Cascade cyclizations of acyclic and macrocyclic alkynones: Studies toward the synthesis of phomactin A

Article abstract of DOI:10.1021/jo4007514

A study of the reactivity and diastereoselectivity of the Lewis acid promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a β-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI₂) was found to promote irreversible ring closure, while cyclizations using BF₃OEt₂ as promoter occurred reversibly. For both acyclic and macrocyclic alkynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI₂ protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI ₂-promoted process.

Full text of DOI:10.1021/jo4007514

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pubs.acs.org/joc
Cascade Cyclizations of Acyclic and Macrocyclic Alkynones: Studies
toward the Synthesis of Phomactin A
Jennifer Ciesielski,† Vincent Gandon,‡ and Alison J. Frontier*,†
†Department of Chemistry, University of Rochester, Rochester, New York 14627, United States
‡Universite
́
Paris-sud, ICMMO (UMR CNRS 8182), Orsay 91405, France
S
* Supporting Information
ABSTRACT: A study of the reactivity and diastereoselectivity of
the Lewis acid promoted cascade cyclizations of both acyclic and
macrocyclic alkynones is described. In these reactions, a β-
iodoallenolate intermediate is generated via conjugate addition of
iodide to an alkynone followed by an intramolecular aldol reaction
with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis
acid magnesium iodide (MgI2) was found to promote irreversible
ring closure, while cyclizations using BF3·OEt2 as promoter occurred
reversibly. For both acyclic and macrocyclic alkynones, high
diastereoselectivity was observed in the intramolecular aldol
reaction. The MgI2 protocol for cyclization was applied to the
synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular
cation−olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-
promoted process.
Scheme 1. Lewis Acid-Initiated β-Iodoallenolate Cyclization
INTRODUCTION
■
Significant progress has been made in the development of new
cyclizations and carbon−carbon bond-forming reactions
initiated by the conjugate addition of halide nucleophiles to
different unsaturated carbonyl systems.1 The variant involving
the addition of iodide to alkynone derivatives, which generates
β-iodoallenolate intermediates, was first described by Kishi in
1986.2 Since then, β-iodoallenolates have proven to be versatile
nucleophilic intermediates in reactions with aldehydes,3
imines,4 oxiranes,5 and ketones.3a−d Asymmetric reactions
have also been achieved using chiral Lewis acids6 or chiral
auxiliaries.7 We have developed two related cascade cycliza-
tions, promoted by two different Lewis acids, involving β-
iodoallenolates II (Scheme 1).8
We proposed that treatment of alkynones I with titanium
tetrachloride (TiCl4) gave cyclohexenol products IV through
chelated intermediates III, while treatment with boron
trifluoride diethyl etherate (BF3·OEt2) led to intermediates of
type V, which have rotational freedom to undergo oxa-Michael
ring closure to produce oxacycles of type VI.
These cascades are some of the only examples of
intramolecular reactions of β-iodoallenolates that have been
reported,9 despite their potential value as a method for the
synthesis of highly functionalized ring systems. To effectively
apply this reaction chemistry to problems in natural product
synthesis, it will be important to develop an understanding of
the factors governing diastereoselectivity in β-iodoallenolate
cyclizations. In this paper, we assess diastereoselectivity and
reversibility in the cyclizations of both acyclic and macrocyclic
β-iodoallenolates using different Lewis acid promoters. We
have also applied this method to the synthesis of the ABD core
of phomactin A and observed an unexpected transannular
cyclization that we analyzed using DFT calculations.
RESULTS AND DISCUSSION
■
Cascade Cyclization Strategy for the Synthesis of the
ABD Core of Phomactin A. Over the past few years, we have
sought to implement this cascade cyclization in the preparation
of oxadecalin (1), which contains the ABD ring system of
Received: April 12, 2013
Published: May 31, 2013
© 2013 American Chemical Society
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Scheme 2. Strategy for the Synthesis of Phomactin A
phomactin A and appropriate handles for further functionaliza-
tion (Scheme 2).8,10,11 The idea was to generate a β-
iodoallenolate intermediate from macrocyclic alkynone 2,
which would undergo intramolecular aldol/oxa-Michael
addition to deliver 1 via bicyclo[9.3.1]pentadecane 3.
each primary alcohol with the Ley−Griffith reagent13 afforded
the alkynones 2 and 6, respectively (Scheme 3).
Attempts to cyclize macrocyclic alkynone 2 with the usual
promoters (BF3·OEt2 and TiCl4) were unsuccessful, producing
complex mixtures of products. Since magnesium iodide (MgI2)
has been reported to promote β-iodoallenolate formation/aldol
reaction,3g,i,9 we next tried cyclizing 2 using MgI2 (1.3 equiv) in
dichloromethane. The reaction did not produce either
cyclohexenyl alcohol 3 or oxadecalin 1; instead, a 1:1 mixture
of products was generated: cyclohexenyl alcohol 7 (isolated as a
single diastereomer) and tricycles 8a/8b (isolated as a 2.7:1
mixture of endo/exo isomers; see Scheme 4, top).
Macrocycle 2 was prepared as shown in Scheme 3.10
Scheme 3. Synthesis of Macrocycles 2 and 6
We tried adding n-Bu4NI (1.3−5 equiv) to the reaction
mixture,8 in an attempt to favor the formation of phomactin
skeleton 7 over the tricyclic system 8, but the ratio of 7 to 8 did
not change. However, we were able to avoid the formation of
tricycles 8 by changing the solvent: if the reaction was run in
tetrahydrofuran instead of dichloromethane, cyclohexenyl
alcohol 7 was produced as the sole product in 60% yield and
as a single diastereomer (Scheme 4, bottom).
We converted the mixture of tricycles 8a (endo)/8b (exo)
into p-nitrobenzoyl esters 9a (endo) /9b (exo), which enabled
us to obtain X-ray crystal structures of both the endo and exo
isomers.14 The stereochemistry of the tricyclic system is shown
in Scheme 4.
Since we needed cyclohexenyl 3 to assess the strategy
outlined in Scheme 2, we performed a standard Mitsunobu
inversion25 on cyclohexenyl alcohol 7, which furnished target 3
in 52% yield (Scheme 5). The oxa-Michael ring closure of 3
could be achieved under the standard conditions (BF3·OEt2 at
low temperature)8 to afford target oxadecalin 1 in 20% yield.
To summarize, synthetic studies targeting phomactin
revealed that macrocycles 2 and 3 exhibit unusual cyclization
behavior. In particular, (1) MgI2 was identified as a mild
alternative to BF3·OEt2 and TiCl4 and optimal for promoting
the β-iodoallenolate cyclization of acid-sensitive alkynone 2;
(2) the cyclization of 2 is highly diastereoselective; (3) tricycles
8 are produced unexpectedly from 2, through an unknown
mechanism; and (4) the BF3·OEt2-promoted oxa-Michael ring
closure of cyclohexenyl alcohol 3 is inefficient. We conducted
further cyclization studies on both acyclic and macrocyclic
Intramolecular Nozaki−Hiyama−Kishi Cr(II)/Ni(II)-
coupling12 followed by MnO2 oxidation gave enone 5Z in
two steps from iodoalkyne 4, along with isomeric enone 5E
(3.6: 1 ratio of Z and E isomers). After chromatographic
separation of the E- and Z-isomers, both could be desilylated
using a HF−pyridine solution in tetrahydrofuran. Oxidation of
Scheme 4. β-Iodoallenolate Cyclization with Alkynone 2
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Scheme 5. Synthesis of Oxadecalin 1 Using BF3·OEt2 as Promoter
Scheme 6. Diastereoselectivity in the Intramolecular Aldol Reaction
systems to improve our understanding of these four
experimental observations.
reaction times and warmer temperatures compared to the
cyclizations carried out with iodide as the nucleophile (cf. entry
2 vs 4 and entry 3 vs 5).
Finally, treatment of ketone 15 with MgI2 produced 16 in
78% yield (eq 1), whereas TiCl4 and BF3·OEt2 were not
competent promoters.16 This result further demonstrates that
MgI2 is a viable alternative to TiCl4 and BF3·OEt2 for acid-
sensitive substrates. It is also convenient that the MgI2-
promoted protocol does not require an external halide source
(Table 1, entries 2 and 4, and eq 1).
MgI2-Promoted Cyclizations of Acyclic and Macro-
cyclic Alkynones. Further experimentation with MgI2 as a
promoter indicated that cyclization results were comparable to
experiments employing TiCl4, producing cyclohexenols of type
IV rather than oxadecalins of type VI (Scheme 1). Cyclization
of 10 with TiCl4 gives cyclohexenyl alcohol 11 in 82% yield
(Table 1, entry 1), while MgI2 produces 11 in 75% yield (entry
a
Table 1. β-Haloallenolate Cyclizations
In additional experiments on the macrocyclic phomactin
system, we found that E-enone 6 could be cyclized upon
treatment with MgI2 in tetrahydrofuran, without isomerization
of the α,β-unsaturated ketone. Cyclohexenyl alcohol 17 was
obtained as a single diastereomer in 62% yield (eq 2).17
Importantly, compound 17 represents an alternative inter-
mediate useful for synthesis of the phomactin skeleton, as it
contains the relevant bicyclo[9.3.1]pentadecane core.
entry Lewis acid
iodide
conditions
product yield (%)
1
2
3
4
5
TiCl4
n-Bu4NI
−78 to 0 °C, 2 h
0 °C, 3 h
−40 to 0 °C, 3 h
0 °C to rt, 24 h
−40 °C to rt, 7 h
11
11
12
13
14
82
75
77
52
46
MgI2
BF3·OEt2
MgBr2
BF3·OEt2
n-Bu4NI
b
n-Bu4NBr
a
Reaction conditions: Alkynone (1.0 equiv), Lewis acid (1.3 equiv),
and n-Bu4NX (1.3 equiv) in CH2Cl2 (0.10 M) for the indicated time at
the indicated temperature. 65% conversion.
b
2). The analogous cyclization using BF3·OEt2 produces 12
(entry 3). The observed reactivity is readily explained by
chelation: like TiCl4, MgI2 is able to bind both oxygens of the
aldol product (cf. III, Scheme 1), which prevents oxa-Michael
ring closure.8
The two cyclization protocols were also successfully applied
to the synthesis of β-bromocyclohexenyl alcohols. Cyclization
of 10 using MgBr2 as promoter generated 13 in moderate yield
(entry 4).15 Treatment of 10 with BF3·OEt2/n-Bu4NBr
promoted the cascade cyclization to produce oxadecalin 14 in
46% yield (entry 5). In general, these reactions required longer
Diastereoselectivity of the β-Iodoallenolate Aldol
Cyclization. To explain why the intramolecular aldol
cyclization of alkynone 2 selectively produces diastereoisomer
7 rather than 3, it was helpful to perform a conformational
analysis of β-iodoallenolate intermediates complexed with
magnesium (Scheme 6). When macrocyclic alkynone 2 is
exposed to MgI2, 1,4-addition of iodide is expected to produce
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Scheme 7. Synthesis of Alkynone 20
Scheme 8. Intramolecular Aldol Reaction of Alkynone 20
two β-iodoallenolate diastereoisomers (18 and 19; Scheme 6).
Cyclization of 18 via a Zimmerman-Traxler transition state is
predicted to produce the major diastereoisomer 7.18,19 In
contrast, β-iodoallenolate 18 (axial) is not aligned to form the
magnesium chelate, while chelation of β-iodoallenolate 19
would produce two boat-like complexes, which may not form
within the rigid macrocyclic system. Cyclization of 18
(equatorial) would deliver the observed cyclohexenol 7. To
account for the high isolated yield of 7, it is reasonable to
propose that β-iodoallenolate isomers 18 and 19 can equilibrate
via reversible 1,4-addition of iodide,20 allowing selective
cyclization via chelate 18 (equatorial).
When pure samples of cyclohexenyl alcohol 27 and 2824,25
were treated with BF3·OEt2 to promote the oxa-Michael
reaction,26 27 afforded oxadecalin 29 in 90% yield, but the
reaction of 28 did not produce any of the corresponding
oxadecalin 30. Instead, oxadecalin 29 was isolated in 30% yield
(Scheme 9).
Scheme 9. Oxa-Michael Reactions of 27 and 28
Cyclization studies on acyclic alkynone 20 provided further
insight on the diastereoselectivity and reversibility of the
intramolecular aldol reactions of β-iodoallenolate intermediates.
Alkynone 20 was prepared as shown in Scheme 7.
Selective monoprotection of the primary alcohol using tert-
butyldimethylchlorosilane provided compound 22 in good
yield. Then, oxidation of the neopentyl alcohol with Dess-
Martin periodinane21 followed by a one-carbon homologation
using the Ohira-Bestmann reagent22 afforded desired alkyne 23.
Then, addition of the lithium acetylide to aldehyde 2411g and
oxidation of the resulting allylic alcohol gave the desired ketone
25 in 61% yield over two steps. Deprotection followed by
oxidation of the resulting alcohol gave alkynone 20.
Cyclization of 20 with MgI2 in dichloromethane provided
cyclohexenyl alcohols 27 and 28 in 77% yield as a 10:1 mixture
of diastereomers (Scheme 8).23 This result is consistent with
the model in Scheme 6, which predicts preferential formation
of 27 through a magnesium chelate analogous to 18
(equatorial). The flexibility of the acyclic system must allow
the intramolecular aldol reaction to occur through one of the
axial conformations as well, resulting in formation of minor
diastereomer 28.
This result suggests that treatment of 28 with BF3·OEt2 can
lead to the formation of 27 (with only moderate efficiency), via
the corresponding β-iodoallenolate intermediates. The high-
yielding, diastereoselective oxa-Michael ring closure of 27 then
produces 29 (Scheme 10). The fact that only one oxadecalin
isomer was obtained (29 and not 30) indicates that
cyclohexenol 28 must undergo retro-aldol reaction more
readily than oxa-Michael ring closure.
In contrast, no reaction occurred upon treatment of either
cyclohexenyl alcohol 28 or cyclohexenyl alcohol 3 (see Scheme
5) with MgI2. Taken together, these results suggest that
intramolecular aldol reactions of β-iodoallenolate intermediates
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require the formation of a high energy intermediate such as
strained allene 33 or vinyl cation 34 (Scheme 12).
Scheme 10. Cyclization of 28 via Retro-Aldol Reaction
Pathway
We performed DFT calculations to assess the feasibility of
these different reaction pathways.28,29 Although DFT is rarely
used with magnesium,30 it is the only reasonable computational
method that can be used with such a large system. Because
MgI2 can decompose into several species in solution,31 we
modeled multiple promoters: MgI2, MgI2·2THF, MgI+, MgI+·
THF, and Mg2+. In each case, solvation corrections were
obtained by the PCM method. We observed the systematic
formation of a chelate as starting complex (see B, Table 2).
Its formation is weakly exothermic in CH2Cl2. In THF, it is
moderately exothermic with MgI2, MgI+, or Mg2+, appreciably
exothermic with MgI+·THF, but strongly endothermic with
MgI2·2THF because of the steric strain.32 The cyclization of the
chelate gave rise to the tricyclic core D in a concerted fashion
(cf. intermediate 32 in Scheme 12) via transition state C. The
formation of the two rings is asynchronous, as shown by the
very distinct values between d1 and d2 in C (Table 2),
suggesting that C is more similar to 33 than to 34.33
Dissociation of the metallic fragment from D leads directly to
the tricycle. In CH2Cl2, a reasonable free energy of activation
was calculated with Mg2+. On the other hand, MgI+·THF gave
rise to the lowest lying transition state in THF. All cyclizations
were endothermic, but the decomplexation of the catalyst from
D always proved exothermic. Overall, the cyclization of A into
E liberates 26.6 kcal/mol of free energy. The subsequent
isomerization of E into the observed product 8 presumably
relieves strain in the tricyclic system.
Thus, DFT calculations support a concerted, Lewis acid-
catalyzed cation−olefin cascade as the most reasonable reaction
pathway for cyclization of 2 to 8. To the best of our knowledge,
this is a unique example of a reaction in which activation of an
aldehyde triggers a tandem cyclization involving an electron-
deficient alkyne and an alkene.34 The transannular relationship
of the alkyne and the alkene is probably an important factor.
We did not make attempts to optimize the reaction to favor the
formation of 8 over the desired target 7, but further
experimentation is planned to further evaluate this interesting
cyclization.
with BF3·OEt2 can occur reversibly, while the analogous MgI2-
promoted cyclizations are irreversible.20 Thus, the inability to
achieve efficient oxa-Michael ring closure in both 28 and the
phomactin system 3 (see Scheme 5) using BF3·OEt2 may be
attributed to a competing retro-aldol reaction. Fortunately, we
were able to identify two other methods for inducing the oxa-
Michael addition of 3. These results are described in the next
section.
Synthesis of the ABD Ring System of Phomactin. To
advance the synthesis of phomactin A, we explored alternative
strategies for obtaining oxadecalin 1 from cyclohexenyl alcohol
3. Treatment with 10 mol % of AuCl3 in dichloromethane at 0
°C effectively induced oxa-Michael addition, affording
oxadecalin 1 in 50% yield,26 or alternatively, exposure to tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) in the
presence of 2,6-lutidine afforded silyl enol ether 31 in 54% yield
(Scheme 11).10 This sequence is particularly advantageous
Scheme 11. Alternative Methods for Inducing Oxa-Michael
Cyclization in Cyclohexenyl Alcohol 3
CONCLUSION
■
In summary, these studies provide new insight into the
reactivity and diastereoselectivity of the Lewis acid promoted
cyclizations of both acyclic and macrocyclic alkynones. Our
experiments indicate that the 1,4-addition of iodide to an
alkynone is a reversible process using either MgI2 or BF3·OEt2
and generates a β-iodoallenolate intermediate. This intermedi-
ate can then undergo an intramolecular aldol reaction with a
tethered aldehyde to afford a cyclohexenyl alcohol. We present
evidence that MgI2 promotes irreversible ring closure, while the
analogous BF3·OEt2-promoted cyclization occurs reversibly.
For both acyclic and macrocyclic alkynones, we found that the
aldol reaction is highly diastereoselective. The MgI2 protocol
was employed in the synthesis of a tricycle corresponding to the
ABD ring system of phomactin A. Finally, we examined an
interesting transannular cyclization generated under the Lewis
acidic conditions, and gained insight into the process using
DFT calculations.
because the oxa-Michael addition occurs with simultaneous
protection of the ketone, providing a flexible intermediate that
can be functionalized in different ways.
Mechanism of Formation of Tricycles 8a and 8b: DFT
studies. The Lewis acid-promoted cyclization of 2 in
dichloromethane resulted in significant production of tricycles
8 (see Scheme 4). Different reaction pathways can be proposed
to rationalize this outcome. One possibility involves a cation-
olefin cyclization cascade,27 with concerted formation of two
new bonds to generate intermediate 32, followed by
elimination to produce tricycles 8 (Scheme 12). Alternatively,
stepwise mechanisms can be invoked, although these would
EXPERIMENTAL SECTION
■
General Methods. Reactions were carried out in oven-dried
glassware under an argon atmosphere. Reagents were used as obtained
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Scheme 12. Proposed Mechanisms for the Formation of Tricycles 8
Table 2. Computed Intermediates and Gibbs Free Energies after Solvation Correction (B3LYP/6-311G**[Mg,I]/6-
31G*[Other Elements]//PCM; kcal/mol) Corresponding to the Formation of the Tricyclic Framework
‡
ΔGAB
[ΔGAC
]
ΔGAD
entry
M
DCM
THF
DCM
25.0
THF
DCM
18.2
THF
d1 (Å)
d2 (Å)
1
2
3
4
5
MgI2
−1.3
−2.8
10.0
24.2
39.2
25.0
8.9
17.6
3.0
1.68
1.68
1.85
1.66
1.61
1.95
1.97
2.64
2.12
2.30
MgI2·2THF
MgI+
MgI+·THF
Mg2+
−1.3
−0.5
−1.3
−15.3
−4.6
26.8
16.1
26.0
5.3
23.6
0.2
12.0
1.2
from commercial suppliers without further purification. ACS grade
hexanes and ethyl acetate were used for column chromatography.
Thin-layer chromatography (TLC) was performed on precoated silica
gel 60 F254 glass-supported plates. Column chromatography was
carried out on 60 Å silica gel (230−400 mesh). Visualization on thin-
layer chromatography was done with a UV lamp followed by staining
with either potassium permanganate/heat or p-anisaldehyde/heat.
Infrared (IR) absorbance frequencies are given in cm−1 at the peak
maximum. High-resolution mass spectra were obtained using a time-
of-flight (TOF) mass spectrometer.
Spectroscopic Data. Structural assignment, including the
identification of E/Z isomers and cis/trans isomers, was determined
1
by either H and 13C NMR spectroscopy (at either 400 or 500 MHz
and 100 or 125 MHz, respectively) and by NOE experiments and 2D
COSY (when necessary) or an X-ray crystal structure. Chemical shifts
are given in ppm, referenced to the residual proton resonance of the
solvents (δ = 7.26 for CHCl3, δ = 7.16 for C6H6) or to the residual
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carbon resonance of the solvent (δ = 77.1 for CHCl3, δ = 128.0 for
C6H6). Coupling constants (J) are given in hertz (Hz). The terms m, s,
d, and t refer to multiplet, singlet, doublet, and triplet. In all cases,
unless otherwise noted, the major diastereomer is reported.
Experimental conditions and spectral data for the preparation of the
following compounds have been reported previously: 10 and 15;8 4
and 21.10 Experimental details and spectral data for other compounds
previously studied in our laboratories (1, 2, 3, 5Z, 5E, 7, 12, 14 ,and
31)8,10 are provided below.
(302 mg, 69%, traces of the E-isomer are present, only the Z-isomer is
reported) as a yellow oil and the E-ketone (85 mg, 19%) as a yellow
oil. The geometry of the Z-isomer was confirmed by NOE analysis
(see Supporting Information).
1
5Z. H NMR (400 MHz, CDCl3): δ 5.84 (s, 1H), 5.47−5.39 (m,
1H), 3.74−3.66 (m, 1H), 3.65−3.58 (m, 1H), 2.61−2.46 (m, 2H),
2.27−2.15 (m, 4H), 2.00−1.91 (m, 1H), 1.88 (s, 3H), 1.86−1.75 (m,
2H), 1.66 (s, 3H), 1.51−1.43 (m, 1H), 1.30−1.20 (m, 1H), 1.18 (s,
3H), 0.92 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H). 13C NMR
(100 MHz, CDCl3): δ 180.3, 152.4, 134.3, 128.2, 125.4, 103.0, 84.6,
61.5, 38.2, 36.7, 35.2, 35.0, 32.1, 31.8, 25.9, 25.4, 24.0, 22.6, 18.2, 15.6,
13.7, −5.3 (2C). IR (neat): 2947, 2928, 2366, 2335, 2193, 1654, 1633,
1604. HRMS (ESI-TOF): m/z calcd for C25H42O2Si [M+] 402.2954,
found 402.2951.
General Procedure for β-Iodoallenolate Cyclizations Run
with MgI2. Magnesium iodide (at the indicated equivalents) was
added to a stirred solution of the alkynone (1.0 equiv) in dry CH2Cl2
(0.10 M) or THF (0.10 M) at 0 °C. The reaction was then carried out
at the indicated temperature and time. After completion of the
reaction, the mixture was diluted with ethyl acetate, quenched with
saturated NaHCO3 solution, and extracted with ethyl acetate (3×).
The combined organic layers were washed with saturated Na2S2O3
solution (2×) and brine (1×), dried over MgSO4, and concentrated.
The resulting residue was purified by flash chromatography on silica
gel using different gradients of hexanes and ethyl acetate to afford the
pure products.
General Procedure for β-Iodoallenolate Cyclizations Run
with BF3·OEt2. Tetra-n-butylammonium iodide (at the indicated
equivalents) was added to a stirred solution of the alkynone (1.0
equiv) in dry CH2Cl2 (0.10 M) at −40 °C. Boron trifluoride diethyl
etherate (1.3 equiv) was then added dropwise. The reaction was
carried out at the indicated temperature and time. After completion of
the reaction, the mixture was diluted with ethyl acetate, quenched with
saturated NaHCO3 solution, and extracted with ethyl acetate (3×).
The combined organic layers were washed with saturated Na2S2O3
solution (2×) and brine (1×), dried over MgSO4, and concentrated.
The resulting residue was purified by flash chromatography on silica
gel using different gradients of hexanes and ethyl acetate to afford the
pure products.
(2Z,6E,10S,11R)-13-((tert-Butyldimethylsilyl)oxy)-10-(iodoe-
thynyl)-3,7,10,11-tetramethyltrideca-2,6-dienal (4).10 1H NMR
(400 MHz, CDCl3): δ 9.94 (d, J = 8.2 Hz, 1H), 5.91 (d, J = 8.0 Hz,
1H), 5.18 (t, J = 6.9 Hz, 1H), 3.77−3.69 (m, 1H), 3.66−3.60 (m, 1H),
2.62 (t, J = 7.6 Hz, 2H), 2.32−2.24 (m, 2H), 2.16−2.05 (m, 2H), 2.02
(s, 3H), 1.96−1.93 (m, 1H), 1.69−1.55 (m, 2H), 1.64 (s, 3H), 1.48−
1.40 (m, 1H), 1.32−1.23 (m, 1H), 1.12 (s, 3H), 0.93 (s, 12H), 0.09 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 190.5, 163.7, 137.4, 128.5,
122.0, 100.7, 61.8, 40.9, 37.5, 36.9, 35.5, 34.6, 32.5, 27.0, 25.9, 25.0,
22.5, 18.2, 16.2, 13.9, −5.3 (1 carbon is missing due to overlap). IR
(neat): 2949, 2926, 2854, 1669, 1631.
5E. 1H NMR (400 MHz, CDCl3) δ 6.11 (s, 1H), 5.11 (t, J = 7.4 Hz,
1H), 3.72−3.62 (m, 1H), 3.61−3.54 (m, 1H), 2.37−2.19 (m, 4H),
2.09 (t, J = 6.1 Hz, 2H), 1.91−1.88 (m, 2H), 1.84 (s, 3H), 1.75−1.68
(m, 1H), 1.58−1.47 (m, 1H), 1.52 (s, 3H), 1.23−1.16 (m, 1H), 1.10
(s, 3H), 0.87 (s, 12H), 0.02 (s, 6H). 13C NMR (100 MHz, CDCl3): δ
178.7, 147.6, 137.2, 132.3, 123.5, 106.6, 84.5, 61.4, 38.2, 37.6, 36.4,
35.3, 34.3, 33.1, 27.2, 25.9, 22.0, 18.2, 18.0, 14.8, 13.5, −5.3, −5.4. IR
(neat): 2928, 2858, 2187, 1666, 1631, 1462, 1435, 1384, 1253, 1207,
1091. HRMS (ESI-TOF): m/z calcd for C25H42O2Si [M+] 402.2954,
found 402.2954.
(R)-3-((S,5Z,9E)-1,6,10-Trimethyl-4-oxocyclododeca-5,9-
dien-2-ynyl)butanal (2). As described previously,10 in a plastic
reaction vessel, 5Z (209 mg, 519 mmol) was dissolved in 4.2 mL of
tetrahydrofuran and 0.42 mL of pyridine and cooled to 0 °C. Then,
HF−pyridine (∼70% HF in ∼30% pyridine, 0.51 mL, 0.561 mmol)
was slowly added. After 2 h, the reaction mixture was diluted in 2 mL
of ethyl acetate and quenched with 10 mL of saturated solution of
NaHCO3. The reaction mixture was extracted with ethyl acetate (3 ×
20 mL). The combined organic layers were washed with 50 mL of
saturated solution of NaHCO3, 10 mL of saturated CuSO4 solution,
and 20 mL of brine, dried over MgSO4, and concentrated. The
resulting residue was purified by flash chromatography on silica gel to
afford the primary alcohol (146 mg, 98%, traces of the E-isomer are
present, only the Z-isomer is reported) as a yellow oil. 1H NMR (400
MHz, CDCl3): δ 5.88 (s, 1H), 5.48 (t, J = 7.9 Hz, 1H), 3.86−3.74 (m,
1H), 3.70−3.59 (m, 1H), 2.69−2.60 (m, 1H), 2.57−2.48 (m, 1H),
2.33−2.22 (m, 4H), 2.08−1.98 (m, 2H), 1.92 (s, 3H), 1.90−1.80 (m,
2H), 1.69 (s, 3H), 1.57−1.48 (m, 1H), 1.43−1.32 (m, 1H), 1.21 (s,
3H), 0.97 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 180.3,
153.3, 134.2, 128.1, 125.5, 103.2, 84.7, 61.2, 38.2, 37.4, 35.4, 35.1, 32.0,
31.9, 25.4, 24.1, 21.6, 15.5, 13.8. IR (neat): 3658−3090, 2973, 2939,
2874, 2195, 1627, 1600, 1442, 1377, 1348, 1280, 1249. HRMS (ESI-
TOF): m/z calcd for C19H28O2 [M+] 288.2089, found 288.2092.
The primary alcohol (227 mg, 0.788 mmol), from above, was stirred
with 4-methylmorpholine N-oxide (138 mg, 1.18 mmol) and 4 Å
molecular sieves in 7.6 mL of dry CH2Cl2. After 20 min at rt, tetra-n-
propylammonium perruthenate (14 mg, 0.04 mmol) was added, and
the mixture was stirred at rt for 2 h. The reaction was quenched with
10 mL of saturated Na2SO3 solution, extracted with diethyl ether (3 ×
20 mL), and washed with brine and and saturated CuSO4 solution.
The combined organic layers were dried over MgSO4 and filtered over
Celite. The resulting residue was concentrated to afford the aldehyde 2
(129 mg, 73%, traces of the E-isomer are present, only the Z-isomer is
reported) as a yellow oil. The aldehyde was immediately used in the
next reaction. (This compound was not stable to silica gel
chromatography but was sufficiently pure to use in the next step
without further purification.) 1H NMR (500 MHz, CDCl3): δ 9.74 (s,
1H), 5.79 (s, 1H), 5.41 (t, J = 8.1 Hz, 1H), 2.84−2.75 (m, 1H), 2.54−
2.44 (m, 1H), 2.34−2.24 (m, 2H), 2.24−2.14 (m, 4H), 1.84 (s, 3H),
1.79−1.69 (m, 1H), 1.61 (s, 3H), 1.59−1.44 (m, 2H), 1.14 (s, 3H),
0.91 (d, J = 6.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 201.6,
179.7, 153.2, 134.0, 128.1, 125.7, 101.0, 85.1, 47.4, 37.6, 35.0, 32.3,
32.0, 25.4, 24.1, 21.8, 15.5, 14.5 (1 carbon is missing due to overlap).
IR (neat): 2966, 2935, 2877, 2854, 2198, 1724, 1627, 1600, 1466,
1377, 1280, 1249.
(S,2Z,6E)-10-((R)-4-((tert-Butyldimethylsilyl)oxy)butan-2-yl)-
3,7,10-trimethylcyclododeca-2,6-dien-11-ynone (5Z) and
(S,2E,6E)-10-((R)-4-((tert-Butyldimethylsilyl)oxy)butan-2-yl)-
3,7,10-trimethylcyclododeca-2,6-dien-11-ynone (5E). As de-
scribed previously,10 iodoalkyne 4 (295 mg, 0.556 mmol) was diluted
in 6.3 mL of tetrahydrofuran and slowly added, over 3 h, to a
vigorously stirring solution of CrCl2 (509 mg, 4.1 mmol) and NiCl2
(0.07 mg, 0.055 mmol) in 44.8 mL of tetrahydrofuran. (Note: The
tetrahydrofuran was thoroughly degassed (three times before each
cyclization), and CrCl2 was dried for at least 3 h at 180 °C under
vacuum. All operations were carried out in the glovebox; the addition
of the iodoalkyne was carried out in the atmosphere.) After
approximately 3 h, the reaction mixture was quenched with 10 mL
of saturated NH4Cl solution, extracted with diethyl ether (3 × 50 mL),
washed with NaS2O3 (2 × 30 mL), H2O (2 × 30 mL), and brine (2 ×
30 mL), dried over MgSO4, and concentrated. The resulting residue
was purified by flash chromatography on silica gel (hexanes/ethyl
acetate 95:5) to give the macrocycle (142 mg, 63%) as an unidentified
1
mixture of diastereomers with a complicated H NMR spectrum and
was carried on to the next step without further purification.
The macrocycle (600 mg, 1.48 mmol), from above, was diluted in
15 mL of CH2Cl2, and MnO2 (2.50 g, 28.73 mmol) was added and rt.
After 2 days, the reaction mixture was filtered over Celite and
concentrated. The resulting residue was purified by flash chromatog-
raphy on silica gel (hexanes/ethyl acetate 99:1) to give the Z-ketone
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(R)-3-((S,5E,9E)-1,6,10-Trimethyl-4-oxocyclododeca-5,9-
dien-2-yn-1-yl)butanal (6). In a plastic reaction vessel, ketone 5E
(201 mg, 500 mmol) was dissolved in 4.0 mL of tetrahydrofuran and
0.40 mL of pyridine and cooled to 0 °C. Then, 0.10 mL of HF−
pyridine (∼70% HF in ∼30% pyridine) was slowly added. After 1 h, an
additional 0.10 mL of HF−pyridine was added, and this process was
repeated until completion of the reaction as indicated by TLC. (Note:
If HF−pyridine is added rapidly or in one portion isomerization of the
double bond will occur.) The reaction mixture was diluted in 2 mL of
ethyl acetate and quenched with 10 mL of saturated solution of
NaHCO3. The reaction mixture was extracted with ethyl acetate (3 ×
20 mL). The combined organic layers were washed with saturated
NaHCO3 solution, saturated CuSO4 solution, and brine, dried over
MgSO4, and concentrated. The resulting residue was purified by flash
chromatography on silica gel (hexanes:ethyl acetate 80:20) to give the
alcohol (137 mg, 95%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ
6.09 (s, 1H), 5.10 (t, J = 7.3 Hz, 1H), 3.72−3.66 (m, 1H), 3.58−3.52
(m, 1H), 2.58 (bs, 1H), 2.37−2.24 (m, 3H), 2.23−2.13 (m, 2H),
2.12−2.05 (m, 2H), 1.92−1.86 (m, 3H), 1.82 (s, 3H), 1.72−1.62 (m,
1H), 1.50 (s, 1H), 1.47−1.45 (m, 1H), 1.29−1.19 (m, 1H), 1.09 (s,
3H), 0.86 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 179.0,
148.2, 137.1, 132.1, 123.5, 106.6, 84.5, 61.1, 38.3, 37.6, 37.0, 35.3, 34.2,
33.1, 27.2, 21.5, 18.1, 14.8, 13.6. IR (neat): 3600−3045, 2974, 2931,
2858, 2719, 2191, 1730, 1675, 1637, 1450, 1343, 1275. HRMS (ESI-
TOF): m/z calcd for C19H29O2 [M + H]+ 289.4244, found 289.4248.
The above alcohol (137 mg, 0.475 mmol) was stirred with 4-
methylmorpholine N-oxide (83 mg, 1.18 mmol) and 4 Å molecular
sieves in 7.6 mL of dry CH2Cl2. After 20 min at rt, tetra-n-
propylammonium perruthenate (8.0 mg, 0.04 mmol) was added, and
the mixture was stirred at rt for 2 h. The reaction was quenched with
10 mL of saturated Na2SO3 solution and extracted with diethyl ether
(3 × 15 mL). The combined organic layers were washed with brine
and saturated CuSO4 solution, dried over MgSO4, filtered over Celite,
and concentrated to give the aldehyde 6 (81 mg, 60%) as a yellow oil.
(This compound was not stable to silica gel chromatography but was
sufficiently pure to use in the next step without further purification.)
1H NMR (400 MHz, CDCl3): δ 9.76 (s, 1H), 6.09 (s, 1H), 5.14 (t, J =
7.3 Hz, 1H), 2.77 (d, J = 13.8, 1H), 2.38−2.17 (m, 8H), 2.17−2.07
(m, 2H), 1.85 (s, 3H), 1.52 (s, 3H), 1.12 (s, 3H), 0.90 (d, J = 6.0 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 201.5, 178.4, 148.5, 136.1,
131.9, 123.8, 104.5, 85.1, 47.5, 37.8, 37.6, 34.6, 34.2, 33.5, 27.3, 21.4,
18.1, 14.8, 14.4. IR (neat): 2974, 2931, 2858, 2719, 2191, 1724, 1662,
1631, 1450, 1435, 1384, 1211. HRMS (ESI-TOF): m/z calcd for
C19H26O2 [M+] 287.1933, found 287.1937.
(3Z,7E,11S,12R,14S)-14-Hydroxy-15-iodo-4,8,11,12-
tetramethylbicyclo[9.3.1]pentadeca-1(15),3,7-trien-2-one (7).
As described previously,10 compound 7 was prepared from alkynone
2 using the general protocol for the MgI2-promoted cyclization. Yield:
35 mg, 60%. Eluent: hexanes/ethyl acetate, 90:10. 1H NMR (500
MHz, C6D6): δ 6.39 (s, 1H), 5.18 (dd, J = 11.3 Hz, 4.6 Hz, 1H), 4.37−
4.32 (m, 1H), 2.65 (d, J = 8.2 Hz, 1H), 2.40−2.33 (m, 1H), 2.19−2.12
(m, 1H), 2.10 (d, J = 13.7 Hz, 1H), 2.02−1.97 (m, 2H), 1.97−1.88
(m, 1H), 1.86−1.81 (m, 1H), 1.70 (s, 3H), 1.67−1.66 (m, 1H), 1.63−
1.59 (m, 1H), 1.55 (d, J = 1.2 Hz, 3H), 1.30−1.21 (m, 1H), 1.11−1.07
(m, 1H), 0.88 (s, 3H), 0.70 (d, J = 6.9 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 200.5, 147.9, 142.5, 133.2, 128.7, 128.3, 125.7, 122.4, 70.4,
46.8, 36.8, 34.5, 33.5, 28.7, 24.8, 24.6, 21.8, 18.0, 17.4. IR (neat):
3631−3108, 2966, 2935, 2854, 1689, 1602, 1556, 1446, 1381. HRMS
(ESI-TOF): m/z calcd for C19H28IO2 [M + H]+ 415.1134, found
415.1146. [α]20D: +82.9 (c 0.51, CHCl3).
were washed with H2O (1 × 4 mL), brine (1 × 4 mL), dried over
MgSO4, filtered over silica gel, and concentrated. The resulting residue
was dissolved in 2 mL of methanol, and K2CO3 (46 mg, 0.338 mmol)
was added at 0 °C. The reaction mixture was warmed to rt. After 30
min, the reaction mixture was quenched with 4 mL of 1 N HCl and
extracted with ethyl acetate (3 × 10 mL). The combined organic layers
were washed with H2O (1 × 4 mL) and brine (1 × 4 mL), dried over
MgSO4, and concentrated. The resulting residue was purified by flash
chromatography on silica gel (hexanes/ethyl acetate 98:2 to hexanes/
ethyl acetate 90:10 to hexanes/ethyl acetate 80:20) to afford the
cyclohexenyl alcohol (31 mg, 52%) and the starting material (22 mg,
1
36%). H NMR (400 MHz, CDCl3): δ 6.14 (s, 1H), 5.34−5.24 (m,
1H), 4.76 (s, 1H), 2.91−2.81 (m, 1H), 2.80−2.75 (m, 1H), 2.41 (t, J =
13.5, 1H), 2.31−2.17 (m, 3H), 2.04−2.01 (m, 1H), 1.96−1.86 (m,
2H), 1.85 (s, 3H), 1.80−1.62 (m, 2H), 1.73 (s, 3H), 1.51 (dd, J = 15.2,
3.2, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.83 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 202.1, 145.8, 143.2, 136.4, 131.9, 128.8, 127.4, 67.2, 47.5,
36.4, 35.7, 34.6, 32.0, 27.8, 24.4, 23.5, 23.4, 18.0, 17.3. IR (neat):
3640−3189, 1639, 1592, 1450, 1380, 1298, 1249. HRMS (ESI-TOF):
m/z calcd for C19H27IO2 [M + Na+] 437.0954, found 437.0954.
[α]20D: +298.7 (c 0.53, CHCl3).
(1R,3R,3aS,6aR,Z)-1-Hydroxy-3,3a,6,9-tetramethyl-
2,3,3a,4,7,8-hexahydro-1H-cycloocta[de]naphthalen-11(6aH)-
one (8a) and (3aS,4R,6R,11aR,Z)-6-Hydroxy-3a,4,9-trimethyl-1-
methylene-2,3,3a,4,5,6,11,11a-octahydro-1H-cycloocta[de]-
naphthalen-7(10H)-one (8b). Compounds 8a and 8b were
prepared from alkynone 2 using the general protocol for the MgI2
promoted cyclization. Compounds 8a (endo) and 8b (exo) were
obtained in a 2.7:1 ratio. Yield: 10 mg, 23%. Eluent: hexanes/ethyl
acetate, 80:20. 1H NMR (400 MHz, CDCl3): δ 6.32 (s, 0.4H), 6.29 (s,
1H), 5.65 (d, J = 7.7 Hz, 1H), 4.98 (d, J = 7.4 Hz, 1H), 4.95 (d, J = 6.5
Hz, 0.4H), 4.89 (s, 0.4H), 4.80 (s, 0.4H), 3.46−3.39 (m, 0.4H), 3.28−
3.18 (m, 1.4H), 3.17−3.10 (m, 1H), 2.68−2.46 (m, 1.1H), 2.38 (bs,
1H), 2.15−1.97 (m, 5.1H), 2.03 (s, 5.4H), 1.93−1.80 (m, 5.8H), 1.78
(s, 3.6H), 1.72−1.59 (m, 1.8 H), 0.96−0.92 (m, 5H), 0.88 (s, 1.2H),
0.08 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 196.5, 155.7, 155.4,
151.3, 150.9, 138.4, 137.7, 136.6, 132.8 (2C), 121.0, 110.0, 64.3, 44.0,
40.2, 40.0, 38.4, 36.5, 36.0, 35.1, 34.2, 33.7, 33.0, 32.3, 30.5, 30.1, 26.7,
26.3, 24.8, 21.6, 19.2, 17.4, 15.6, 15.4 (4 carbons are missing due to
overlap). IR (neat): 3601−3202, 2950, 2923, 2872, 2815, 1730, 1636,
1603, 1554, 1484, 1452, 1435, 1376, 1298, 1258. HRMS (ESI-TOF):
m/z calcd for C19H26O2 [M+] 286.1927, found 286.1928.
(1R,3R,3aS,6aR,Z)-3,3a,6,9-Tetramethyl-11-oxo-
2,3,3a,4,6a,7,8,11-octahydro-1H-cycloocta[de]naphthalen-1-yl
4-nitrobenzoate (9a) and (1R,3R,3aS,6aR,Z)-3,3a,9-Trimethyl-6-
methylene-11-oxo-2,3,3a,4,5,6,6a,7,8,11-decahydro-1H-
cycloocta[de]naphthalen-1-yl 4-nitrobenzoate (9b). The 8a/8b
mixture from above (10 mg, 0.035 mmol) was stirred with p-
nitrobenzoyl chloride (7 mg, 0.038 mmol) and pyridine (3.3 μL, 0.038
mmol) in 0.10 mL of CH2Cl2 at rt. After 1 h, the reaction mixture was
quenched with 2 mL of 1 N HCl, extracted with diethyl ether (3 × 5
mL), washed with H2O and brine, dried over MgSO4, and
concentrated. The reaction mixture was purified by flash chromatog-
raphy on silica gel (hexanes/ethyl acetate, 90:10 to 70:30) and then
recrystallized from hexane to give p-nitrobenzoates 9a and 9b (8 mg,
53%; obtained in 2.4:1 ratio). 1H NMR (500 MHz, CDCl3): δ 8.21 (d,
J = 8.4 Hz, 6H), 8.03 (d, J = 8.3 Hz, 6H), 6.24−6.16 (m, 6.2H), 5.61
(d, J = 7.5 Hz, 2.1H), 4.83 (d, J = 4.1 Hz, 2H), 3.46−3.39 (m, 1H),
3.35−3.28 (m, 2.2H), 3.27−3.20 (m, 1.1H), 3.15−3.09 (m, 2.2H),
2.63−2.56 (m, 1H), 2.55−2.46 (m, 1.1H), 2.24−2.15 (m, 2H), 2.15−
2.09 (m, 3H), 2.09−2.01 (m, 4.3H), 1.99−1.96 (m, 9.1H), 1.92−1.80
(m, 12.1H), 1.74 (s, 1H), 0.92−0.86 (m, 12.2H), 0.80 (s, 6H). 13C
NMR (125 MHz, CDCl3): δ (9a (endo) is reported) 194.3, 163.6,
155.3, 153.0, 150.3, 132.3, 130.5, 123.4, 121.1, 70.4, 40.2, 39.7, 34.4,
33.9, 33.6, 32.2, 30.3, 26.4, 21.6, 21.6, 20.0, 15.2 (2 carbons are missing
due to overlap). IR (neat): 2924, 2854, 1720, 1653, 1608, 1527, 1450,
1342, 1265, 1099, 1014. HRMS (ESI-TOF) m/z calcd for C26H29NO5
[M + Na+] 458.1943, found 458.1933.
(3Z,7E,11S,12R,14R)-14-Hydroxy-15-iodo-4,8,11,12-
tetramethylbicyclo[9.3.1]pentadeca-1(15),3,7-trien-2-one (3).
As described previously,10 cyclohexenyl alcohol 7 (60 mg, 0.169
mmol) was dissolved in 1.34 mL of benzene, and p-nitrobenzoic acid
(442 mg, 1.69 mmol) and triphenylphosphine (282 mg, 1.69 mmol)
were added. Then, diethyl azodicarboxylate (DEAD) (0.264 mL, 1.69
mmol) was slowly added to the reaction mixture at 0 °C. After
completion of the reaction, as indicated by TLC, the reaction mixture
was quenched with 4 mL of saturated solution of NaHCO3 and
extracted with ethyl acetate (3 × 10 mL). The combined organic layers
4,4,9-Trimethyl-7-oxodec-8-en-5-ynal (10).8 1H NMR (500
MHz, CDCl3): δ 9.86 (s, 1H), 6.14 (s, 1H), 2.68 (t, J = 5 Hz, 2H),
2.23 (s, 3H), 1.96 (s, 3H), 1.84 (t, J = 5 Hz, 2H), 1.31 (s, 6H). 13C
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NMR (125 MHz, CDCl3): δ 201.6, 176.7, 157.8, 126.2, 96.8, 83.6,
40.5, 34.4, 31.1, 28.3, 27.7, 21.1. IR (neat): 2970, 2924, 2854, 2206,
1724, 1651, 1608.
promoted cyclization. Yield: 49 mg, 62%. Eluent: hexanes:ethyl
acetate, 90:10. 1H NMR (400 MHz, C6D6): δ 6.11 (s, 1H), 4.89 (d, J =
9.7 Hz, 1H), 4.44−4.40 (m, 1H), 3.23 (bs, 1H), 2.34−2.18 (m, 1H),
2.07 (s, 3H), 1.99−1.86 (m, 4H), 1.83−1.70 (m, 4H), 1.66 (s, 3H),
1.47−1.38 (m, 1H), 1.20−1.09 (m, 1H), 0.86 (s, 3H), 0.75 (d, J = 6.9
Hz, 3H). 13C NMR (100 MHz, C6D6): δ 196.2, 151.7, 148.6, 133.9,
126.9, 125.6, 119.3, 70.0, 46.2, 38.7, 36.3, 34.2, 33.9, 30.3, 26.6, 23.6,
18.9, 17.6, 17.5. IR (neat): 3608−3084, 2966, 2928, 2877, 2858, 1689,
1627, 1435, 1381, 1225, 1053. HRMS (ESI-TOF): m/z calcd for
C19H27IO2 [M + Na+] 437.0954, found 437.0953. [α]20D: −7.8 (c 0.25,
CHCl3).
1-(6-Hydroxy-2-iodo-3,3-dimethylcyclohex-1-en-1-yl)-3-
methylbut-2-en-1-one (11). Compound 11 was prepared from
alkynone 10 using the general protocol for the MgI2-promoted
cyclization. Yield: 526 mg, 82%. Eluent: hexanes:ethyl acetate, 80:20).
All spectral data for 11 were in agreement with published data.8 1H
NMR (500 MHz, CDCl3): δ 6.27 (s, 1H), 4.34 (m, 1H), 2.62 (s, 1H),
2.24 (s, 3H), 2.00 (s, 3H), 2.06−1.93 (m, 1H), 1.85−1.83 (m, 1H),
1.78−1.74 (m, 1H), 1.20 (s, 3H), 1.12 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 197.5, 158.4, 147.3, 123.7, 118.8, 68.0, 39.1, 32.6, 31.5, 29.0,
27.8, 21.3. IR (neat): 3623−3095, 2962, 2930, 2860, 1664, 1603.
HRMS (ESI-TOF): m/z calcd for C13H19O2I1Na [M + Na+]
357.0321, found 357.0322.
(2S,3R)-2,3-Dimethyl-2-vinylpentane-1,5-diol (21). As de-
scribed previously,10 an inseparable mixture of diastereomers (5.5:1)
at the tertiary center was obtained. The mixture was carried on to the
next step, and the ratio remained constant through all subsequent
1
5-Iodo-2,2,6,6-tetramethyl-6,7,8,8a-tetrahydro-2H-chro-
men-4(3H)-one (12). As previously described,8 compound 12 was
prepared from alkynone 10 using the general protocol for the BF3·
OEt2-promoted cyclization. Yield: 197 mg, 77%. Eluent: hexanes/ethyl
transformations. The major diastereomer is reported in all cases. H
NMR (400 MHz, CDCl3): δ 5.85 (dd, J = 17.7, 10.9 Hz, 1H), 5.21−
5.05 (m, 2H), 3.83−3.75 (m, 1H), 3.67−3.60 (m, 1H), 3.59−3.38 (m,
2H), 2.45 (bs, 2H), 1.86−1.71 (m, 2H), 1.27−1.16 (m, 1H), 0.94 (s,
3H), 0.89 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 143.7,
114.4, 68.5, 61.5, 44.8, 33.8, 33.3, 15.3, 14.7. IR (neat): 3721−3027,
2962, 2877, 1728, 1635, 1454, 1415, 1377. HRMS (ESI-TOF): m/z
calcd for C9H19O2 [M + H]+ 159.1385, found 159.1387.
1
acetate, 90:10. H NMR (500 MHz, CDCl3): δ 4.48−4.45 (m, 1H),
2.63 (d, J = 15 Hz, 1H), 2.57 (d, J = 15 Hz, 1H), 2.08−2.02 (m, 1H),
1.95−1.91 (m, 1H), 1.87−1.83 (m, 1H), 1.72−1.66 (m, 1H), 1.34 (s,
3H), 1.31 (s, 3H), 1.25 (s, 3H), 1.21 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 199.7, 140.9, 121.6, 74.8, 71.7, 53.3, 41.3, 33.9, 30.6, 27.9,
26.5, 24.6. IR (neat): 2967, 2929, 2866, 1701, 1574. HRMS (ESI-
TOF): m/z calcd for C13H19O2I1 [M+] 334.0424, found 334.0423.
1-(2-Bromo-6-hydroxy-3,3-dimethylcyclohex-1-en-1-yl)-3-
methylbut-2-en-1-one (13). Prepared from alkynone 10 using the
general protocol for the MgI2-promoted cyclization, except MgBr2 was
used, and the reaction was warmed to rt for 24 h. Yield: 41 mg, 52%.
(2S,3R)-5-((tert-Butyldimethylsilyl)oxy)-2,3-dimethyl-2-vinyl-
pentan-1-ol (22). Diol 21 (4.2 g, 26.7 mmol) was diluted in 104 mL
of CH2Cl2 and cooled to 0 °C, and imidazole (4.3 g, 66.7 mmol) was
added. After 20 min, tert-butyldimethylchlorosilane (4.2 g, 26.9 mmol)
was slowly added to the reaction mixture at 0 °C. After 20 min, the
reaction mixture was quenched with 30 mL of saturated NH4Cl
solution. The reaction mixture was then extracted with diethyl ether (3
× 50 mL), washed with H2O and brine, dried over MgSO4, and
concentrated. The resulting residue was purified by flash chromatog-
raphy on silica gel (hexanes/ethyl acetate, 90:10) to give the
monoprotected alcohol (5.7 g, 80%, the major diastereomer is
reported). 1H NMR (400 MHz, CDCl3): δ 5.81 (dd, J = 17.7, 10.9 Hz,
1H), 5.15 (d, J = 10.9 Hz, 1H), 5.03 (d, J = 17.7, 1H), 3.74−3.68 (m,
1H), 3.60−3.46 (m, 2H), 3.42−3.35 (m, 1H), 1.94 (dd, J = 9.4, 3.9
Hz, 1H), 1.77−1.72 (m, 1H), 1.70−1.62 (m, 1H), 1.15−1.04 (m, 1H),
0.90 (s, 12H), 0.83 (d, J = 6.9 Hz, 3H), 0.06 (s, 6H). 13C NMR (100
MHz, CDCl3): δ 144.1, 114.0, 68.8, 62.1, 44.8, 34.1, 33.5, 25.9, 18.3,
15.0, 14.9, −5.3, −5.4. IR (neat): 3577−3130, 2954, 2927, 2882, 2856.
HRMS (ESI-TOF): m/z calcd for C15H33O2Si [M + H]+ 273.2250,
found 273.2253.
1
Eluent: hexanes/ethyl acetate, 80:20. H NMR (400 MHz, C6D6): δ
6.30 (s, 1H), 4.33−4.30 (m, 1H), 2.69 (d, J = 4.1 Hz, 1H), 2.08 (s,
3H), 1.81−1.72 (m, 1H), 1.57−1.49 (m, 2H), 1.47 (s, 3H), 1.26−1.18
(m, 1H), 1.03 (s, 3H), 0.90 (s, 3H). 13C NMR (100 MHz, C6D6): δ
195.5, 156.3, 142.1, 135.8, 124.9, 68.2, 38.3, 34.0, 28.8, 27.6, 27.2, 26.9,
20.8. IR (neat): 3664−3140, 2966, 2935, 2866, 1666, 1608, 1442,
1381, 1238, 1168, 1067, 1041. HRMS (ESI-TOF): m/z calcd for
C13H19BrO2 [M + Na+] 309.0466, found 309.0475.
5-Bromo-2,2,6,6-tetramethyl-6,7,8,8a-tetrahydro-2H-chro-
men-4(3H)-one (14). As described previously,8 compound 14 was
prepared from alkynone 10 using the general protocol for the BF3·
OEt2-promoted cyclization. Yield: 35 mg, 46%. Eluent: hexanes/ethyl
1
acetate, 90:10. H NMR (500 MHz, CDCl3): δ 4.45−4.42 (m, 1H),
2.59 (d, J = 15 Hz, 1H), 2.53 (d, J = 15 Hz, 1H), 2.05−2.03 (m, 1H),
1.85−1.77 (m, 2H), 1.66−1.62 (m, 1H), 1.35 (s, 3H), 1.30 (s, 3H),
1.28 (s, 3H), 1.24 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 198.3,
139.0, 135.3, 74.7, 71.6, 53.9, 40.3, 35.1, 30.8, 30.5, 26.9, 26.3, 24.5. IR
(neat): 2970, 2943, 2866, 1701, 1593. HRMS (ESI-TOF): m/z calcd
for C13H19O2Br1 [M+] 286.0563, found 286.0567.
tert-Butyl(((3R,4S)-4-ethynyl-3,4-dimethylhex-5-en-1-yl)-
oxy)dimethylsilane (23). Alcohol 22 (2.1 g, 7.7 mmol) was
dissolved in 228 mL of CH2Cl2, and Dess−Martin periodinane21
(4.2 g, 10.0 mmol) was added. After 15 min, the reaction mixture was
diluted with 50 mL of CH2Cl2 and quenched with 80 mL of a
saturated NaHCO3 solution and 80 mL of a saturated Na2S2O3
solution. After the solution became clear, the reaction mixture was
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were washed with H2O and brine, dried over MgSO4, filtered over a
short pad of silica gel, and concentrated. The resulting residue was
used in the next step without further purification.
The aldehyde (1.9 g, 1.0 mmol), from above, was stirred with
K2CO3 (1.9 g, 14.0 mmol) in 32 mL of methanol. The Ohira−
Bestmann reagent22 (2.0 g, 10.5 mmol) was added at 0 °C. After 25
min, the reaction mixture was warmed to rt. After 24 h, the mixture
was quenched with 10 mL of NaHCO3 and extracted with hexanes (3
× 50 mL). The combined organic layers were washed with brine, dried
over MgSO4, and concentrated. The reaction mixture was purified by
flash chromatography on silica gel (hexanes/ethyl acetate, 97:3) to
give the alkyne (1.8 g, 95% over two steps, the major diastereomer is
reported) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 5.65 (dd, J =
17.0, 10.2 Hz, 1H), 5.40 (dd, J = 17.0 Hz, 1.5 Hz, 1H), 5.10 (dd, J =
10.2 Hz, 1.5 Hz, 1H), 3.70−3.64 (m, 1H), 3.61−3.54 (m, 1H), 2.26 (s,
1H), 1.89−1.79 (m, 1H), 1.60−1.49 (m, 1H), 1.27 (s, 3H), 1.27−1.14
(m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H). 13C
NMR (100 MHz, CDCl3): δ 142.4, 113.7, 86.9, 71.9, 61.6, 43.1, 38.1,
35.4, 25.9, 25.7, 18.2, 14.4, −5.3, −5.4. IR (neat): 3311, 2954, 2929,
10-Methylundec-9-en-6-yne-2,8-dione (15).8 1H NMR (400
MHz, CDCl3): δ 6.12 (s, 1H), 2.58 (t, J = 8 Hz, 2H), 2.40 (t, J = 8 Hz,
2H), 2.19 (s, 3H), 2.15 (s, 3H), 1.86 (s, 3H), 1.85−1.80 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 207.7, 176.6, 157.8, 125.9, 91.1, 83.7,
41.9, 30.1, 27.8, 21.5, 21.1, 18.3. IR (neat): 2915, 2205, 1712, 1650,
1607.
1-(6-Hydroxy-2-iodo-6-methylcyclohex-1-en-1-yl)-3-methyl-
but-2-en-1-one (16). Prepared from alkynone 15 using the general
protocol for the MgI2-promoted cyclization. Yield 40 mg, 78%. Eluent:
hexanes/ethyl acetate, 90:10. All spectral data for 16 were in
agreement with published data.8 1H NMR (500 MHz, CDCl3): δ
6.30 (s, 1H), 3.42 (bs, 1H), 2.79−2.75 (m, 1H), 2.70−2.63 (m, 1H),
2.26 (s, 3H), 2.01 (s, 3H), 1.92−1.91 (m, 1H), 1.89−1.88 (m, 1H),
1.69−1.62 (m, 2H), 1.32 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
198.1, 158.7, 149.6, 124.3, 100.1, 72.0, 41.5, 36.9, 28.5, 28.1, 21.7, 21.3.
IR (neat): 3645, 3143, 2966, 2931, 2855, 1660, 1650, 1599. HRMS
(ESI-TOF): m/z calcd for C12H17O2INa [M + Na+] 343.0165, found
343.0166.
(3E,7E,11S,12R,14S)-14-Hydroxy-15-iodo-4,8,11,12-
tetramethylbicyclo[9.3.1]pentadeca-1(15),3,7-trien-2-one (17).
Prepared from alkynone 6 using the general protocol for the MgI2-
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2857, 2386. HRMS (ESI-TOF): m/z calcd for C16H30OSi [M+]
266.2066, 266.2061.
of saturated Na2SO3 solution, extracted with diethyl ether (3 × 50
mL). The combined organic layers were washed with brine and a
saturated CuSO4 solution, dried over MgSO4, filtered over Celite, and
concentrated. The resulting residue was purified by flash chromatog-
raphy on silica gel (hexanes/ethyl acetate, 90:10) to give the aldehyde
(101 mg, 66%, the major diastereomer is reported) as a yellow oil.
(Note: Purification of alkynone 20 was rapid, and it was not allowed to
(E)-3-Methyloct-2-en-6-ynal (24).11g (E)-3-Methyloct-2-en-6-
yn-1-ol (1.0 g, 7.2 mmol) was diluted in 66 mL of CH2Cl2, MnO2
(12.6 g, 145.0 mmol) was added, and the mixture was stirred at rt.
After 2 d, the mixture was diluted with CH2Cl2, filtered over Celite,
and concentrated. The resulting residue was purified by flash
chromatography on silica gel (hexane/ethyl acetate, 97:3) to give
1
remain on silica gel for extended periods of time.) H NMR (400
1
the aldehyde (800 mg, 80%) as a yellow oil. H NMR (400 MHz,
MHz, CDCl3): δ 9.71 (s, 1H), 6.15 (s, 1H), 5.67 (dd, J = 17.1, 10.2
Hz, 1H), 5.38 (d, J = 17.1, 1.0 Hz, 1H), 5.15 (d, J = 10.2 Hz, 1H), 2.67
(dd, J = 17.3, 2.9 Hz, 1H), 2.35−2.25 (m, 6H), 2.17 (s, 3H), 1.73 (s,
3H), 1.32 (s, 3H), 1.04 (d, J = 6.7 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 201.5, 176.3, 159.0, 140.8, 126.0, 115.4, 92.4, 87.5, 47.6,
43.2, 40.1, 36.1, 24.8, 19.5, 17.2, 15.5, 3.4 (2 carbons are missing due
to overlap). IR (neat): 2974, 2920, 2854, 2723, 2210, 1774, 1724,
1651, 1604, 1442, 1441, 1381, 1338, 1280, 1222. HRMS (ESI-TOF):
m/z calcd for C19H25O2 [M + H]+ 285.1855, found 285.1865.
(E)-1-((3S,4R,6S)-6-Hydroxy-2-iodo-3,4-dimethyl-3-vinylcy-
clohex-1-en-1-yl)-3-methyloct-2-en-6-yn-1-one (27). Prepared
from alkynone 20 using the general protocol for the MgI2 promoted
cyclization. Yield: 23 mg, 77%. Eluent: hexanes/ethyl acetate, 90:10.
1H NMR (400 MHz, CDCl3): δ 6.24 (s, 1H), 5.51 (dd, J = 17.3, 10.6
Hz, 1H), 5.24 (d, J = 10.7 Hz, 1H), 5.04 (d, J = 17.3 Hz, 1H), 4.64−
4.57 (m, 1H), 2.36 (s, 5H), 2.20 (s, 3H), 2.06−1.98 (m, 1H), 1.89−
1.80 (m, 1H), 1.76 (s, 3H), 1.67−1.55 (m, 1H), 1.14 (s, 3H), 0.96 (d,
J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 196.8, 159.0, 149.3,
145.8, 124.0, 114.9, 114.0, 77.6, 77.1, 70.2, 49.5, 40.4, 35.6, 35.4, 19.6,
18.0, 17.1, 16.6, 3.5. IR (neat): 3657−3126, 2966, 2920, 2874, 1666,
1608, 1446, 1411, 1377, 1320, 1176, 1141, 1060. HRMS (ESI-TOF):
m/z calcd for C19H25IO2 [M+] 412.0899, found 412.0906.
CDCl3): δ 10.02 (d, J = 8.0 Hz, 1H), 5.92 (d, J = 8.0 Hz, 1H), 2.43−
2.32 (m, 4H), 2.19 (s, 3H), 1.76 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 191.1, 161.7, 127.7, 77.0, 76.9, 39.4, 17.3, 16.8, 3.3. IR
(neat): 2919, 2854, 1667, 1633, 1611. HRMS (ESI-TOF): m/z calcd
for C9H12O [M+] 137.0602, found 137.0604.
(3R,4S,E)-1-((tert-Butyldimethylsilyl)oxy)-3,4,9-trimethyl-4-
vinyltetradeca-8-en-5,12-diyn-7-one (25). Alkyne 23 (1.0 g, 3.7
mmol) was diluted in 11 mL of dry tetrahydrofuran, and n-
butyllithium (1.8 M in Hexanes 2.3 mL, 4.1 mmol) was slowly
added at −78 °C. After 30 min, aldehyde 24 (6.13 mg, 4.5 mmol) was
slowly added in 6.6 mL of tetrahydrofuran. After 3 h, the mixture was
quenched with 10 mL of saturated NH4Cl solution and extracted with
diethyl ether (3 × 50 mL). The combined organic layers were washed
with brine, dried over MgSO4, filtered over a short pad of silica gel,
and concentrated. The resulting residue was used in the next step
without further purification.
The alcohol, from above, was diluted in 22 mL of CH2Cl2, MnO2
(4.3 g, 49.7 mmol) was added and the mixture was stirred at rt. After 2
h, the mixture was diluted with CH2Cl2, filtered over Celite, and
concentrated. The resulting residue was purified by flash chromatog-
raphy on silica gel (hexanes/ethyl acetate, 97:3) to give the ketone
(924 mg, 61% over two steps, the major diastereomer is reported) as a
yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.16 (s, 1H), 5.76 (dd, J =
17.1, 10.3 Hz, 1H), 5.36 (dd, J = 17.1, 1.0 Hz, 1H), 5.13 (dd, J = 10.2
Hz, 1.0 Hz, 1H), 3.72−3.62 (m, 1H), 3.62−3.53 (m, 1H), 2.32 (s,
4H), 2.19 (s, 3H), 1.90−1.79 (m, 1H), 1.76 (s, 3H), 1.72−1.60 (m,
1H), 1.32 (s, 3H), 1.28−1.17 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.88
(s, 9H), 0.03 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 176.7, 158.2,
141.2, 126.2, 114.4, 94.6, 86.8, 77.3, 76.7, 61.3, 43.5, 40.1, 38.3, 35.3,
25.8, 25.0, 19.4, 18.2, 17.2, 14.6, 3.3, −5.3, −5.4. IR (neat): 2951,
2927, 2855, 2206, 1654, 1651, 1608, 1384, 1360, 1255, 1220, 1125.
HRMS (ESI-TOF): m/z calcd for C25H40O2Si [M+] 400.2797, found
400.2806.
(E)-1-((3S,4R,6R)-6-Hydroxy-2-iodo-3,4-dimethyl-3-vinylcy-
clohex-1-en-1-yl)-3-methyloct-2-en-6-yn-1-one (28). Cyclohex-
enyl alcohol 27 (30 mg, 0.072 mmol) was stirred with p-nitrobenzoic
acid (60 mg, 0.363 mmol) and PPh3 (95 mg, 0.363 mmol) in 0.72 mL
of dry benzene. Then, diethyl azodicarboxylate (DEAD) (56 μL, 0.363
mmol) was slowly added to the reaction mixture at 0 °C. After 3 h at
rt, the reaction mixture was quenched with 4 mL of saturated
NaHCO3 solution and extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were washed with H2O and brine, dried over
MgSO4, filtered over a short pad of silica gel, and concentrated. The
resulting residue was dissolved in 2.2 mL of methanol, and K2CO3 (19
mg, 0.144 mmol) was added at 0 °C. The reaction mixture was
warmed to rt. After 30 min, the reaction mixture was quenched with 4
mL of saturated NaHCO3 solution and extracted with ethyl acetate (3
× 10 mL). The combined organic layers were washed with H2O and
brine, dried over MgSO4, and concentrated. The resulting residue was
purified by flash chromatography on silica gel (hexanes/ethyl acetate
98:2 to hexanes/ethyl acetate 90:10 to hexanes/ethyl acetate 80:20) to
give the inverted cyclohexenyl alcohol (23 mg, 76% over two steps, the
(3R,4S,E)-1-Hydroxy-3,4,9-trimethyl-4-vinyltetradeca-8-en-
5,12-diyn-7-one (26). In a plastic reaction vessel, ketone 25 (220
mg, 550 mmol) was dissolved in 4.5 mL of tetrahydrofuran and 0.45
mL of pyridine and cooled to 0 °C. Then, HF−pyridine (∼70% HF in
∼30% pyridine, 0.54 mL, 0.594 mmol) was slowly added. After 2 h, the
reaction mixture was diluted in 2 mL of ethyl acetate and quenched
with 10 mL of saturated NaHCO3 solution. The reaction mixture was
extracted with ethyl acetate (3 × 20 mL). The combined organic layers
were washed with a saturated NaHCO3 solution, a saturated CuSO4
solution, brine, dried over MgSO4, and concentrated. The resulting
residue was purified by flash chromatography on silica gel to give the
alcohol (154 mg, 98%, the major diastereomer is reported) as a yellow
1
major isomer is reported). H NMR (400 MHz, CDCl3): δ 6.33 (s,
1H), 5.63 (dd, J = 17.3, 10.6 Hz, 1H), 5.33 (d, J = 10.7 Hz, 1H), 5.12
(d, J = 17.3 Hz, 1H), 4.33 (s, 1H), 2.83−2.67 (m, 1H), 2.42 (s, 3H),
2.25 (s, 3H), 2.08 (d, J = 10.6 Hz, 1H), 1.90−1.69 (m, 6H), 1.10 (s,
3H), 1.01 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 197.4,
159.8, 147.1, 145.6, 123.565, 118.1, 115.0, 77.5, 67.2, 49.7, 40.4, 34.2,
32.2, 19.7, 17.6, 17.0, 15.8, 3.5 (1 carbon is missing due to overlap). IR
(neat): 3720−3098, 2924, 2874, 2854, 1735, 1666, 1604, 1446, 1373,
1238, 1165. HRMS (ESI-TOF): m/z calcd for C19H25IO2 [M+]
412.0899, found 412.0906.
(2S,6S,7R,8aS)-5-Iodo-2,6,7-trimethyl-2-(pent-3-yn-1-yl)-6-
vinyl-6,7,8,8a-tetrahydro-2H-chromen-4(3H)-one (29). Prepared
from cyclohexenyl alcohol 27 using the general protocol for the BF3·
OEt2-promoted cyclization. Yield: 10 mg, 90%. Eluent: hexanes/ethyl
acetate, 95:5. 1H NMR (500 MHz, CDCl3): δ 5.51 (dd, J = 17.3, 10.7
Hz, 1H), 5.29 (d, J = 12.9 Hz, 1H), 5.07 (d, J = 17.3 Hz, 1H), 4.51−
4.46 (m, 1H), 2.60 (d, J = 2.8 Hz, 2H), 2.21−2.14 (m, 2H), 2.02−1.87
(m, 2H), 1.76 (s, 4H), 1.72−1.62 (m, 2H), 1.24 (s, 3H), 1.18 (s, 3H),
0.97 (d, J = 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 198.6,
145.2, 140.9, 119.8, 115.3, 78.3, 76.0, 75.9, 71.6, 52.5, 51.9, 36.4, 34.7,
33.0, 26.7, 18.1, 16.8, 12.8, 3.4. IR (neat): 2974, 2931, 2870, 1747,
1
oil. H NMR (400 MHz, CDCl3): δ 6.21 (s, 1H), 5.72 (dd, J = 17.1,
10.2 Hz, 1H), 5.41 (d, J = 17.1 Hz, 1H), 5.19 (d, J = 10.3 Hz, 1H),
3.81−3.73 (m, 1H), 3.68−3.60 (m, 1H), 2.42−2.35 (m, 4H), 2.24 (s,
3H), 1.99−1.89 (m, 1H), 1.81−1.78 (m, 2H), 1.80 (s, 3H), 1.76−1.69
(m, 1H), 1.37 (s, 3H), 1.06 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 176.7, 158.6, 141.1, 126.1, 114.6, 94.5, 61.0, 43.5, 40.1, 38.3,
35.3, 24.6, 19.5, 17.1, 14.5, 3.3 (3 carbons are missing due to overlap).
IR (neat): 3678−3126, 2974, 2920, 2877, 2206, 1651, 1604, 1438,
1381, 1334, 1280, 1226, 1130. HRMS (ESI-TOF): m/z calcd for
C19H26O2 [M + Na+] 309.1831, found 309.1834.
(3R,4S,E)-3,4,9-Trimethyl-7-oxo-4-vinyltetradeca-8-en-5,12-
diynal (20). Alcohol 26 (154 mg, 0.538 mmol) was stirred with 4-
methylmorpholine N-oxide (94 mg, 0.807 mmol) and 4 Å molecular
sieves in 5.1 mL of dry CH2Cl2 at rt. After 20 min, tetra-n-
propylammonium perruthenate (10 mg, 0.027 mmol) was added, and
the mixture was stirred for 2 h. The reaction was quenched with 10 mL
9550
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The Journal of Organic Chemistry
Featured Article
1701, 1582, 1449, 1379, 1327, 1230, 1165. HRMS (ESI-TOF): m/z
calcd for C19H25IO2 [M+] 412.0899, found 412.0906.
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Oxadecalin (1). Cyclohexenyl alcohol 3 (20 mg, 0.048 mmol) was
diluted in 0.48 mL of dry CH2Cl2. AuCl3 (1.4 mg, 0.004 mmol) was
then added at 0 °C, and the mixture was warmed to rt. After
completion of the reaction by TLC, the reaction mixture was purified
by flash chromatography on silica gel (hexane/ethyl acetate, 99:1) to
afford the oxadecalin (10 mg, 50%) as a pale yellow oil. All spectral
data for 1 were in agreement with published data.10 1H NMR (400
MHz, CDCl3): δ 5.51−5.44 (m, 1H), 4.16−4.11 (m, 1H), 3.06−2.94
(m, 1H), 2.78 (d, J = 17.1 Hz, 1H), 2.56 (d, J = 17.1 Hz, 1H), 2.47−
2.32 (m, 2H), 2.08−1.95 (m, 3H), 1.87−1.76 (m, 1H), 1.75−1.41 (m,
4H), 1.66 (s, 3H), 1.29 (s, 3H), 1.06 (d, J = 7.0 Hz, 3H), 0.94 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 197.1, 143.5, 136.9, 130.5, 130.0,
76.1, 68.7, 48.7, 47.1, 41.6, 35.7, 35.0, 31.8, 29.7, 29.6, 26.1, 23.6, 23.5,
17.3. IR (neat): 2966, 2924, 2854, 1693, 1570, 1450, 1373, 1292, 1207,
1140, 1053. HRMS (ESI-TOF): m/z calcd for C19H27IO2 [M+]
415.1134, found 415.1137. [α]20D: +200.4 (c 0.15, CHCl3).
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Tricycle 31. As described previously,10 compound 3 (20 mg, 0.048
mmol) was dissolved in 0.5 mL of toluene at rt. Then, 2,6-lutidine
(0.11 mL, 0.48 mmol) and tert-butyldimethylsilyl trifluoromethanesul-
fonate (TBSOTf) (0.05 mL, 0.48 mmol) were rapidly added to the
reaction mixture. After 10 min, the reaction mixture was diluted in 2
mL of ethyl acetate, quenched with 0.5 mL of saturated NH4Cl
solution, and extracted with ethyl acetate (3 × 10 mL). The combined
organic layers were washed with H2O (1 × 10 mL) and brine (1 × 10
mL), dried of MgSO4, and concentrated. The resulting residue was
purified by flash chromatography on silica gel (hexanes/ethyl acetate
98:2) to give the tricycle (15 mg, 54%) as a yellow oil. 1H NMR (400
MHz, CDCl3): δ 5.41 (d, J = 8.5 Hz, 1H), 4.56 (s, 1H), 3.86 (t, J = 2.8
Hz, 1H), 2.97−2.83 (m, 1H), 2.36−2.18 (m, 3H), 2.01−1.86 (m, 3H),
1.75 (s, 3H), 1.67−1.157 (m, 4H), 1.23 (s, 3H), 1.01 (d, J = 7.1 Hz,
3H), 0.99 (s, 9H), 0.89 (s, 3H), 0.22 (s, 3H), 0.19 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 150.2, 133.5, 131.3, 129.0, 120.4, 112.2, 77.9,
70.6, 46.2, 41.9, 35.8, 35.5, 32.3, 27.8, 26.4, 26.3, 24.8, 22.5, 19.5, 18.7,
17.5, −4.1, −4.3. IR (neat): 2958, 2928, 1635, 1462, 1323, 1253, 1200,
1085. HRMS (ESI-TOF): m/z calcd for C25H42IO2Si [M + H]+
529.1999, found 529.1990. [α]20D: +21.3 (c 0.37, CHCl3).
́
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ASSOCIATED CONTENT
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■
S
* Supporting Information
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Spectra (1H and 13C) of all new compounds, DFT computa-
tional details, and X-ray crystallographic data for 9a and 9b.
This material is available free of charge via the Internet at
http://pubs.acs.org/.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: frontier@chem.rochester.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institute of Health (NIGMS R01
GM079364) for funding this work. We are also grateful to Dr.
Alice Bergmann (University of Buffalo) and Dr. Furong Sun
(University of Illinois, Urbana−Champaign) for carrying out
high-resolution mass spectroscopy and to Dr. William
Brennessel (University of Rochester) for solving structures by
X-ray crystallography. We thank Dr. Daniel P. Canterbury
(University of Rochester) for helpful discussions. We used the
computing facility of the CRIHAN (project 2006-013). Photo
of the Chionoecetes opilio crab on the cover courtesy of the
Alaska Fisheries Science Center, NOAA Fisheries.
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(14) See the Supporting Information.
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The Journal of Organic Chemistry
Featured Article
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(33) [D+MgI+] is the only intermediate with a structure closely
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carbon and the central allene carbon is 1.7 Å. However, dissociation of
the metallic fragment directly leads to the cyclized product E.
(34) In light of these findings, a concerted pathway must also be
considered as a possible mechanism for the cyclization of type I
alkynones into type IV cyclohexenyl alcohols (Scheme 1). By analogy,
this cascade could be initiated by activation of the aldehyde with Lewis
acid, which would suffer attack by the electron-deficient alkynone and
intermolecular trapping with iodide. Studies are underway to assess the
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mixture of diastereomers.
(24) Cyclohexenyl alcohols 27 and 28 were easily separated via flash
chromatography, or alternatively, 28 could be obtained in 76% yield
from cyclohexenyl alcohol 27 using standard Mitsunobu conditions.
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for dichloromethane and THF were carried out using the PCM
method (UFF radii). Only the solvent corrected free energies are
presented (kcal/mol).
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(32) See the Supporting Information for the geometries.
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