.94−1.80 (m, 3H),
1.74−1.66 (m, 1H), 1.63−1.44 (m, 3H), 1.39−1.34 (m, 2H), 0.91 (s,
9H), 0.21 (s, 3H), 0.14 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
217.9, 84.4, 68.6, 37.8, 34.1, 28.9, 26.3, 26.2, 25.3, 22.3, 18.9, −2.3,
−2.7; MS (ESI) calcd for [C15H30O3SiH]+ 287.20370, found
287.20376.
38a-trans: Yield 0.045 g, 33%; Rf = 0.36 in hexanes/EtOAc 5:1; 1H
NMR (500 MHz, CDCl3) δ 4.18 (d, J = 10.8 Hz, 1H), 3.73 (d, J =
10.7 Hz, 1H), 2.99 (d, J = 2.2 Hz, 1H), 2.14−2.04 (m, 2H), 1.84 (tt, J
= 13.9, 1.7 Hz, 1H), 1.78−1.69 (m, 3H), 1.68−1.52 (m, 3H), 1.39−
1.31 (m, 1H), 0.90 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 164.6, 79.8, 73.3, 70.8, 62.8, 33.9, 29.9, 25.9, 25.3,
19.9, 18.2, 17.4, −2.6, −3.1; IR (film) 3515.4 (b), 2952.2, 2932.9,
2859.6, 2102.5, 1699.4, 1465.9, 1383, 1302.9, 1264.4 cm−1; MS (ESI)
calcd for [C16H28N2O4SiH]+ 341.18911, found 341.18915.
rel-(3aS,9aR)-3a-((tert-Butyldimethylsilyl)oxy)-3-diazo-9a-
(hydroxymethyl)octahydrocycloocta[b]furan-2(3H)-one (39).
Lithium bis(trimethylsilyl)amide (1 M in THF/ethylbenzene, 1.90
mL, 1.89 mmol) was added to THF (142 mL) at −78 °C. A solution
of diazo ester 37b (0.50 g, 1.42 mmol) in THF (10 mL) was added
dropwise via a syringe pump over 24 h while maintaining the
temperature at −78 °C. The reaction mixture was then quenched with
saturated aqueous NH4Cl (70 mL) and allowed to warm to room
temperature. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (3 × 70 mL). The organic layers were
combined, washed with brine, dried over anhydrous CaCl2, and
concentrated to give a solid residue. Flash column chromatography
(hexanes/EtOAc 6:1, 4:1, 2:1, 1:1) afforded 0.32 g (64% yield) of the
title compound as an oil (Rf = 0.16 in hexanes/EtOAc 5:1). 1H NMR
(500 MHz, CDCl3) δ 3.99−3.94 (m, 1H), 3.88−3.84 (m, 1H), 2.33
(dt, J = 13.3, 2.5 Hz, 1H), 2.04−1.74 (m, 9H), 1.46−1.35 (m, 2H),
1.13−1.05 (m, 1H), 0.98 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 167.9, 96.4, 81.4, 65.1, 62.6, 33.7, 29.5, 28.6,
28.4, 26.5, 26.3, 25.3, 18.8, −2.9, −3.1; IR (film) 3490.9 (b), 2930.9,
2857.7, 2095.75, 1743.7, 1471.8, 1464.0, 1371.5, 1255.7 cm−1; MS
(ESI) calcd for [C17H30N2O4SiH]+ 355.20476, found 355.20539.
rel-(3aS,9aR)-3a-((tert-Butyldimethylsilyl)oxy)octahydro-2H-
3,9a-(epoxymethano)cycloocta[b]furan-2-one (40). According
to representative experimental procedure 1 that was used to prepare
9, diazo lactone 39 (0.027 g, 0.075 mmol) reacted at 0 °C to give
0.020 g (80% yield) of ether 40 after purification via flash column
chromatography on Davisil (hexanes/EtOAc 10:1; Rf = 0.57 in
hexanes/EtOAc 2:1). 1H NMR (500 MHz, CDCl3) δ 4.31 (d, J = 8.9
Hz, 1H), 3.91 (s, 1H), 3.74 (d, J = 9.0 Hz, 1H), 2.16−2.10 (m, 1H),
2.06−1.93 (m, 5H), 1.86−1.81 (m, 1H), 1.78−1.71 (m, 1H), 1.63−
1.55 (m, 1H), 1.31−1.22 (m, 2H), 1.13−1.06 (m, 1H), 0.91 (m, 9H),
0.14 (s, 3H), 0.12 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.3,
95.6, 84.9, 83.4, 70.9, 33.1, 31.1, 29.2, 25.8, 25.7, 23.8, 22.5, 18.4, −2.3,
−2.4; IR (film) 2929.0, 2857.7, 1791.9, 1472.7, 1454.4, 1362.8, 1255.7,
1199.8, 1174.7, 1133.2, 1087.9, 1067.7, 1007.9, 907.6, 837.1, 809.2,
778.3, 675.1 cm−1; MS (ESI) calcd for [C17H30O4SiH]+ 327.19861,
found 327.19871.
(1-(tert-Butyldimethylsilyloxy)-2-oxocycloheptyl)methyl 2-
Bromoacetate (36a). The title compound was prepared from 35a
(1.38 g, 5.08 mmol) according to the same procedure as used to
prepare 15. The crude product was purified via flash silica gel column
chromatography (hexanes/EtOAc 10:1; Rf = 0.56 in hexanes/EtOAc
1
5:1) to provide compound 36a in 95% yield (1.91 g). H NMR (500
MHz, CDCl3) δ 4.34 (d, J = 11.2 Hz, 1H), 4.15 (d, J = 11.3 Hz, 1H),
3.82 (s, 2H), 2.70 (ddd, J = 11.7, 7.1, 4.7 Hz, 1H), 2.52 (ddd, J = 12.8,
10.6, 4.1 Hz, 1H), 1.86−1.75 (m, 4H), 1.68−1.61 (m, 2H), 1.59−1.50
(m, 1H), 1.47−1.38 (m, 1H), 0.88 (s, 9H), 0.19 (s, 3H), 0.08 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 211.4, 166.8, 82.6, 69.9, 40.3, 35.7,
29.3, 25.9, 25.6, 25.5, 23.6, 18.6, −2.4, −2.9; MS (ESI) calcd for
[C16H29BrO4SiH]+ 393.10913, found 393.10927.
(1-(tert-Butyldimethylsilyloxy)-2-oxocyclooctyl)methyl 2-
Bromoacetate (36b). The title compound was prepared from 35b
(0.11 g, 0.38 mmol) according to the same procedure as used to
prepare 15. The crude product was purified via flash silica gel column
chromatography (hexanes/EtOAc 8:1; Rf = 0.68 in hexanes/EtOAc
1
5:1) to provide compound 36b in 98% yield (0.15 g). H NMR (500
MHz, CDCl3) δ 4.41 (d, J = 11.6 Hz, 1H), 4.15 (d, J = 11.6 Hz, 1H),
3.80 (s, 2H), 2.63 (ddd, J = 12.3, 7.6, 3.6 Hz, 1H), 2.45 (ddd, J = 12.3,
10.2, 4.0 Hz, 1H), 2.09 (ddd, J = 14.5, 11.2, 3.5 Hz, 1H), 1.95−1.80
(m, 3H), 1.74−1.66 (m, 1H), 1.64−1.57 (m, 1H), 1.52−1.44 (m, 2H),
1.40−1.29 (m, 2H), 0.89 (s, 9H), 0.18 (s, 3H), 0.13 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 214.8, 166.8, 82.5, 70.2, 37.6, 33.7, 29.1, 26.3,
26.0, 25.4, 24.8, 22.2, 18.8, −2.4, −2.8; MS (ESI) calcd for
[C17H31BrO4SiNa]+ 429.10672, found 429.10707.
(1-(tert-Butyldimethylsilyloxy)-2-oxocyclooctyl)methyl 2-Di-
azoacetate (37b). Diazo ester 37b was prepared from the
corresponding bromo ester 36b (2.64 g, 6.48 mmol) by the method
used to make 16-cis. Purification of the crude product by flash
chromatography on a Davisil support (hexanes/EtOAc 10:1, 8:1, 6:1,
4:1, 2:1, 1:1; Rf = 0.46 in hexanes/EtOAc 5:1) provided diazoester 37b
1
in 68% yield (1.57 g). H NMR (500 MHz, CDCl3) δ 4.72 (bs, 1H),
4.38 (d, J = 11.5 Hz, 1H), 4.16 (d, J = 11.5 Hz, 1H), 2.57 (ddd, J =
12.3, 6.8, 3.9 Hz, 1H), 2.46 (dt, J = 11.2, 4.3 Hz, 1H), 2.08 (ddd, J =
14.3, 11.6, 3.3 Hz, 1H), 1.92−1.78 (m, 3H), 1.75−1.67 (m, 1H),
1.65−1.58 (m, 1H), 1.51−1.35 (m, 3H), 1.32−1.24 (m, 1H), 0.88 (s,
9H), 0.16 (s, 3H), 0.12 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
215.0, 166.2 (b), 82.8, 69.1, 46.3 (b), 37.7, 33.6, 29.2, 26.3, 25.9, 24.8,
22.2, 18.8, −2.5, −2.8; IR (film) 3125.8, 2946.4, 2857.7, 2114.1,
1701.3, 1471.8, 1388.8, 1351.2, 1249.9, 1156.4 cm−1; MS (ESI) calcd
for [C17H30N2O4SiNa]+ 377.18671, found 377.18683.
9 a - ( t e r t - B u t y l d i m e t h y l s i l y l o x y ) - 4 - d i a z o - 4 a -
hydroxyoctahydrocyclohepta[c]pyran-3(1H)-one (38a-cis and
38a-trans). Diazo lactones 38a-cis and 38a-trans were prepared from
bromoester 36a (0.16 g, 0.40 mmol) by the same method as used to
make 16-cis. Purification of the crude product by flash chromatog-
raphy on a Davisil support (hexanes/EtOAc 12:1, 10:1, 5:1, 3:1)
provided the bicyclic diazo lactones as two separated diastereomers
with the following spectral data:
4-Oxacycloundecyne-3,6-dione (41). According to representa-
tive experimental procedure 1 or 2 used to prepare 9, diazo lactone
38a-cis provided 11-membered cyclic ynoate 39 in 64% yield (0.056 g)
at 0 °C and 84% yield (0.089 g) at 40 °C. Diazo lactone 38a-trans
provided 39 in 57% yield (0.0093 g) at 0 °C and 67% yield (0.074 g)
at 40 °C. The product was purified via flash chromatography on
Davisil (hexanes/EtOAc 8:1, 6:1, 4:1, 2:1, and 1:1; Rf = 0.22 in
1
hexanes/EtOAc 1:1). H NMR (500 MHz, CDCl3) δ 4.90 (s, 2H),
2.54−2.51 (m, 2H), 2.45 (t, J = 6.3 Hz, 2H), 1.84 (dtd, J = 12.6, 7.0,
3.5 Hz, 2H), 1.67−1.62 (m, 2H), 1.59 (ddt, J = 19.5, 7.1, 1.7 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 204.2, 153.5, 97.2, 72.8, 71.7, 37.7,
24.1, 23.0, 22.9, 18.3; IR (film) 2946.4, 2876.9, 2224.0, 1726.4, 1554.7,
1464.0, 1430.3, 1371.5, 1280.8, 1209.4, 1192.1, 1162.2, 1128.4, 1092.7,
1028.1, 1011.7, 954.8, 738.8 cm−1; MS (ESI) calcd for [C10H12O3H]+
181.08592, found 181.08585.
6045
dx.doi.org/10.1021/jo500634d | J. Org. Chem. 2014, 79, 6037−6046

The Journal of Organic Chemistry
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
CCDC 992222 contains the supplementary crystallographic
data for this paper.
(29) The relative configuration of 8 was assigned by comparison to
related compounds.
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Maegawa, T.; Sajiki, H. Synlett 2008, 2291.
AUTHOR INFORMATION
Corresponding Author
*E-mail: matthias.brewer@uvm.edu.
Notes
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(32) The cis- and trans-fused bicycles were easily distinguishable by
NMR spectroscopy. The conformational flexibility of the cis-fused
The authors declare no competing financial interest.
bicyclic systems led to broad signals in the H and 13C NMR spectra,
1
which sharpened upon warming. The trans-fused diastereomers
showed sharp signals in the 1H and 13C NMR spectra at room
temperature.
(33) CCDC 992222 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
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D. M. Tetrahedron Lett. 1989, 30, 3499.
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ACKNOWLEDGMENTS
■
We thank Bruce O’Rourke (University of Vermont) for
obtaining mass spectral data and Prof. Rory Waterman and
Mr. Justin K. Pagano for X-ray data collection. This work was
financially supported by Award R01GM092870 from the
National Institute of General Medical Sciences (NIGMS), a
component of the National Institutes of Health (NIH), and was
made possible by the use of a facility supported by the Vermont
Genetics Network through Grant P20GM103449 from the
INBRE Program of NIH NIGMS. Its contents are solely the
responsibility of the authors and do not necessarily represent
the official views of NIGMS or NIH. The National Science
Foundation supported this work through instrumentation
grants CHE-1039436, CHE-1126265, and CHE-0821501.
(38) For general experimental information, see: Jabre, N. D.; Brewer,
M. J. Org. Chem. 2012, 77, 9910−9914.
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