Asymmetric Total Synthesis of the Indole Diterpene Alkaloid Paspaline

Article abstract of DOI:10.1021/acs.joc.5b01844

An enantioselective synthesis of the indole diterpenoid natural product paspaline is disclosed. Critical to this approach was the implementation of stereoselective desymmetrization reactions to assemble key stereocenters of the molecule. The design and execution of these tactics are described in detail, and a thorough analysis of observed outcomes is presented, ultimately providing the title compound in high stereopurity. This synthesis provides a novel template for preparing key stereocenters in this family of molecules, and the reactions developed en route to paspaline present a series of new synthetic disconnections in preparing steroidal natural products.

Full text of DOI:10.1021/acs.joc.5b01844

Article
pubs.acs.org/joc
Asymmetric Total Synthesis of the Indole Diterpene Alkaloid
Paspaline
Robert J. Sharpe and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: An enantioselective synthesis of the indole
diterpenoid natural product paspaline is disclosed. Critical to
this approach was the implementation of stereoselective
desymmetrization reactions to assemble key stereocenters of
the molecule. The design and execution of these tactics are
described in detail, and a thorough analysis of observed
outcomes is presented, ultimately providing the title
compound in high stereopurity. This synthesis provides a
novel template for preparing key stereocenters in this family of
molecules, and the reactions developed en route to paspaline present a series of new synthetic disconnections in preparing
steroidal natural products.
derivatives have demonstrated marked activity as Maxi-K
channel antagonists and, as a result, are under examination as
treatments for Alzheimer’s disease and other neurological
disorders.9 Paxilline is currently under study for its properties as
a BK channel antagonist toward the suppression of seizures in
postnatal mammals.10 From a standpoint of structure−activity,
prior work by Cole has underscored the significance of the axial
tert-hydroxyl functionality (C4b, paspaline numbering) as an
important source of activity for these structures, evidenced by
the lack of tremorgenicity demonstrated by paspaline and
paspalicine.11
INTRODUCTION
■
Production of novel metabolites by the ergot fungus has been
well-documented.1 Most notably, those produced by Claviceps
purpurea have long been implicated in the contamination of
various grains.2 Claviceps paspali, another species in this genus,
has been linked to “paspalum stagger” poisoning in livestock,3
and it was from this fungus that Arigoni and co-workers isolated
paspaline (1, Figure 1) and paspalicine (4), the first of a now
The absolute structure of 1 was confirmed in 1980 by
Springer and Clardy on the basis of X-ray diffraction studies.11a
Paspaline and its related compounds are characterized by their
unique indole and tetrahydropyran (or derivatives thereof) ring
fusions. Furthermore, grafted onto the D/E decalin core, three
all-carbon quaternary atoms are encountered (C4a, C12b,
C12c). These salient features necessitate careful planning for
endeavors in total synthesis. These challenges were first
addressed by the Smith laboratory,12 whose body of work in
this area has defined the state of the art for the synthesis of
paspaline and its related structures. Subsequent partial13 and
total14 synthetic studies of these molecules have since been
disclosed, building on these advances. As an extension to
previous work in our laboratory in developing total synthesis
platforms for complex molecular frameworks,15 we sought to
develop an expedient synthesis of 1, particularly of the key C4a,
C12b, and C12c stereocenters, which could serve as a template
for assembly of the remaining structures in this family. Our
work toward this goal culminated in a highly stereocontrolled
total synthesis of paspaline.16 Herein, we disclose the entirety of
Figure 1. Paspaline and related indole diterpenoid natural products.
extensive family of indole diterpene alkaloid natural products.4
A diverse range of related structures have since been reported
including paspaline B (2),5 paspalinine (3),6 JBIR-03 (5),7 and
paxilline (6).8
The varied biological profiles of these compounds have
rendered them particularly attractive to the chemical industry.
The recently discovered JBIR-03 has displayed significant
inhibition of Valsa ceratosperma (MIC = 128 μg/mL) while
showing no cytotoxic effects to the human fibrosarcoma cell
line HT-1080 at 100 μM.7 Moreover, paspalinine and its
Received: August 10, 2015
© XXXX American Chemical Society
A
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our efforts, ultimately leading to the conception and
implementation of two critical stereoselective desymmetrization
reactions for facile target assembly. These studies have laid the
groundwork for future investigations in this family of natural
products.
Scheme 2. Synthesis of Tetrahydropyranyl F Ring and C4a
Stereocenter
a
Our preliminary synthetic plan for 1 began with translation
to hydroxyalkene 7 (Scheme 1). The decalin functionality (D
Scheme 1. Preliminary Synthesis Plan for Paspaline
a
Reagents and conditions: (a) TsCl, NEt3, DMAP (10 mol %),
CH2Cl2, 0 °C; (b) N-methylmorpholine, ethyl propiolate, CH2Cl2, rt;
(c) NaI, acetone, rt; (d) CH2(CO2Me)2, Cs2CO3, DMF, rt; (e)
DIBAL-H, THF, 0 °C; (f) (i) I2, PPh3, imidazole, CH2Cl2, 0 °C to rt;
(ii) (isopropenyl)2CuLi, Et2O, −78 to 0 °C; (g) KOH, THF/MeOH
(1.75:1), rt; (h) MeLi, THF, −78 °C; (i) (i) EtLi, THF, −78 °C; (ii)
LDA, THF, −78 °C, then PhSeBr; (iii) H2O2(aq), CH2Cl2, 0 °C.
and E rings) in 7 would be constructed via a transannular
ketone addition/Friedel−Crafts alkylation cascade arising from
cyclodecenone 8,17 establishing the vicinal C12b and C12c
quaternary centers in a single operation. The tetrasubstituted
(E)-alkene in 8 would be prepared via intramolecular coupling
of the corresponding diene 9 or dicarbonyl 10 via a
metathesis18 or McMurry process.19 Synthesis of this ketone
would rely on the union of fragments 11 and 12 to assemble
the C6a, C6, and C5 carbon−carbon bonds. Access to the
tetrahydropyran 12 was envisioned via an alkylation/Michael
addition cascade between dimethylmalonate and 13 inspired by
methodology developed by Gharpure.20
With the pyran subunit in place, the next challenge became
introduction of the indole fragment bearing the atoms
necessary for cyclodecenone synthesis (Scheme 3); however,
we found this union to be significantly more challenging than
first expected. In the first iteration, Michael addition of the
enolate of 20 to the indole-derived enone 2223 using a variety
of bases (LDA, LHMDS, NaOMe) showed no productive
reactivity, presumably due to low reactivity of enone 22.
Mukaiyama Michael addition to 22 using the enolsilane derived
from 20 resulted in rapid desilylation prior to engaging 22
under all conditions examined. Methyl vinyl ketone also failed
to react with 20 under these conditions. An alternative strategy
explored reversal of the nucleophile/electrophile identities via
the reaction of enolsilane 24 and pyranyl enone 21. However,
exposure of these compounds to Lewis acidic conditions (BF3·
OEt2, TiCl4, Cu(OTf)2, etc.) resulted only in desilylation of 24
and decomposition of enone 21. Finally, a Lewis acid promoted
ene reaction was examined as a method for the union of enone
21 and nucleophilic alkene 25; unfortunately, the inherent
instability of enone 21 remained problematic in this approach.
These failed efforts led us to conclude that direct
intermolecular coupling methodologies of these fragments to
1 from the C4a functionality were prohibitively challenging,
and as a result, this approach was abandoned.
RESULTS AND DISCUSSION
■
In accordance with the above strategy, initial focus was placed
on synthesizing the tetrahydropyranyl F ring and C2/C14a
stereodiad in 1 (Scheme 2). In a forward sense, tosylation of
the previously reported diol 14 followed by oxy-Michael
addition and iodination furnished the requisite iodoalkene 13 in
62% yield over three steps,21 setting the stage for the proposed
annulation. Thus, treatment of 13 with CH2(CO2Me)2 and
Cs2CO3 in DMF provided exclusively the desired 2,6-cis-pyran
in 99% yield and >20:1 dr. Selective reduction of the ethyl ester
in 17 proceeded smoothly to give alcohol 18 in 72% yield, and
subsequent iodination and alkylation installed the requisite
alkene in 12. With this compound in hand, we turned our
attention to desymmetrization of the C4a gem-diester in 12 via
nucleophilic addition. Experiments with this compound
revealed a strong diastereotopic group bias for the equatorial
ester, giving the desired relative stereochemistry at C4a.22 To
enable maximum flexibility in the downstream strategy, the
corresponding carboxylic acid 19, methyl ketone 20, and enone
21 were prepared.
In an effort to circumvent the issues associated with the
above strategy, we postulated that an intramolecular approach
to the critical bond disconnection might be more facile
(Scheme 4). This process would be enabled via appendage of
the appropriate functionality to the iodide 27 (which had been
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the interest of validating the proposed downstream reactivity.
Operating first on small scale (15 mg), treatment of diketone
29 with NaCl in DMSO afforded a ∼1:1 ratio of the Krapcho
adduct 31 and the cyclization product 32 as a single
diastereomer. However, a single-crystal X-ray diffraction study
revealed 32 to be the undesired cis-decalinone product (e.g.,
epimeric at C12c). Fortunately, formation of 32 was suppressed
when the reaction was further scaled (70 mg), giving exclusively
the Krapcho adduct 31 in 43% yield. In hopes that a stepwise
Krapcho/aldol process might proceed with selectivity orthog-
onal to 32, we began screening conditions for the conversion of
31 to 33. Toward this aim, treatment of 31 with Brønsted or
Lewis acidic conditions gave either no reaction or starting
material decomposition upon heating. Alternatively, exposure
to basic conditions resulted in no reaction or retro-Dieckmann
decomposition of the dione functionality.
Scheme 3. Unsuccessful Approaches to C5−C6a Bond
Construction
Having arrived at another critical impasse, we began to
question the viability of this route in providing access to 1.
While the alkylation/Michael cascade sequence (13 → 17)
provided expedient access to the F ring tetrahydropyran
stereochemistry and desymmetrization of the C4a stereocenter
proceeded as planned, further elaboration of this material to 1
seemed an unlikely venture. At this critical stage in our studies,
we began to examine alternative points of initiation for our
synthesis (Scheme 5).
Scheme 5. Revised Approach to 1 via Enantioselective
Desymmetrization
Scheme 4. Decarboxylative Annulation Approach to
Paspaline D,E Rings
a
Guided by our previous work in developing symmetry-
breaking processes to enable rapid construction of complex
natural products,15g,h we surmised that a synthesis beginning
from desymmetrization of a paspaline E ring precursor might
circumvent the problems associated with our initial strategy. It
is important to note at this juncture that Smith’s synthesis of 1
also commences via a symmetry-breaking process;12a namely,
the Wieland−Miescher ketone synthesis (28 → 34) assembles
the D−E ring fusion of 1 concomitant with the C12c
quaternary stereocenter. While this reaction is a classic “single
stereocenter” desymmetrization, we envisioned an alternative E
ring desymmetrization arising from stereoselective monore-
duction of functionalized diketone 35. Reduction of this
compound would establish the stereochemical identity of C4a
and C14a in 36 in a single operation while supplying the
needed functional handles for tetrahydropyran assembly and
synthesis completion. Armed with this new hypothesis, we
refocused our efforts in the synthesis of 1 via this approach.
a
Reagents and conditions: (a) Cs2CO3, DMF, 65 °C; (b) NaCl,
DMSO, 150 °C.
synthesized previously in the described route to alkene 12). We
selected 2-methyl-1,3-cyclohexanedione 28 as this nucleophile,
anticipating that Krapcho decarboxylation of the corresponding
alkylation product 29 might initiate an intramolecular aldol
addition process to assemble the D,E ring decalin moiety as
well as the C12c and C4b stereocenters (33). In practice,
alkylation of iodide 27 with 28 gave a ∼1:2 mixture of diketone
29 and the undesired O-alkylation product 30 in 34 and 56%
yields, respectively.23 While this issue of regiochemistry
rendered material throughput challenging, we carried on in
C
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a
Scheme 6. Desymmetrization Approach to 1: E,F Ring Synthesis
a
Reagents and conditions: (a) NaH, DMF, 0 °C, then 37, rt; (b) H2NNMe2, TsOH (3.0 mol %), C6H6, 100 °C; (c) (i) KH, THF, 0 °C, then 37,
−78 °C to rt; (ii) Cu(OAc)2, THF/H2O (1:1), rt; (d) NaBH4, MeOH, 0 °C; (e) YSC-2, H2O/DMSO (10:1), 30 °C; (f) m-CPBA, CH2Cl2, 0 °C;
(g) PPTS (20 mol %), CH2Cl2, rt; (h) TsHNNH2, C7H8, 70 °C; (i) m-CPBA, CH2Cl2, 0 °C, then PPTS.
The first challenge in our revised synthesis plan was
preparation of the desymmetrization precursor 35 via alkylation
of dione 28 or its derivatives (Scheme 6). In the event,
deprotonation of 28 with NaH followed by addition of iodide
37 provided the desired cycloalkanone 35 in 7% yield along
with 26% of the undesired O-alkylation product 38. This result
was not entirely unexpected: challenges associated with
regioselective C-alkylation of cyclic α-dicarbonyls have been
well-documented.24 In hopes of enhancing C-nucleophilicity of
this structure, we prepared hydrazone 39.24 Screening of
conditions revealed that enolization with KH followed by
addition of iodide 37 provided exclusively the corresponding C-
alkylation adduct which, following hydrazone deprotection,
afforded functionalized diketone 35 in 76% yield over two
steps. Of particular importance is the scalability of this process:
diketone 35 can be prepared in >10 g scale in a single batch.
This reaction represents a useful advance over prior art in
preparing this compound,25 and the scope of this method is
currently under study.
greater concern was that treatment of this diastereomeric
mixture 41 with conditions requisite for ring closure (PPTS)
gave an inseparable 5:1 mixture of products with the desired
tetrahydropyran 42 as the minor product. The major material
was identified as alcohol 43, the result of epoxide trapping by
the enol tautomer of the ketone in 41. To circumvent this issue,
we envisaged that masking the ketone in 36 would preclude this
undesired mode of ring closure. Since it translated well to our
downstream strategy for D ring construction, 36 was converted
to the corresponding tosyl hydrazone 44 in 97% yield. To our
surprise, the reaction of this compound with m-CPBA followed
by PPTS initiated an epoxidation/cyclization cascade, providing
the desired tetrahydropyran 45 directly in 77% yield and >20:1
dr. This reaction gave expedient preparation of the paspaline F
ring in a single operation.
We were unaware of any previously reported directing effects
of tosyl hydrazones on analogous systems (Scheme 7). To
provide understanding to this difference in reactivity between
With the critical desymmetrization precursor in our
possession, we began investigating selective monoreduction of
35 to access the C4a−C14a stereodiad. Treatment of 35 with
NaBH4 provided the racemic monoreduction product 40 with
excellent yield and diastereoselectivity (19:1), albeit the
opposite diastereomer to that desired. It is reasonable to
expect formation of this diastereomer under strictly substrate-
controlled conditions, although we were surprised by the
magnitude of selectivity for this diastereomer. We were
encouraged, however, by the recent reports of Nakada26 and
Node27 which demonstrated access to the diastereomer needed
for our synthesis on similar cyclic diketones using biocatalytic
reducing conditions. In experimenting with our compound, we
were pleased to find that monoreduction of 35 with yeast from
Saccharomyces cerevisiae type 2 (YSC-2) proceeded with
virtually complete reagent control, giving the desired alcohol
diastereomer 36 in 65% yield, 10:1 dr, and >99:1 er. The
success of this transformation provided encouragement to the
viability of our revised synthesis plan and set the stage for
further manipulation to 1.
Scheme 7. Mechanistic Investigations in the Conversion of
44 to 45
a
From hydroxy olefin 36, we anticipated assembly of the
tetrahydropyranyl F ring via an oxidative cyclization sequence.
With this goal in mind, treating the alkene in 36 with m-CPBA
provided the corresponding epoxide 41 in 93% yield and poor
diastereoselectivity (2:1). While any number of asymmetric
epoxidation methods could likely enhance this selectivity, of
a
Reagents and conditions: (a) H2 (1 atm), Pd/C (1.50 mass equiv),
MeOH, rt; (b) m-CPBA, CH2Cl2, 0 °C.
D
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hydroxyketone 36 and hydrazone 44, we carried out the
following experiments. First, the alkene in hydrazone 44 was
removed via hydrogenation to give alcohol 46. Treatment of 46
with the exact reaction conditions used in the epoxidation of 44
resulted in quantitative starting material recovery. This datum
excluded the possibility of intramolecular oxygen delivery in the
reaction via a transient oxazidirine such as 47. Concluding that
the reactivity may be a consequence of underlying conforma-
tional differences between 36 and 44, we calculated both
structures using density functional theory (DFT) at the level of
B3LYP/6-311G(d).28 Interestingly, the optimized structures of
36 and 44 showed a significant difference in the dihedral angle
about the C14a C−OH bond and the C4a C−CH2R bond (69°
for 36 and 85° for 44). On the basis of these facts, we
hypothesize that the observed selectivity is a consequence of
the hydrazone in 44 imposing a favorable reactive conformation
(48) on the cyclohexane such that the C14a hydroxyl is in close
proximity to the alkene during the oxidation. It follows that this
would enhance transfer of the substrate’s chiral information to
C2 during the oxidation, giving the observed pyran 45
following ring closure. To the best of our knowledge, this
reaction is the first example of an alkene epoxidation
stereoselectivity being influenced by the presence of a tosyl
hydrazone.29
Scheme 8. Synthesis of Enone 53 and Attempts at D Ring
Synthesis
a
With assembly of the E and F rings complete, attention was
directed to construction of the sterically congested D ring and
C12c stereocenter (Scheme 8). We believed that the tosyl
hydrazone in 45 would be engaged via the Shapiro reaction to
produce a transient vinyllithium which, upon trapping with the
appropriate electrophile, would provide the functionality
required to meet these synthetic challenges.30
Thus, TBS protection of the tert-alcohol in 45 proceeded to
give silyl ether 49 in 77% yield. Shapiro reaction of 49 followed
by DMF trapping furnished unsaturated aldehyde 50 in 62%
yield which, upon olefination, gave diene 51 poised for a Diels−
Alder cycloaddition. Nitroethylene proved to be an effective
dienophile in this reaction, giving the annulation product 52 in
94% yield and with complete regioselectivity under thermal
conditions. Subsequent Nef reaction and alkene isomerization
afforded the ketone 53, from which we envisioned manipu-
lation of the alkene would complete D ring assembly to give 58.
Accordingly, Birch reduction of 53 followed by electrophilic
trapping with MeI furnished decalinone 54 in 67% yield and
high stereoselectivity (>20:1). Unfortunately, this compound
was identified as the undesired cis-decalinone (bearing the
desired C4b stereochemistry and undesired C12c stereo-
chemistry) via X-ray diffraction analysis of a derivative.31
After a screen of reducing metals, solvents, and addition
methods showed no promise for over-riding this selectivity, we
began exploring auxiliary methods for stereoselective introduc-
tion of the C12c methyl group. In the first iteration, Birch
reduction of 53 followed by protic quenching and epimeriza-
tion with DBU gave the trans-decalinone 55 as a single
diastereomer. However, all attempts at thermodynamic
methylation of this compound proved fruitless, giving either
polymethylated products or starting material decomposition.
We next examined whether the C12c methyl group could be
introduced stereospecifically via an epoxidation/semipinacol
reaction sequence. While epoxidation of 53 was achieved upon
treatment with p-NPBA32 to give the desired oxirane 56 as a
single diastereomer in 46% yield, the subsequent ketone
methylation requisite for rearrangement consistently gave
starting material recovery or decomposition under more forcing
a
Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, −50 °C;
(b) n-BuLi, THF, −50 °C to rt, then DMF; (c) Ph3PCH2, THF, 0
°C; (d) nitroethylene, CH2Cl2, 65 °C; (e) (i) KOH, MeOH, rt, then
MsOH, 0 °C to rt; (ii) DBU, CH2Cl2, rt.
conditions. In a final case, the ketone in 53 was reduced upon
treatment with LiAl(OtBu)3H to give alcohol 57 in 95% yield
and 10:1 dr. From this compound, we pursued radical delivery
of the C12c methyl group via tethering from the secondary
hydroxyl.33 However, this approach also proved unsuccessful, as
the alkene in 57 failed to engage all radical precursors bound to
the alcohol.
Collectively, these reactions indicated that the inherent bias
of enone 53 for the α-face of the D−E ring fusion (presumably
influenced by the C4a angular methyl group) would preclude
all attempts at late-stage introduction of the C12c methyl
group. At this key juncture in our studies, we determined that if
D ring assembly was preceded by introduction of this methyl
group, then the subsequent annulation step might also proceed
with α-face selectivity to give the requisite syn-diaxial methyl
group relationship (Scheme 9). Thus, methylation of
hydrazone 49 upon treatment with n-BuLi and MeI proceeded
smoothly to give the monomethylated product 59 in excellent
yield. In accordance with our Diels−Alder strategy, Shapiro
E
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allyltriphenylphosphonium bromide gave the simplified triene
63 in 36% yield, and irradiation of 63 (Hg vapor lamp) gave
complete conversion to a single product after 1 h.
Unfortunately, this material was identified as the sigmatropic
rearrangement product 65 and not the desired cyclization
product 64. Suspecting that this rearrangement might
predominate using any analogue of this triene, we abandoned
this pathway in favor of alternative cyclization modes. Toward
these aims, substrates 66−68 were prepared via modification of
the electrophilic trap (and subsequent product manipulation)
in the Shapiro reaction and examined for their viability in D
ring synthesis. Electron-rich Diels−Alder diene 66 and Nazarov
substrate 67 failed to participate in any productive reactivity,
either giving no reaction or decomposing to complex mixtures.
Iodide 68 was synthesized with the goal of completing D ring
synthesis via cross-coupling; however, this approach also
proved fruitless.
Scheme 9. Strategies Examined toward D Ring Synthesis via
Methyl-Group-First Approach
a
Our options diminishing, we prepared primary alcohol 69 via
trapping the Shapiro intermediate of 59 with (HCHO)n (Table
1). We surmised that the appropriately selected ester of 69
Table 1. Ireland−Claisen Screenings for D Ring Assembly
a
Reagents and conditions: (a) n-BuLi, THF, −50 °C, then MeI; (b) n-
BuLi, THF, −50 °C to rt, then DMF; (c) Ph3PCH2, THF, 0 °C; (d)
Ph3PCHCHCH2, THF, 0 °C to rt; (e) hν, hexanes, rt.
reaction of 59 followed by trapping with DMF afforded
aldehyde 60 in 61% yield, giving the diene 61 upon olefination.
While we at first anticipated that the [4 + 2] annulation of 61
with nitroethylene would proceed in a manner similar to the
previously described desmethyl cycloaddition (51 → 52), we
quickly found the steric impact of the newly introduced methyl
group to be much greater than expected. In our initial trials, the
reaction of 61 with nitroethylene failed to produce cycloadduct
62 under both thermal and Lewis acidic conditions. An
extensive screen of Diels−Alder dienophiles and promotors
ensued, showing no further promise for D ring construction via
this method. We then turned our attention to alternative
annulation methods, making use of the flexibility of electrophile
choice in the Shapiro reaction step and its subsequent
intermediates. To bypass an intermolecular cycloaddition, we
pursued an electrocyclization pathway to form the requisite D
ring. Olefination of aldehyde 60 with the ylide derived from
a
b
Isolated yields. Conditions: Ac2O, NEt3, DMAP (10 mol %),
c
1
CH2Cl2, rt. Determined by H NMR analysis of crude mixtures.
would participate in an Ireland−Claisen rearrangement,34
influenced by the C4a stereocenter, to install the C12c (and
potentially C12b) quaternary methyl group(s) while providing
functional handles for D ring construction. We then began
screening esters of 69 compatible with our synthetic manifold.
In the simplest cases, acetate 70a (entry 1) and propionate 70b
(entry 2) did not undergo rearrangement as the corresponding
silyl ketene acetals were labile at elevated reaction temperatures.
Isobutyrate 70c (entry 3) performed exceptionally to give 71a
F
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a
Scheme 10. D Ring Synthesis Completion and Symmetry-Breaking C−H Activation of C12b Stereocenter
a
Reagents and conditions: (a) n-BuLi, THF, −50 °C, then MeI; n-BuLi, −50 °C to rt, then (HCHO)n; (b) isobutyric acid, DCC, DMAP (10 mol
%), CH2Cl2, rt; (c) LDA, THF, −78 °C, then TMSCl, −78 to 75 °C; (d) (i) TMSCHN2, MeOH/C7H8 (2:1), rt; (ii) MeLi, Et2O, 0 °C to rt; (e)
BH3·THF, THF, 50 °C, then H2O2, NaOH, 0 °C to rt; (f) (COCl)2, DMSO, CH2Cl2, −78 °C, then DIPEA, −78 to 0 °C; (g) KOH(aq), THF/
MeOH (1:1), 0 °C to rt; (h) (i) H2 (1 atm), Pd/C (1.50 mass equiv), EtOAc, rt; (ii) NH2OBn·HCl, NaOAc, MeOH/H2O (5:1), 85 °C; (i)
Pd(OAc)2 (15 mol %), PhI(OAc)2, AcOH/Ac2O (1:1), 100 °C.
(80% yield, 6:1 dr, 4 g scale), although a downstream C−H
activation at C12b would be required for this product to be a
viable intermediate toward 1. With the reaction’s viability
demonstrated, functionalized esters 70d−h were probed.
Indole ester 70d or protected analogues thereof failed to
rearrange, presumably due to a steric impact of the indole on
silyl ketene acetal generation. Esters 70e−g (entries 5−7)
likewise suffered from the same issue. We were excited to find
promising reactivity, however, in the case of silyl-functionalized
isobutyrate 70h (entry 8, 52% yield, 6.6:1.1:1 dr). The
stereochemistry at C12c of this compound was assigned by
analogy to rearrangement product 71a (vide infra). The
identity of the C12b stereocenter could not be identified.
The next portion of our strategy involved conversion of the
rearrangement product to its methyl ketone for subsequent ring
closure (Scheme 10). After first reoptimizing the Shapiro
reaction step to facilitate one-pot conversion of desmethylhy-
drazone 49 to alcohol 69, we moved forward in this approach.
Unfortunately, conversion of silyl-functionalized isobutyrate
product 71b to its derived methyl ketone proved unfeasible due
to a significant steric impact at the α-position. In contrast, early
returns on the simpler isobutyrate rearrangement product 71a
showed that the methyl ketone synthesis worked well, and as a
result, we moved forward in our synthesis with this compound.
Thus, esterification of acid 71a with TMSCHN2 followed by
treatment with MeLi furnished ketone 72 in 84% yield. The
C4b stereocenter was established via hydroboration/oxidation
of 72 to give diol 73 in 74% yield and >20:1 dr. After some
experimentation, bisoxidation of 73 was accomplished via
Swern conditions to give ketoaldehyde 74 poised for
intramolecular condensation. Exposure of 74 to basic
conditions cleanly afforded enone 75 in 74% yield over two
steps, thereby completing D ring synthesis. The resultant
alkene was removed via hydrogenation to give the correspond-
ing ketone, which was converted to oxime 76 in 82% yield.
With D ring synthesis concluded, desymmetrization of the
nonstereogenic C12b dimethyl group in 76 became compulsory
for synthesis completion. The success of this transformation
would require a selective functionalization of the equatorial
methyl group at C12b over its axial counterpart to provide the
diastereomer needed; we were aware that the lowest energy
conformer of 76 places the oxime C−N double bond in the
same plane as the equatorial methyl group and anticipated that
the appropriate catalytic system would operate on 76 using the
oxime as a directing group. We selected the catalytic C−H
oxidation reaction developed by Sanford and co-workers,35
which had demonstrated applicability to substituted cyclo-
hexanone oximes. In the event, treatment of oxime 76 with
Sanford’s conditions provided acetate 78 in 79% yield (via 77)
with complete diastereoselection, establishing the stereo-
chemistry of the final quaternary center in 1 and providing
the necessary functional handle for synthesis completion.
The yield and selectivity of this transformation are
noteworthy; examples for the successful execution of this
reaction as a platform for desymmetrization of achiral
quaternary centers are scarce in recent literature (Scheme
11). In 2008, Yu and co-workers reported a stoichiometric
desymmetrization of dimethyl oxime 79, proceeding in 72%
yield and complete selectivity (assisted by the conformational
Scheme 11. Recent Examples of Substrate-Directed sp3 C−H
Oxidation/Desymmetrization
G
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rigidity of 79) en route to the synthesis of lobatoside E.36 Six
years later, the Sorenson laboratory described the first
symmetry-breaking implementation of Sanford’s catalytic
reaction in their synthesis of jiadifenolide.37 In this reaction,
treating oxime 81 with Pd(OAc)2 and PhI(OAc)2 afforded the
desired acetate 82 in 22% yield and 1:1 dr. The poor selectivity
in this transformation may be attributed to the oxime in 81
bisecting the two methyl groups. In our case, exposure of oxime
76 to Sanford’s conditions provided the desired acetate
diastereomer 78 in 79% yield and >20:1 dr (presumably
aided by the coplanar oxime and equatorial methyl group).
That this reaction (76 → 78) provided the desired product
diastereomer in such high yield illustrates the viability of this
and related transformations in the late-stage pursuit of
challenging quaternary stereocenters, particularly scenarios in
which inherent structural biases may lend a degree of
stereochemical predictability.
that simply subjecting 85 to acidic conditions (TFA) resulted in
direct elimination of the tert-hydroxyl to give nonconjugated
enone 86 in 71% yield. This set the stage for hydrogenation of
the resultant alkene to install the final stereocenter found in 1.
In the event, catalytic hydrogenation of alkene 86 with Pd/C
1
provided ketone 87 in 87% yield and >20:1 dr. However, H
NMR spectral data of this compound were not consistent with
that of the desired compound previously synthesized by Smith
and co-workers,12d leading to the conclusion that this
hydrogenation had delivered the opposite diastereomer to
that required. In order to rationalize this result, we calculated
the structure of nonconjugated enone 86. As anticipated, the
DFT-optimized structure of 86 revealed a marked puckering of
the C−D ring fusion; catalytic hydrogenation of this alkene to
give the desired diastereomer at C6a would necessitate
approach of H2 to the concave Re face of 86. This result is in
accord with prior studies on similar steroidal systems39 which
also describe convex surface hydrogenation on related enones.
Upon assessing our available functional handles, we surmised
that selective reduction of the ketone in 86 might alter the
outcome of the ensuing alkene hydrogenation by virtue of the
hydroxyl’s function as a directing group (Scheme 13). The use
With acetate 78 in hand, we faced the remaining challenges
of C ring installation, C6a reduction, and indolization to
complete our synthesis (Scheme 12). Acetate 78 was subjected
Scheme 12. Paspaline C Ring Construction and Synthesis of
a
C6a Epimeric Ketone
Scheme 13. Substrate-Directed Control of the C6a
Stereocenter and Completion of the Total Synthesis of
a
Paspaline
a
Reagents and conditions: (a) (i) HCl, H2O/MeOH/THF/acetone
(10:10:10:1), 85 °C; (ii) DMP, CH2Cl2, rt; (b) vinylmagnesium
bromide, CeCl3·2LiCl, THF, −78 °C; (c) Grubbs second generation
catalyst (20 mol %), CH2Cl2, rt; (d) TFA, CH2Cl2, 0 °C to rt; (e) H2
(1 atm), Pd/C (1.50 mass equiv), EtOH, rt.
a
Reagents and conditions: (a) LiAlH4, THF, 0 °C; (b) H2 (1 atm),
C8H12IrP(C6H11)3C5H5N]PF6 (15 mol %), CH2Cl2, rt; (c) DMP,
CH2Cl2, rt; (d) (i) LDA, THF, 0 °C, then HMPA, Me2S2; (ii) N-
chloroaniline, CH2Cl2, −78 °C, then NEt3; (iii) Raney Ni, EtOH, rt;
(iv) TsOH (66 mol %), CH2Cl2, 50 °C.
to global hydrolysis to remove the acetate, oxime, and silyl
ether functionalities. The resulting primary alcohol was oxidized
with Dess-Martin periodinane (DMP) to give ketoaldehyde 83
in 70% yield over two steps. From 83, we envisioned that
bisvinylation followed by ring-closing metathesis (RCM) would
install the needed carbon skeleton. Unfortunately, treatment of
83 with vinylmagnesium bromide at −78 °C gave predom-
inantly retro-aldol decomposition products with only small
amounts of 84. After some experimentation, we found that the
CeCl3·2LiCl complex recently reported by Knochel aided in
suppressing the retro-aldol product completely,38 giving diol 84
in 95% yield. Treatment of 84 with Grubb’s second generation
catalyst provided allylic alcohol 85 in 71% yield. While an
alcohol oxidation/hydroxyl elimination pathway was first
pursued for the conversion of diol 85 to enone 86, we found
of Crabtree’s catalyst in alcohol-directed alkene hydrogenations
has been well-documented40 and would presumably engage the
alkene on the same face as the hydroxyl. To this end, treatment
of ketone 86 with LiAlH4 afforded the desired (S)-alcohol 88 in
60% yield and >20:1 dr over two steps from diol 85. The steric
impact of the C12c methyl group on the outcome of this
reaction cannot be overstated; ketone reduction in analogous
steroidal systems not bearing this methyl group generally
proceed with the opposite sense of selectivity.39,41
With this alcohol in hand, catalytic hydrogenation of 88
using Crabtree’s catalyst completely over-rode the inherent
substrate bias, giving the corresponding alcohol 90 (via 89) in
>20:1 dr and subsequently the ketone 91 in 86% over two steps
after reoxidation of the alcohol. The stereochemistry of 91 was
H
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a
Scheme 14. Summary of Paspaline Total Synthesis
a
Reagents and conditions: (a) YSC-2, H2O/DMSO (10:1), 30 °C; (b) TsHNNH2, C7H8, 70 °C; (c) m-CPBA, CH2Cl2, 0 °C, then PPTS; (d)
TBSOTf, 2,6-lutidine, CH2Cl2, −50 °C; (e) n-BuLi, THF, −50 °C, then MeI; n-BuLi, −50 °C to rt, then (HCHO)n; (f) isobutyric acid, DCC,
DMAP (10 mol %), CH2Cl2, rt; (g) LDA, THF, −78 °C, then TMSCl, −78 to 75 °C; (h) Pd(OAc)2 (15 mol %), PhI(OAc)2, AcOH/Ac2O (1:1),
100 °C; (i) (i) Grubbs second generation catalyst (20 mol %), CH2Cl2, rt; (ii) TFA, CH2Cl2, 0 °C to rt; (j) LiAlH4, THF, 0 °C; (k) (i) H2 (1 atm),
C8H12IrP(C6H11)3C5H5N]PF6 (15 mol %), CH2Cl2, rt; (ii) DMP, CH2Cl2, rt.
1
confirmed via H NMR comparison with Smith’s intermediate
and an X-ray diffraction study.12d This left only indolization to
complete our total synthesis of 1. The Gassman indolization
utilized previously by Smith proved to be the method of choice
in affording paspaline (1) in 46% yield from 91.12a,42 Synthetic
1 matched the reported analytical data for paspaline, and single-
crystal X-ray analysis of this sample was in agreement with the
reported structure.11a
EXPERIMENTAL SECTION
■
Materials and Methods: General. Tetrahydrofuran (THF),
diethyl ether (Et2O), dichloromethane (CH2Cl2), and toluene
(C7H8) were dried by passage through a column of neutral alumina
under nitrogen prior to use. Aniline, hexamethylphosphoramide
(HMPA), and diisopropylamine were freshly distilled from calcium
hydride prior to use. Compounds 14,43 37,44 and 3924 were prepared
according to known procedures. All other reagents were purchased
from commercial sources and were used as received unless otherwise
noted. Proton and carbon magnetic resonance spectra (1H NMR and
13C NMR) were recorded with solvent resonance as the internal
standard (1H NMR: CDCl3 at 7.26 ppm and C6D6 at 7.16 ppm; 13C
CONCLUSIONS
■
In conclusion, we have described the entirety of our efforts
toward the synthesis of paspaline. The final route totals 28 steps
from commercially available 28 in 0.4% yield (Smith synthesis:
24 steps from 28, 0.2% yield).12a Of particular note is the
stereoselectivity of the described route: the least stereoselective
reactions in our synthesis are the Ireland−Claisen rearrange-
ment (70c → 71a, 6:1 dr) and the biocatalytic reduction (35 →
36, >99:1 er, 10:1 dr). All other stereodetermining trans-
formations occur in >20:1 dr (Scheme 14). After initial
approaches for the assembly of 1 via a cationic transannular
cyclization were unsuccessful, a symmetry-breaking approach to
paspaline was developed to complete construction of the E,F
ring fusion within the first four steps of the synthesis. A novel
tosyl hydrazone influenced epoxidation enabled excellent
control of the C2 stereocenter (>20:1), and the Ireland−
Claisen rearrangement provided access to the D ring and C12c
stereocenter of 1. A substrate-directed symmetry-breaking C−
H acetoxylation inspired by Sanford and co-workers provided
control of the C12b stereocenter (>20:1). To override the
inherent facial bias in the hydrogenation of enone 86,
stereoselective reduction of the ketone followed by hydro-
genation with Crabtree’s catalyst provided the final stereocenter
in 1 with excellent selectivity (>20:1). Emphasis was placed
throughout on expedient assembly of the critical C4a, C12b,
and C12c quaternary methyl groups toward facile preparation
of the remaining structures in this family of molecules. The
route and methods described in this work present a number of
complementary conceptual disconnections in the preparation of
“steroid-like” natural products. Work in our laboratory in
preparing these and related compounds is ongoing and will be
reported in due course.
1
NMR: CDCl3 at 77.0 ppm). H NMR data are reported as follows:
chemical shift, multiplicity (s = singlet, br s = broad singlet, d =
doublet, br d = broad doublet, t = triplet, q = quartet, m = multiplet),
coupling constants (Hz), and integration. Mass spectra were obtained
via Fourier transform mass spectromtetry (FTMS) with electrospray
introduction (ESI) and external calibration in positive ion mode. All
samples were prepared in methanol. Visualization for thin layer
chromatography (TLC) was accomplished with UV light, KMnO4,
and/or Seebach’s stain followed by heating. Purification of the reaction
products was carried out by flash chromatography on silica gel. Unless
otherwise noted, all reactions were carried out under an atmosphere of
dry nitrogen in flame-dried glassware with magnetic stirring. Yield
refers to isolated yield of analytically pure material unless otherwise
noted. Yields are reported for a specific experiment and as a result may
differ slightly from those found in figures, which are averages of at least
two experiments.
Computation Analysis. High-level DFT calculations using the
B3LYP28a,b approximate exchange-correlation energy density func-
tional were performed with the standard Pople triple-ζ basis set 6-
311G(d)28c,d for all elements when stable structures are optimized.
Calculations were performed in the gas phase at 0 K with tight SCF
convergence and ultrafine integration grids. All calculations were
performed with the package of Gaussian 09 version D01.45 Cartesian
coordinates of the studied systems are provided in the Supporting
Information.
3-Hydroxy-4-methylpent-4-en-1-yl 4-Methylbenzenesulfonate
(15). A flame-dried, 1000 mL round-bottomed flask was charged
with diol 14 (4.67 g, 40.2 mmol, 1.00 equiv) and CH2Cl2 (300 mL)
under an atmosphere of N2. The solution was cooled to 0 °C, and
NEt3 (14.0 mL, 100.5 mmol, 2.50 equiv), DMAP (0.49 g, 4.00 mmol,
0.10 equiv), and TsCl (8.43 g, 44.2 mmol, 1.10 equiv) were added
sequentially. The resulting mixture was allowed to stir at this
temperature until complete conversion of the starting material was
observed by TLC analysis, typically 12 h. The mixture was then diluted
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1
with H2O (150 mL) and partitioned in a separatory funnel. The
organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 40 mL). The combined organic extracts were dried with
sodium sulfate and concentrated in vacuo. The product was purified
via flash chromatography (70:30 to 60:40 hexanes/EtOAc) to afford
the tosylate 15 (8.75 g, 81% yield) as a pale yellow oil. Analytical data:
1H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.34 (d, J =
8.4 Hz, 2H), 4.91 (s, 1H), 4.82 (s, 1H), 4.22 (m, 1H), 4.16 (m, 1H),
4.09 (m, 1H), 2.44 (s, 3H), 1.91 (m, 1H), 1.79 (m, 1H), 1.75 (br s,
1H), 1.68 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 146.4, 144.8,
132.9, 129.8, 127.9, 111.4, 71.5, 67.6, 34.1, 21.6, 17.6; HRMS (ESI+)
calcd for C13H18O4S+Na, 293.0824; found 293.0815; IR (thin film,
cm−1) 3545, 3055, 2984, 2686, 1652, 1616, 1456, 1360, 1266, 1189;
TLC (80:20 hexanes/EtOAc) Rf = 0.14.
Analytical data: H NMR (600 MHz, CDCl3) δ 4.86 (s, 1H), 4.75 (s,
1H), 4.31 (dd, J = 9.0, 6.0 Hz, 1H), 4.11 (m, 2H), 3.83 (d, J = 12.0 Hz,
1H), 3.72 (s, 3H), 3.67 (s, 3H), 2.77 (m, 2H), 2.54 (m, 1H), 1.92 (m,
1H), 1.82 (m, 1H), 1.67 (br s, 1H), 1.65 (s, 3H), 1.20 (t, J = 6.6 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 171.4, 170.7, 169.0, 144.6,
110.7, 81.1, 77.3, 60.3, 55.8, 52.5, 52.2, 38.0, 31.7, 26.0, 18.8, 14.1;
HRMS (ESI+) calcd for C16H24O7+Na, 351.1420; found 351.1409; IR
(thin film, cm−1) 3446, 2955, 2849, 1733, 1652, 1455, 1267, 1186,
1072, 904; TLC (80:20 hexanes/EtOAc) Rf = 0.43.
Dimethyl-2-(2-hydroxyethyl)-6-(prop-1-en-2-yl)dihydro-2H-
pyran-3,3(4H)-dicarboxylate (18). A flame-dried, 500 mL round-
bottomed flask was charged with ester 17 (6.00 g, 18.3 mmol, 1.00
equiv) and THF (150 mL) under an atmosphere of N2. The solution
was cooled to 0 °C, and DIBAL-H (1 M solution in hexane, 18.3 mL,
18.3 mmol, 1.00 equiv) was added slowly. The reaction was then
analyzed for reaction completion via TLC analysis, which indicated
incomplete starting material conversion. Another 1.00 equiv of
DIBAL-H was added, whereupon TLC analysis indicated complete
conversion of the starting material. The reaction mixture was
quenched via addition of acetone (30 mL), and the mixture was
stirred 5 min at 0 °C. Saturated Rochelle’s salt(aq) (40 mL) was then
added, and the mixture was transferred to a separatory funnel. The
aqueous layer was extracted with Et2O (3 × 40 mL), and the
combined organic extracts were washed with 1 M HCl(aq) (40 mL) and
brine (40 mL), dried with magnesium sulfate, and concentrated in
vacuo. The product was purified via flash chromatography (60:40 to
50:50 to 40:60 hexanes/EtOAc) to afford alcohol 18 (3.78 g, 72%
Ethyl (E)-3-((2-Methyl-5-(tosyloxy)pent-1-en-3-yl)oxy)acrylate
(16). A flame-dried, 500 mL round-bottomed flask was charged with
alcohol 15 (8.75 g, 32.0 mmol, 1.00 equiv) and CH2Cl2 (160 mL)
under an atmosphere of N2 at rt. N-Methylmorpholine (3.60 mL, 35.7
mmol, 1.10 equiv) and ethyl propiolate (3.92 mL, 35.7 mmol, 1.10
equiv) were added sequentially, and the mixture was allowed to stir
until complete conversion of the starting material was observed by
TLC analysis, typically 4 h. The reaction mixture was concentrated on
a rotary evaporator, and the crude product was purified via flash
chromatography (80:20 to 70:30 hexanes/EtOAc) to give the vinyl
1
ether 16 (11.4 g, 97% yield) as a clear oil. Analytical data: H NMR
(600 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz,
2H), 7.28 (d, J = 12.6 Hz, 1H), 5.14 (d, J = 12.6 Hz, 1H), 4.97 (s, 1H),
4.93 (s, 1H), 4.31 (dd, J = 4.8, 4.2 Hz, 1H), 4.16−4.06 (m, 4H), 2.43
(s, 3H), 1.97 (m, 2H), 1.61 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 167.6, 160.5, 145.0, 141.5, 132.6, 129.9,
127.9, 115.4, 98.6, 81.5, 66.2, 59.8, 32.7, 21.6, 16.7, 14.3; HRMS
(ESI+) calcd for C18H24O6S+Na, 391.1191; found 391.1181; IR (thin
film, cm−1) 2980, 2916, 2849, 1706, 1644, 1488, 1362, 1189, 1097,
923; TLC (80:20 hexanes/EtOAc) Rf = 0.32.
1
yield) as a clear, viscous oil. Analytical data: H NMR (600 MHz,
CDCl3) δ 4.92 (s, 1H), 4.81 (s, 1H), 4.01 (dd, J = 8.4, 1.8 Hz, 1H),
3.88 (m, 1H), 3.79−3.76 (m, 5H), 3.71 (s, 3H), 2.54 (m, 1H), 2.42 (d,
J = 5.4 Hz, 1H), 2.14 (m, 1H), 1.93−1.88 (m, 3H), 1.70 (s, 3H), 1.67
(m, 1H); 13C NMR (150 MHz, CDCl3) δ 171.2, 169.3, 144.7, 111.1,
81.5, 81.1, 62.1, 56.2, 52.6, 52.1, 34.7, 31.9, 26.6, 18.7; HRMS (ESI+)
calcd for C14H22O6+Na, 309.1314; found 309.1305; IR (thin film,
cm−1) 3446, 3055, 2954, 2883, 1731, 1455, 1266, 1078, 906, 737; TLC
(75:25 hexanes/EtOAc) Rf = 0.05.
Ethyl (E)-3-((5-Iodo-2-methylpent-1-en-3-yl)oxy)acrylate (13). To
a solution of tosylate 16 (11.4 g, 30.8 mmol, 1.00 equiv) in acetone
(300 mL) at rt was added NaI (40.0 g, 308.0 mmol, 10.0 equiv)
portionwise with vigorous stirring. The resulting suspension was
allowed to stir 12 h at which point TLC analysis confirmed complete
consumption of the starting material. The reaction mixture was diluted
with brine (150 mL) and transferred to a separatory funnel. The
aqueous layer was extracted with EtOAc (3 × 60 mL), and the
combined organic extracts were dried with magnesium sulfate and
concentrated in vacuo. The product was purified via flash
chromatography (90:10 to 80:20 hexanes/EtOAc) to afford the alkyl
Dimethyl-2-(2-iodoethyl)-6-(prop-1-en-2-yl)dihydro-2H-pyran-
3,3(4H)-dicarboxylate (27). A 500 mL round-bottomed flask was
charged with CH2Cl2 (96 mL), and the solution was cooled to 0 °C.
Imidazole (3.22 g, 47.4 mmol, 4.96 equiv) and PPh3 (5.14 g, 19.0
mmol, 2.05 equiv) were added followed by I2 (4.83 g, 19.0 mmol, 2.00
equiv). The mixture was allowed to stir at 0 °C for 10 min, whereupon
a pale yellow suspension was observed. The alcohol 18 (2.73 g, 9.55
mmol, 1.00 equiv) was then added as a solution in CH2Cl2 (20 mL),
and the mixture was allowed to warm to rt and stirred until complete
consumption of the starting material was observed by TLC analysis,
typically 12 h. The mixture was then quenched via addition of
saturated Na2S2O3(aq) (50 mL) and transferred to a separatory funnel.
The aqueous layer was extracted with CH2Cl2 (3 × 30 mL), and the
combined organic extracts were washed with brine (30 mL), dried
with magnesium sulfate, and concentrated in vacuo. The product was
purified via flash chromatography (95:5 to 90:10 hexanes/EtOAc) to
afford primary iodide 27 (2.64 g, 70% yield) as a white solid. Analytical
data: mp 61−65 °C; 1H NMR (600 MHz, CDCl3) δ 4.93 (s, 1H), 4.83
(s, 1H), 3.88 (d, J = 10.2 Hz, 1H), 3.84 (d, J = 11.4 Hz, 1H), 3.75 (s,
3H), 3.72 (s, 3H), 3.36 (m, 1H), 3.28 (m, 1H), 2.56 (dt, J = 6.6, 3.0
Hz, 1H), 2.37 (m, 1H), 2.13 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H),
1.73 (s, 3H), 1.69 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 171.0,
169.3, 144.8, 110.9, 81.4, 80.9, 56.4, 52.6, 52.2, 35.8, 32.0, 26.3, 19.0,
4.3; HRMS (ESI+) calcd for C14H21IO5+Na, 419.0326; found
419.0320; IR (thin film, cm−1) 2917, 2849, 1731, 1652, 1540, 1455,
1265, 1083, 905; TLC (75:25 hexanes/EtOAc) Rf = 0.50.
1
iodide 13 (8.67 g, 87% yield) as a pale yellow oil. Analytical data: H
NMR (600 MHz, CDCl3) δ 7.46 (d, J = 12.6 Hz, 1H), 5.27 (d, J =
12.6 Hz, 1H), 5.05 (s, 1H), 5.04 (s, 1H), 4.39 (dd, J = 4.8, 3.0 Hz,
1H), 4.14 (m, 2H), 3.17 (m, 2H), 2.21 (m, 1H), 2.07 (m, 1H), 1.67 (s,
3H), 1.25 (t, J = 7.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 167.7,
160.8, 141.5, 115.3, 98.6, 85.5, 59.8, 36.7, 17.0, 14.3, 0.9; HRMS
(ESI+) calcd for C11H17IO3+Na, 347.0120; found 347.0111; IR (thin
film, cm−1) 3078, 2978, 2916, 1707, 1644, 1456, 1322, 1171, 1006,
834; TLC (80:20 hexanes/EtOAc) Rf = 0.64.
Dimethyl 2-(2-Ethoxy-2-oxoethyl)-6-(prop-1-en-2-yl)dihydro-2H-
pyran-3,3(4H)-dicarboxylate (17). A 500 mL round-bottomed flask
was charged with the iodide 13 (8.75 g, 27.00 mmol, 1.00 equiv) and
DMF (130 mL) at rt. Dimethyl malonate (6.20 mL, 54.0 mmol, 2.00
equiv) and Cs2CO3 (26.4 g, 81.0 mmol, 3.00 equiv) were added
sequentially, whereupon a bright orange color was observed. The
resulting mixture was allowed to stir for 14 h and was subsequently
diluted with H2O (50 mL) and Et2O (50 mL). The layers were
partitioned in a separatory funnel, and the aqueous layer was extracted
with Et2O (3 × 30 mL). The combined organic extracts were washed
with brine (40 mL), dried with magnesium sulfate, and concentrated
in vacuo to give the crude pyran as a single diastereomer (as
Dimethyl-2-(3-methylbut-3-en-1-yl)-6-(prop-1-en-2-yl)dihydro-
2H-pyran-3,3(4H)-dicarboxylate (12). A flame-dried, 50 mL round-
bottomed flask was charged with 2-bromopropene (0.67 mL, 7.57
mmol, 3.00 equiv) and Et2O (13 mL) under an atmosphere of N2. The
mixture was cooled to −78 °C, and tBuLi (1.70 M solution in pentane,
8.91 mL, 15.14 mmol, 6.00 equiv) was added dropwise. The reaction
mixture was allowed to stir 30 min at −78 °C, then warmed to rt and
stirred for 1 h. During this time period, a second flame-dried, 100 mL
1
determined by H NMR spectroscopic analysis of the crude mixture,
which revealed a single compound). The product was purified via flash
chromatography (90:10 to 80:20 hexanes/EtOAc) to afford
tetrahydropyran 17 (8.85 g, 99% yield) as a clear, viscous oil.
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round-bottomed flask was charged with CuI (0.72 g, 3.79 mmol, 1.50
equiv) and Et2O (12 mL) and was cooled to −78 °C. The
isopropenyllithium solution was then cooled to −78 °C and
transferred via cannula to the CuI suspension over a period of ∼1
min. The resulting suspension was then warmed to −45 °C and stirred
1 h, upon which a color change from pale brown to dark gray to dark
yellow-green was observed. The mixture was cooled to −78 °C, and a
solution of iodide 27 (1.00 g, 2.52 mmol, 1.00 equiv) in Et2O (5 mL)
was added. The reaction was then warmed to 0 °C and stirred until
complete conversion of the starting material was observed by TLC
analysis, typically 30 min. The reaction was then quenched via addition
of saturated NH4Cl(aq) (20 mL), and the mixture was transferred to a
separatory funnel. The aqueous layer was extracted with Et2O (3 × 20
mL), and the combined organic extracts were washed with saturated
NH4Cl(aq) (20 mL), dried with magnesium sulfate, and concentrated in
vacuo. The product was purified via flash chromatography (100:0 to
95:5 to 90:10 hexanes/EtOAc) to afford the alkene 12 (0.77 g, 99%
single stereoisomer in combination with overaddition products). The
product was purified via flash chromatography (100:0 to 98:2 to 95:5
to 90:10 hexanes/EtOAc) to afford ketone 20 (0.22 g, 65% yield) as a
clear, viscous oil. Analytical data: 1H NMR (600 MHz, CDCl3) δ 4.94
(s, 1H), 4.82 (s, 1H), 4.71 (s, 1H), 4.69 (s, 1H), 3.78−3.75 (m, 4H),
3.71 (d, J = 11.4 Hz, 1H), 2.45 (m, 1H), 2.22 (m, 1H), 2.12 (br s, 4H),
1.99 (m, 1H), 1.75 (br s, 4H), 1.73 (br s, 4H), 1.68 (m, 2H); 13C
NMR (150 MHz, CDCl3) δ 205.1, 171.0, 145.6, 145.2, 110.6, 110.3,
80.8, 80.3, 62.3, 52.0, 34.9, 31.4, 30.2, 27.1, 26.4, 22.3, 19.3; HRMS
(ESI+) calcd for C17H26O4+Na, 317.1729; found 317.1720; IR (thin
film, cm−1) 3445, 3072, 2969, 2857, 1708, 1649, 1436, 1356, 1221,
1081; TLC (75:25 hexanes/EtOAc) Rf = 0.45.
Synthesis of Unsaturated Ketone 21. Methyl-2-(3-methylbut-
3-en-1-yl)-6-(prop-1-en-2-yl)-3-propionyltetrahydro-2H-pyran-3-
carboxylate (S1). A flame-dried, 20 mL scintillation vial was charged
with bromoethane (0.13 mL, 1.69 mmol, 3.50 equiv) and THF (5 mL)
under an atmosphere of N2. The solution was cooled to −78 °C, and
tBuLi (1.70 M in pentane, 1.99 mL, 3.38 mmol, 7.00 equiv) was added
1
yield) as a clear oil. Analytical data: H NMR (600 MHz, CDCl3) δ
dropwise. The mixture was allowed to stir 30 min at −78 °C,
whereupon a solution of the diester 12 (0.15 g, 0.48 mmol, 1.00 equiv)
was added over ∼10 s. The reaction progress was immediately checked
via TLC analysis, which confirmed complete consumption of the
starting material. The reaction was then quenched via addition of
saturated NH4Cl(aq) (5 mL) and warmed to rt. The mixture was
transferred to a separatory funnel, and the aqueous layer was extracted
with Et2O (3 × 10 mL). The combined organic extracts were dried
with magnesium sulfate and concentrated in vacuo to afford the crude
ketone as a single diastereomer (as determined via 1H NMR
spectroscopic analysis of the crude product residue, which revealed a
single stereoisomer in combination with overaddition products). The
product was purified via flash chromatography (100:0 to 98:2 to 95:5
to 90:10 hexanes/EtOAc) to afford ketone S1 (0.13 g, 89% yield) as a
clear, viscous oil. Analytical data: 1H NMR (600 MHz, CDCl3) δ 4.93
(s, 1H), 4.82 (s, 1H), 4.71 (s, 1H), 4.68 (s, 1H), 3.79−3.77 (m, 4H),
3.71 (d, J = 3.6 Hz, 1H), 2.42 (m, 3H), 2.21 (m, 1H), 2.12 (m, 1H),
1.95 (m, 1H), 1.78 (m, 1H), 1.74 (s, 3H), 1.73 (s, 3H), 1.69 (m, 2H),
1.60 (br s, 1H), 1.03 (t, J = 7.2 Hz, H); 13C NMR (150 MHz, CDCl3)
δ 208.0, 171.2, 145.6, 145.2, 110.6, 110.3, 80.8, 80.5, 62.4, 51.9, 34.9,
32.6, 31.7, 30.2, 26.4, 22.3, 19.3, 7.9; HRMS (ESI+) calcd for
C18H28O4+Na, 331.1885; found 331.1876; IR (thin film, cm−1) 3446,
3073, 2970, 2855, 1739, 1650, 1455, 1342, 1159, 892; TLC (75:25
hexanes/EtOAc) Rf = 0.47.
4.93 (s, 1H), 4.81 (s, 1H), 4.72 (s, 1H), 4.69 (s, 1H), 3.75 (br s, 4H),
3.70 (br s, 4H), 2.53 (m, 1H), 2.21 (m, 1H), 2.12 (m, 1H), 1.94−1.78
(m, 4H), 1.74 (s, 3H), 1,72 (s, 3H), 1.67 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 171.6, 169.7, 154.4, 145.1, 110.6, 110.3, 81.0, 80.5,
56.6, 52.4, 52.0, 34.9, 32.2, 30.1, 26.2, 22.2, 19.2; HRMS (ESI+) calcd
for C17H26O5+Na, 333.1678; found 333.1669; IR (thin film, cm−1)
3446, 3056, 2953, 2849, 1731, 1669, 1636, 1520, 1455, 1203, 1266;
TLC (75:25 hexanes/EtOAc) Rf = 0.52.
3-(Methoxycarbonyl)-2-(3-methylbut-3-en-1-yl)-6-(prop-1-en-2-
yl)tetrahydro-2H-pyran-3-carboxylic Acid (19). A 20 mL scintillation
vial was charged with diester 12 (0.10 g, 0.32 mmol, 1.00 equiv) and
THF (3 mL) with stirring at rt. KOH (1 M in MeOH, 1.70 mL, 1.70
mmol, 5.27 equiv) was added, and the resulting mixture was allowed to
stir at rt until complete consumption of the starting material was
observed by TLC analysis. This time period varied widely for each
experiment (from 12 h to 6 days dependent on scale; in this iteration,
5 days were required to reach complete conversion). Once complete,
the reaction mixture was concentrated on a rotary evaporator. The
residue was diluted with H2O (10 mL), transferred to a separatory
funnel, and extracted with Et2O (2 × 5 mL). The aqueous layer was
acidified to pH = 1 with 1 M HCl(aq) and extracted with EtOAc (3 × 5
mL). The combined EtOAc extracts were dried with magnesium
sulfate and concentrated in vacuo to afford the crude monoacid 19
(0.094 g, >99% crude yield) as a pale yellow, viscous oil. The
diastereomeric ratio was determined via 1H NMR spectroscopic
analysis of this crude material, which revealed a single compound.
Methyl 3-Acryloyl-2-(3-methylbut-3-en-1-yl)-6-(prop-1-en-2-yl)-
tetrahydro-2H-pyran-3-carboxylate (21). A flame-dried, 20 mL
scintillation vial was charged with THF (4 mL) and diisopropylamine
(0.08 mL, 0.55 mmol, 1.30 equiv) under an atmosphere of N2. The
1
Analytical data: H NMR (600 MHz, C6D6) δ 10.56 (br s, 1H), 5.02
(s, 1H), 4.90 (s, 1H), 4.84 (s, 1H), 4.80 (s, 1H), 3.84 (dd, J = 7.2, 1.8
Hz, 1H), 3.58 (d, J = 11.4 Hz, 1H), 3.31 (s, 3H), 2.56 (d, J = 13.2 Hz,
1H), 2.33 (m, 2H), 2.17 (m, 2H), 2.08 (m, 1H), 1.71 (s, 3H), 1.68−
1.67 (m, 4H), 1.34 (d, J = 1.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
δ 177.1, 169.6, 145.3, 145.0, 110.8, 110.4, 81.1, 80.3, 56.6, 52.2, 34.8,
32.2, 30.1, 26.1, 22.2, 19.2; HRMS (ESI+) calcd for C16H24O5+Na,
319.1521; found 319.1513; IR (thin film, cm−1) 3566, 3074, 2952,
2857, 2633, 1732, 1650, 1438, 1268, 1080, 891; TLC (75:25 hexanes/
EtOAc) Rf = 0.32.
Methyl-3-acetyl-2-(3-methylbut-3-en-1-yl)-6-(prop-1-en-2-yl)-
tetrahydro-2H-pyran-3-carboxylate (20). A flame-dried, 25 mL
round-bottomed flask was charged with diester 12 (0.35 g, 1.13
mmol, 1.00 equiv) and THF (11 mL) under an atmosphere of N2. The
solution was cooled to −78 °C, and MeLi (1.60 M in Et2O, 0.6 mL,
0.97 mmol, 2.00 equiv) was added over 5 s. The reaction was then
checked via TLC analysis, which showed incomplete conversion of the
starting material. Another 1.00 equiv of MeLi was added, whereupon
TLC analysis showed complete conversion of the starting material.
The reaction mixture was then quenched via addition of saturated
NH4Cl(aq) (5 mL) and subsequently warmed to rt. The mixture was
transferred to a separatory funnel, and the aqueous layer was extracted
with Et2O (3 × 10 mL). The combined organic extracts were dried
with magnesium sulfate and concentrated in vacuo to give the crude
ketone as a single diastereomer (as determined via 1H NMR
spectroscopic analysis of the crude product residue, which revealed a
n
mixture was cooled to 0 °C, and BuLi (1.74 M in hexanes, 0.32 mL,
0.55 mmol, 1.30 equiv) was added dropwise. After being stirred 30
min, the mixture was cooled to −78 °C, and a solution of ketone S1
(0.13 g, 0.42 mmol, 1.00 equiv) in THF (1 mL) was added. After
being stirred 45 min at −78 °C, PhSeBr (0.11 g, 0.51 mmol, 1.10
equiv) was added, and the mixture was allowed to stir until complete
consumption of the starting material was observed by TLC analysis,
typically 45 min. The reaction mixture was diluted with H2O (10 mL),
warmed to rt, and transferred to a separatory funnel. The organic layer
was separated, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic extracts were dried with magnesium
sulfate and concentrated in vacuo to give the crude α-selenide, which
was used in the next step without further purification.
The intermediate selenide was dissolved in CH2Cl2 (2 mL), and the
mixture was cooled to 0 °C. H2O2 (30% w/w in H2O, 0.80 mL) was
added dropwise, and the mixture was stirred at 0 °C until complete
consumption of the starting material was observed by TLC analysis,
typically 15 min. The reaction mixture was diluted with H2O (7 mL)
and transferred to a separatory funnel. The aqueous layer was
extracted with EtOAc (3 × 7 mL), and the combined organic extracts
were dried with magnesium sulfate and concentrated in vacuo. The
product was purified via flash chromatography (100:0 to 98:2 to 95:5
hexanes/EtOAc) to afford unsaturated ketone 21 (0.079 g, 56%) as a
1
pale yellow, viscous oil. Analytical data: H NMR (600 MHz, CDCl3)
K
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Article
δ 6.39 (d, J = 3.0 Hz, 1H), 6.38 (s, 1H), 5.71 (dd, J = 4.2, 3.0 Hz, 1H),
4.95 (s, 1H), 4.84 (s, 1H), 4.72 (s, 1H), 4.70 (s, 1H), 3.84 (d, J = 10.2
Hz, 1H), 3.76 (s, 3H), 3.72 (d, J = 11.4 Hz, 1H), 2.43 (m, 1H), 2.22
(m, 1H), 2.17 (m, 1H), 2.08 (m, 1H), 1.81 (m, 1H), 1.77 (s, 3H), 1.74
(s, 3H), 1.72−1.66 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 195.6,
170.9, 145.6, 145.2, 131.7, 129.7, 110.7, 110.4, 80.7, 79.9, 60.8, 52.0,
34.8, 31.0, 30.2, 26.2, 22.3, 19.4; HRMS (ESI+) calcd for
C18H26O4+Na, 329.1729; found 329.1720; IR (thin film, cm−1)
3420, 3054, 2952, 2852, 1740, 1636, 1455, 1265, 1049, 894; TLC
(75:25 hexanes/EtOAc) Rf = 0.63.
Synthesis of Unsaturated Ketone 22. tert-Butyl 3-(3-
oxopropyl)-1H-indole-1-carboxylate (S2). A flame-dried, 50 mL
round-bottomed flask was charged with 3-(1H-indol-3-yl)propanal46
(0.37 g, 2.10 mmol, 1.00 equiv), CH2Cl2 (14 mL), NEt3 (0.44 mL,
3.15 mmol, 1.50 equiv), and DMAP (0.005 g, 0.21 mmol, 0.10 equiv)
at rt under an atmosphere of N2. Boc2O (0.55 g, 2.52 mmol, 1.20
equiv) was added in one porition, and the resulting mixture was
allowed to stir until complete consumption of the starting material was
observed by TLC analysis, typically 5 h. The mixture was then diluted
with H2O (10 mL) and transferred to a separatory funnel. The organic
layer was separated, and the aqueous layer was extracted with CH2Cl2
(3 × 10 mL). The combined organic extracts were dried with
magnesium sulfate and concentrated in vacuo. The product was
purified via flash chromatography (100:0 to 90:10 to 80:20 hexanes/
EtOAc) to afford the protected indole S2 (0.24 g, 42% yield) as a
clear, viscous oil. Analytical data: 1H NMR (600 MHz, CDCl3) δ 9.87
(s, 1H), 8.13 (br s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.38 (br s, 1H), 7.33
(t, J = 7.2 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H), 3.04 (t, J = 7.2 Hz, 2H),
2.87 (t, J = 7.8 Hz, 2H), 1.67 (s, 9H); 13C NMR (150 MHz, CDCl3) δ
201.5, 124.5, 122.6, 122.4, 119.1, 118.7, 115.3, 43.1, 28.2, 17.4; HRMS
(ESI+) calcd for C16H19NO3+Na, 296.1263; found 296.1256; IR (thin
film, cm−1) 3446, 2977, 2916, 1731, 1670, 1636, 1455, 1373, 1256,
1158, 1018, 746; TLC (80:20 hexanes/EtOAc) Rf = 0.53.
tert-Butyl 3-(2-formylallyl)-1H-indole-1-carboxylate (S3). A flame-
dried, 50 mL round-bottomed flask was charged with aldehyde S2
(0.16 g, 0.60 mmol, 1.00 equiv) and CH2Cl2 (12 mL) at rt under an
atmosphere of N2. NEt3 (0.84 mL, 6.00 mmol, 10.0 equiv) was added
followed last by dimethylmethylideneiminium iodide (0.33 g, 1.8
mmol, 3.00 equiv). The mixture was allowed to stir at rt until complete
conversion of the starting material was observed by TLC analysis,
typically 12 h. The reaction was then concentrated on a rotary
evaporator and purified via flash chromatography (95:5 to 90:10
hexanes/EtOAc) to afford unsaturated aldehyde S3 (0.08 g, 45% yield)
as a yellow, viscous oil. Analytical data: 1H NMR (600 MHz, CDCl3) δ
9.67 (s, 1H), 8.13 (br s, 1H), 7.42 (br s, 1H), 7.39 (d, J = 7.8 Hz, 1H),
7.32 (t, J = 8.4 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 3.65 (s, 2H), 1.67 (s,
9H); 13C NMR (150 MHz, CDCl3) δ 194.0, 149.7, 147.9, 135.3,
130.1, 124.4, 124.1, 122.5, 119.1, 116.8, 115.3, 83.6, 28.2, 23.3; HRMS
(ESI+) calcd for C17H19NO3+Na, 308.1263; found 308.1255; IR (thin
film, cm−1) 3446, 2916, 1732, 1685, 1488, 1455, 1370, 1255, 1158,
1083, 959; TLC (80:20 hexanes/EtOAc) Rf = 0.60.
tert-Butyl 3-(2-methylene-3-oxobutyl)-1H-indole-1-carboxylate
(22). A flame-dried, 20 mL scintillation vial was charged with aldehyde
S3 (0.04 g, 0.12 mmol, 1.00 equiv) and THF (2 mL) under an
atmosphere of N2. The solution was cooled to 0 °C, and MeMgBr (3
M in Et2O, 0.12 mL, 0.37 mmol, 3.00 equiv) was added over a period
of ∼1 min. The mixture was allowed to stir until complete
consumption of the starting material was observed by TLC analysis,
typically 30 min. The reaction was then quenched via addition of
saturated NH4Cl(aq) (5 mL), and the mixture was transferred to a
separatory funnel. The aqueous layer was extracted with Et2O (3 × 10
mL), and the combined organic extracts were dried with magnesium
sulfate and concentrated in vacuo to give the crude alcohol, which was
used in the next step without further purification.
saturated Na2S2O3(aq) (5 mL) and allowed to stir 5 min. The mixture
was then transferred to a separatory funnel, and the aqueous layer was
extracted with Et2O (3 × 5 mL). The combined organic extracts were
dried with magnesium sulfate and concentrated in vacuo. The product
was purified via flash chromatography (95:5 to 90:10 hexanes/EtOAc)
to afford enone 22 (0.026 g, 71% yield) as a yellow viscous oil.
1
Analytical data: H NMR (600 MHz, CDCl3) δ 8.12 (br s, 1H), 7.41
(d, J = 9.0 Hz, 1H), 7.39 (br s, 1H), 7.31 (t, J = 9.0 Hz, 1H), 7.21 (t, J
= 9.0 Hz, 1H), 6.10 (s, 1H), 5.72(s, 1H), 3.67 (s, 2H), 2.39 (s, 3H),
1.67 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 199.4, 146.8, 126.5,
124.3, 124.0, 122.4, 119.2, 117.8, 115.2, 36.6, 28.2, 25.9; HRMS (ESI+)
calcd for C18H21NO3+Na, 322.1419; found 322.1411; IR (thin film,
cm−1) 3445, 3054, 2980, 2930, 1731, 1680, 1628, 1454, 1368, 1256,
1158, 1082; TLC (80:20 hexanes/EtOAc) Rf = 0.60.
Synthesis of Enol Silane 24. 4-(1-(2,2,2-Trifluoroacetyl)-1H-
indol-3-yl)butan-2-one (S4). A flame-dried, 100 mL round-bottomed
flask was charged with TFAA (1.51 mL, 10.7 mmol, 4.00 equiv) and
CH2Cl2 (25 mL) under an atmosphere of N2. 4-(1H-Indol-3-yl)butan-
2-one47 (0.50 g, 2.67 mmol, 1.00 equiv) was dissolved in CH2Cl2 (2
mL) and added dropwise to the TFAA solution. Once the addition
was complete, the mixture was allowed to stir at rt until complete
consumption of the starting material was observed by TLC analysis,
typically 12 h. The reaction was quenched via addition of saturated
NaHCO3(aq) (10 mL) and transferred to a separatory funnel. The
aqueous layer was extracted with EtOAc (3 × 10 mL), and the
combined organic extracts were dried with sodium sulfate and
concentrated in vacuo. The product was purified via flash
chromatography (90:10 to 80:20 hexanes/EtOAc) to afford TFA-
protected indole S4 (0.54 g, 71% yield) as a pale yellow solid.
1
Analytical data: mp 55−58 °C; H NMR (600 MHz, CDCl3) δ 8.43
(d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.42 (m, 2H), 7.25 (br s,
1H), 2.99 (t, J = 7.8 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.20 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 207.0, 136.2, 130.5, 126.4, 125.5,
125.2, 120.3, 120.2, 119.2, 117.0, 42.2, 30.0, 18.6; HRMS (ESI+) calcd
for C14H12F3NO2+Na, 306.0718; found 306.0709; IR (thin film, cm−1)
2917, 1717, 1459, 1419, 1292, 1207, 1155, 880; TLC (80:20 hexanes/
EtOAc) Rf = 0.48.
2,2,2-Trifluoro-1-(3-(3-((trimethylsilyl)oxy)but-2-en-1-yl)-1H-
indol-1-yl)ethan-1-one (24). A flame-dried, 20 mL scintillation vial
was charged with ketone S4 (0.05 g, 0.267 mmol, 1.00 equiv) and
CH2Cl2 (3 mL) under an atmosphere of N2. The mixture was cooled
to −10 °C, and HMDS (0.17 mL, 0.801 mmol, 3.00 equiv) was added
followed by TMSI (0.02 mL, 0.267 mmol, 1.00 equiv) dropwise. The
reaction mixture was warmed to rt and stirred until TLC analysis
confirmed complete consumption of the starting material, typically 45
min. The reaction mixture was then quenched via addition of saturated
NaHCO3(aq) (5 mL) and transferred to a separatory funnel. The
organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 5 mL). The combined organic extracts were dried with
magnesium sulfate and concentrated in vacuo to afford the crude enol
silane as a ∼3:1 mixture of alkene isomers as determined by 1H NMR
analysis. This material was unstable to further purification and was
1
used directly in reaction screenings. The crude H NMR spectrum is
included in the Supporting Information.
tert-Butyl 3-(3-Methylbut-2-en-1-yl)-1H-indole-1-carboxylate
(25). A flame-dried, 20 mL scintillation vial was charged with 3-(3-
methylbut-2-en-1-yl)-1H-indole48 (0.05 g, 0.27 mmol, 1.00 equiv),
NEt3 (0.06 mL, 0.41 mmol, 1.50 equiv), DMAP (0.003 g, 0.027 mmol,
0.10 equiv), and CH2Cl2 (3 mL) at rt under an atmosphere of N2.
Boc2O (0.07 mL, 0.32 mmol, 1.20 equiv) was added, and the mixture
was allowed to stir at rt until TLC analysis confirmed complete
consumption of the starting material, typically 12 h. The mixture was
diluted with H2O (5 mL) and transferred to a separatory funnel. The
aqueous layer was extracted with CH2Cl2 (3 × 5 mL), and the
combined organic extracts were washed with H2O (5 mL), dried with
sodium sulfate, and concentrated in vacuo. The product was purified
via flash chromatography (100:0 to 98:2 hexanes/EtOAc) to afford
protected indole 25 (0.06 g, 73% yield) as a yellow viscous oil.
The crude residue was dissolved in CH2Cl2 (2 mL) and transferred
to a 20 mL scintillation vial. Dess-Martin periodinane (0.10 g, 0.25
mmol, 2.00 equiv) was added to the vial, and the resulting mixture was
allowed to stir until complete consumption of the starting material was
observed by TLC analysis, typically 20 min. The reaction mixture was
then quenched via a 1:1 mixture of saturated NaHCO3(aq) and
1
Analytical data: H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 9.0 Hz,
1H), 7.53 (d, J = 7.8 Hz, 1H), 7.35−7.31 (m, 2H), 7.25 (t, J = 7.8 Hz,
L
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The Journal of Organic Chemistry
Article
1H), 5,41 (t, J = 7.2 Hz, 1H), 3.39 (d, J = 7.2 Hz, 2H), 1.78 (br s, 6H),
1.68 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 133.0, 124.2, 123.1,
122.3, 122.2, 121.5, 120.6, 120.5, 119.1, 115.2, 107.1, 28.2, 25.7, 23.9,
17.8; HRMS (ESI+) calcd for C18H23NO2+Na, 308.1626; found
308.1619; IR (thin film, cm−1) 3421, 3053, 2980, 2931, 1730, 1454,
1371, 1265, 1158, 855; TLC (80:20 hexanes/EtOAc) Rf = 0.95.
Dimethyl 2-(2-(1-Methyl-2,6-dioxocyclohexyl)ethyl)-6-(prop-1-
en-2-yl)dihydro-2H-pyran-3,3(4H)-dicarboxylate (29). A flame-
dried, 20 mL scintillation vial was charged with iodide 27 (0.60 g,
1.51 mmol, 1.00 equiv), 2-methyl-1,3-cyclohexanedione (0.27 g, 2.12
mmol, 1.4 equiv), and DMF (3 mL) at rt under an atmosphere of N2.
Cs2CO3 (0.74 g, 2.27 mmol, 1.50 equiv) was added, and the mixture
was warmed to 65 °C. The reaction was allowed to stir at this
temperature until complete consumption of the starting material was
observed by TLC analysis, typically 5 h. The reaction mixture was
cooled to rt, diluted with H2O (6 mL) and Et2O (5 mL), and
transferred to a separatory funnel. The organic layer was separated,
and the aqueous layer was extracted with Et2O (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
with magnesium sulfate, and concentrated in vacuo. The mixture was
purified via flash chromatography (70:30 to 60:40 to 50:50 hexanes/
EtOAc) to afford diketone 29 (0.20 g, 34% yield) as a clear, viscous oil
and enol ether 30 (0.34 g, 56% yield) as a clear, viscous oil. Analytical
data: O-alkylation product 30: 1H NMR (600 MHz, CDCl3) δ 4.90 (s,
1H), 4.79 (s, 1H), 4.09 (m, 2H), 3.92 (d, J = 10.8 Hz, 1H), 3.77 (d, J =
11.4 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.55−2.51 (m, 3H), 2.31 (t, J
= 6.6 Hz, 2H), 2.21 (m, 1H), 2.09 (m, 1H), 1.96−1.90 (m, 3H), 1.79
(m, 1H), 1.70 (s, 3H), 1.68 (s, 3H), 1.66 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 198.8, 171.5, 110.9, 169.3, 144.8, 115.0, 110.8, 81.3,
77.1, 64.6, 56.4, 52.6, 52.1, 36.2, 32.7, 31.9, 26.4, 25.3, 20.9, 18.8, 7.3;
HRMS (ESI+) calcd for C21H30O7+Na, 417.1889; found 417.1879; IR
(thin film, cm−1) 2953, 1731, 1635, 1455, 1377, 1355, 1262, 1095,
921; TLC (75:25 hexanes/EtOAc) Rf = 0.10. C-alkylation product 29:
1H NMR (600 MHz, CDCl3) δ 4.90 (s, 1H), 4.79 (s, 1H), 3.73−3.70
17.9, 17.7, 16.4; HRMS (ESI+) calcd for C19H28O5+Na, 359.1834;
found 359.1825; IR (thin film, cm−1) 3446, 2917, 2849, 1731, 1652,
1540, 1456, 1200, 901; TLC (75:25 hexanes/EtOAc) Rf = 0.17.
1
Annulation product 32: H NMR (600 MHz, CDCl3) δ 4.91 (s, 1H),
4.78 (s, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.66 (dd, J = 7.8, 4.8 Hz, 1H),
3.59 (s, 3H), 2.47 (m, 2H), 2.31 (m, 2H), 2.16 (dd, J = 10.8, 6.0 Hz,
1H), 2.10−2.00 (m, 3H), 1.77 (m, 2H), 1.68 (s, 3H), 1.62 (m, 1H),
1.52 (br s, 1H), 1.45 (m, 1H), 1.35 (m, 1H), 1.18 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 210.0, 172.5, 145.7, 110.9, 82.0, 80.0, 78.2, 53.5,
53.2, 50.5, 34.1, 29.1, 28.1, 27.5, 26.9, 25.9, 25.4, 18.4, 18.1; HRMS
(ESI+) calcd for C19H28O5+Na, 359.1834; found 359.1825; IR (thin
film, cm−1) 3446, 3055, 2950, 1718, 1456, 1339, 1265, 1073, 899; TLC
(75:25 hexanes/EtOAc) Rf = 0.07.
2-Methyl-3-((4-methylpent-3-en-1-yl)oxy)cyclohex-2-en-1-one
(38). A flame-dried, 25 mL round-bottomed flask was charged with 2-
methyl-1,3-cyclohexanedione (1.00 g, 7.93 mmol, 100 equiv) and
DMF (8 mL) under an atmosphere of N2. The mixture was cooled to
0 °C, and NaH (60% dispersion in oil, 0.39 g, 10.3 mmol, 1.30 equiv)
was added portionwise. The mixture was warmed to rt and stirred 10
min, whereupon the iodide 37 (2.16 g, 10.3 mmol, 1.30 equiv) was
added. The mixture was allowed to stir 12 h, and the reaction mixture
was poured into a separatory funnel containing H2O (20 mL). CH2Cl2
(20 mL) was added, and the aqueous layer was extracted with CH2Cl2
(3 × 10 mL). The combined organic extracts were washed with brine
(20 mL), dried with magnesium sulfate, and concentrated in vacuo.
The products were purified via flash chromatography (90:10 to 80:20
to 60:40 hexanes/EtOAc) to afford cycloalkanedione 35 (0.12 g, 7%
yield) as a yellow oil and vinyl ether 38 (0.43 g, 26% yield) as a clear,
1
viscous oil. Analytical data: H NMR (600 MHz, CDCl3) δ 5.11 (m,
1H), 3.93 (t, J = 6.6 Hz, 2H), 2.51 (m, 2H), 2.36 (q, J = 7.2 Hz, 2H),
2.30 (t, J = 6.6 Hz, 2H), 1.93 (m, 2H), 1.68 (s, 3H), 1.66 (t, J = 1.2
Hz, 3H), 1.61 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 198.8, 171.4,
134.8, 118.9, 115.0, 67.4, 36.2, 28.7, 25.7, 25.4, 20.9, 17.7, 7.29; HRMS
(ESI+) calcd for C13H20O2+Na, 231.1361; found 231.1354; IR (thin
film, cm−1) 3446, 2926, 1732, 1646, 1472, 1376, 1238, 1096; TLC
(70:30 hexanes/EtOAc) Rf = 0.26.
(m, 4H), 3.68 (s, 3H), 3.61 (m, 1H), 2.76 (m, 2H), 2.56−2.48 (m,
3H), 2.12 (m, 1H), 2.04 (m, 1H), 1.85−1.74 (m, 4H), 1.69 (s, 3H),
1.63 (m, 1H), 1.59 (m, 2H), 1.18 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 210.0, 209.8, 171.3, 169.2, 145.0, 110.6, 81.1, 80.9, 66.1,
56.2, 52.5, 52.0, 37.5, 35.5, 32.0, 27.6, 26.4, 18.8, 17.8, 17.0; HRMS
(ESI+) calcd for C21H30O7+Na, 417.1889; found 417.1879; IR (thin
film, cm−1) 3403, 3057, 2954, 2872, 1729, 1696, 1455, 1266, 1084,
905; TLC (75:25 hexanes/EtOAc) Rf = 0.13.
(E)-3-(2,2-Dimethylhydrazono)-2-methylcyclohexan-1-one (39).
A 250 mL round-bottomed flask was charged with 2-methyl-1,3-
cyclohexanedione (12.0 g, 95.1 mmol, 1.00 equiv), C6H6 (150 mL),
H2NNMe2 (8.70 mL, 114.2 mmol, 1.20 equiv), and TsOH (0.50 g,
2.63 mmol, 0.03 equiv). A Dean−Stark apparatus was connected to
the flask, and the mixture was heated to 100 °C with vigorous stirring
for 6 h. The mixture was cooled to rt and concentrated on a rotary
evaporator. The crude residue was then recrystallized from C7H8 to
afford ketohydrazone 39 (16.00 g, 99% yield) as a yellow powder.
Analytical data for this compound matched that reported in the
literature:24 1H NMR (600 MHz, CDCl3) δ 5.05 (br s, 1H), 2.64 (m,
2H), 2.53 (s, 6H), 2.32 (t, J = 7.2 Hz, 2H), 1.90 (m, 2H), 1.66 (s, 3H).
2-Methyl-2-(4-methylpent-3-en-1-yl)cyclohexane-1,3-dione(35).
A flame-dried, 500 mL round-bottomed flask was charged with THF
(250 mL) under an atmosphere of N2. KH (10.40 g, 30% dispersion in
oil, 78.50 mmol, 1.20 equiv) was washed free of oil three times with
petroleum ether, suspended in THF (20 mL), and added to the flask
with stirring. The reaction mixture was cooled to −78 °C, and a
solution of ketohydrazone 39 (11.00 g, 65.42 mmol, 1.00 equiv) in
THF (25 mL) was slowly added. The reaction was warmed to 0 °C
and allowed to stir 4.5 h. The resulting dark-brown mixture was
recooled to −78 °C, and iodide S2 (17.3 g, 78.50 mmol, 1.20 equiv)
was added. The reaction mixture was allowed to stir while slowly
warming to rt overnight, producing a cream-white suspension. The
reaction was then quenched with saturated NH4Cl(aq) (50 mL), and
the resulting mixture was partitioned in a separatory funnel. The
aqueous layer was extracted with Et2O (3 × 50 mL), and the
combined organic extracts were washed with brine (40 mL), dried
with magnesium sulfate, and concentrated in vacuo to give the
intermediate alkylation product, which was used in the next step
without further purification.
Methyl 10a-Hydroxy-6a-methyl-7-oxo-3-(prop-1-en-2-yl)-
decahydro-1H-benzo[f]chromene-10b(4aH)-carboxylate (32). A 5
mL dram vial was charged with diketone 29 (0.015 g, 0.04 mmol, 1.00
equiv) and DMSO (2 mL), and NaCl (0.02 g, 0.38 mmol, 10.0 equiv)
was added in one portion. The vial was sealed with a screw-cap, and
the mixture was warmed to 150 °C and stirred 9 h. The mixture was
cooled to rt, diluted with Et2O (2 mL), and transferred to a separatory
funnel containing H2O (10 mL). The aqueous layer was extracted with
Et2O (3 × 5 mL), and the combined organic extracts were washed
with brine (5 mL), dried with magnesium sulfate, and concentrated in
vacuo. Crude 1H NMR analysis revealed a ∼1:1 mixture of the
diastereomeric decarboxylation product 31 and annulation product 32.
This mixture was purified via flash chromatography (70:30 to 60:40
hexanes/EtOAc) to afford annulation product 32 (0.006 g, 47% yield)
as a clear, viscous oil and Krapcho adduct 31 (0.005 g, 39% yield) as a
clear, viscous oil. Slow evaporation of 32 from acetone and hexanes
provided crystals suitable for X-ray crystallographic analysis. (Note:
when this reaction was conducted on 0.07 g, scale, only the Krapcho
adduct 31 was isolated in 43% yield. No cyclization product 32 was
detected on this scale.) Analytical data: Decarboxylation product 31:
1H NMR (600 MHz, CDCl3) δ 4.94 (s, 2H), 4.82−4.81 (m, 2H),
3.73−3.70 (m, 2H), 3.68−6.67 (m, 3H), 3.47−3.41 (m, 2H), 2.80−
2.69 (m, 4H), 2.60−2.54 (m, 4H), 2.24 (m, 1H), 2.14−2.12 (m, 2H),
2.07−1.98 (m, 5H), 1.85−1.77 (m, 3H), 1.74−1.73 (m, 5H), 1.51−
1.39 (m, 5H), 1.21 (s, 3H), 1.18 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 210.3, 210.1, 210.0, 209.9, 174.3, 172.8, 145.8, 145.5, 110.6,
110.2, 81.5, 80.0, 78.0, 77.3, 66.1, 65.5, 51.7, 51.3, 46.7, 37.8, 37.7,
37.5, 34.0, 33.5, 29.7, 29.1, 28.9, 28.8, 27.7, 26.2, 25.7, 19.0, 18.8, 18.3,
Cu(OAc)2·H2O (26.00 g, 130.9 mmol, 2.00 equiv) was dissolved in
H2O (300 mL) in a 1000 mL round-bottomed flask with vigorous
stirring. The crude hydrazone was then dissolved in THF (300 mL)
M
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Article
and added to the Cu(OAc)2·H2O solution, and the reaction mixture
was allowed to stir until TLC analysis confirmed complete conversion
of the starting material, typically 12 h. The resulting mixture was
concentrated on a rotary evaporator to remove the THF, and the
solution was then diluted with saturated NH4Cl(aq) (100 mL) and
CH2Cl2 (100 mL). This mixture was transferred to a separatory funnel
and extracted with CH2Cl2 (3 × 50 mL). The combined organic
extracts were washed with brine (2 × 50 mL), dried with magnesium
sulfate, and concentrated in vacuo. The product was purified via flash
chromatography (90:10 to 80:20 hexanes/EtOAc) to afford diketone
residues were combined and purified simultaneously.) The enantio-
selectivity (>99:1) was determined via 19F NMR analysis of the
resulting Mosher ester S8 (vide infra). Analytical data: [α]D28 −74.7 (c
1
= 0.30, CHCl3); H NMR (600 MHz, CDCl3) δ 5.04 (m, 1H), 3.89
(dd, J = 3.0, 2.4 Hz, 1H), 2.41 (m, 1H), 2.31 (m, 1H), 2.08 (m, 1H),
2.02 (m, 1H), 1.93 (m, 1H), 1.87−1.79 (m, 4H), 1.65 (br s, 4H), 1.56
(s, 3H), 1.53 (m, 1H), 1.10 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
214.4, 132.2, 123.7, 76.3, 54.3, 37.8, 36.2, 28.1, 25.6, 22.6, 20.7, 17.6,
17.3; HRMS (ESI+) calcd for C13H22O2+Na, 233.1518; found
233.1514; IR (thin film, cm−1) 3434, 3054, 2985, 2305, 1703, 1630,
1442, 1265, 738; TLC (80:20 hexanes/EtOAc) Rf = 0.23.
1
35 (10.34 g, 76% yield) as an orange, viscous oil. Analytical data: H
NMR (600 MHz, CDCl3) δ 4.99 (br s, 1H), 2.70 (m, 2H), 2.60 (m,
2H), 2.01 (m, 1H), 1.86−1.80 (m, 5H), 1.64 (s, 3H), 1.55 (s, 3H),
1.23 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 210.3, 132.9, 122.9,
65.6, 37.9, 37.5, 25.6, 23.3, 18.9, 17.7, 17.6; HRMS (ESI+) calcd for
C13H20O2+H, 209.1542; found 209.1537; IR (thin film, cm−1) 3400,
2967, 2929, 1725, 1695, 1602, 1451, 1280, 1169, 1026; TLC (80:20
hexanes/EtOAc) Rf = 0.40.
(1S,2R)-2-Methyl-2-(4-methylpent-3-en-1-yl)-3-oxocyclohexyl-
(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (Mosher Ester of
36). A flame-dried, 20 mL scintillation vial was charged with (R)-
(+)-α-methoxy-α-trifluoromethylphenylacetic acid (0.45 g, 1.90 mmol,
2.00 equiv) and CH2Cl2 (8 mL) with magnetic stirring at rt under an
atmosphere of N2. DCC (0.39 g, 1.90 mmol, 2.00 equiv) was added
followed by DMAP (0.01 g, 0.10 mmol, 0.10 equiv) and a 10:1
diastereomeric mixture of alcohol 36 (0.20 g, 0.95 mmol, 1.00 equiv)
in CH2Cl2 (2 mL). The reaction mixture was allowed to stir at rt until
complete conversion of the starting material was observed by TLC
analysis, typically 12 h. The resulting mixture was filtered through
cotton and concentrated in vacuo. The product was purified via flash
chromatography (95:5 to 90:10 hexanes/EtOAc) to provide the
Mosher ester (0.40 g, 99% yield) as an inseparable 10:1 mixture of
diastereomers (as determined by integration of the resonances at δ
5.33 (major diastereomer) and δ 5.06 (minor diastereomer)). 19F
NMR analysis revealed only a 10:1 mixture of diastereomers at δ
−71.1 ppm (minor diastereomer) and δ −71.2 ppm (major
diastereomer). Analytical data: [α]D +22.6 (c = 0.50, CHCl3); H
NMR (600 MHz, CDCl3) δ 7.50 (m, 2H), 7.39 (m, 3H), 5.33 (dd, J =
3.0, 3.0 Hz, 1H), 3.50 (s, 3H), 2.45 (m, 1H), 2.35 (m, 1H), 2.22 (m,
1H), 1.96−1.74 (m, 5H), 1.66 (s, 3H), 1.57 (s, 3H), 1.54 (m, 2H),
0.96 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 211.5, 165.8, 132.5,
131.9, 129.6, 128.4, 127.2, 123.2, 80.3, 55.3, 52.6, 37.4, 35.9, 25.6, 25.5,
22.4, 20.4, 17.8, 17.6; HRMS (ESI+) calcd for C23H29F3O4+Na,
449.1916; found 449.1923; IR (thin film, cm−1) 3423, 2949, 2855,
1746, 1713, 1451, 1270, 1168, 1019, 807, 721; TLC (80:20 hexanes/
EtOAc) Rf = 0.51.
3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)cyclohexan-1-
one (40). A 20 mL scintillation vial was charged with diketone 35 (0.1
g, 0.48 mmol, 1.00 equiv) and MeOH (10 mL), and the solution was
cooled to 0 °C. NaBH4 (0.005 g, 0.12 mmol, 0.25 equiv) was added,
and the mixture was allowed to stir at this temperature until complete
consumption of the starting material was observed by TLC analysis,
typically 10 min. The reaction was diluted with brine (5 mL) and
CH2Cl2 (5 mL), and the mixture was transferred to a separatory
funnel. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL), and
the combined organic extracts were dried with sodium sulfate and
concentrated in vacuo to give the crude alcohol as a 19.4:1 mixture of
1
28
1
diastereomers. The diastereomeric ratio was determined by H NMR
spectroscopic analysis of the crude reaction mixture by comparison of
the integration of the resonances at δ 1.14 (major diastereomer) and δ
1.09 (minor diastereomer). The product was purified via flash
chromatography (80:20 to 70:30 hexanes/EtOAc) to afford
hydroxyketone 40 (0.093 g, 93% yield) as a clear, viscous oil.
1
Analytical data: H NMR (600 MHz, CDCl3) δ 5.05 (t, J = 6.0 Hz,
1H), 3.65 (d, J = 7.8 Hz, 1H), 2.39 (m, 1H), 2.32 (m, 1H), 1.99−1.88
(m, 5H), 1.73 (m, 1H), 1.66−1.63 (m, 4H), 1.55 (br s, 4H), 1.15 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 214.1, 132.1, 123.9, 77.5, 54.7,
37.6, 31.5, 28.7, 25.6, 21.9, 20.7, 18.7, 17.6; HRMS (ESI+) calcd for
C13H22O2+Na, 233.1518; found 233.1510; IR (thin film, cm−1) 3420,
2939, 2871, 1698, 1455, 1375, 1161, 1059, 993, 831; TLC (70:30
hexanes/EtOAc) Rf = 0.32.
(2R,3S)-2-(2-(3,3-Dimethyloxiran-2-yl)ethyl)-3-hydroxy-2-methyl-
cyclohexan-1-one (41). A 20 mL scintillation vial was charged with
hydroxyketone 36 (0.10 g, 0.48 mmol, 1.00 equiv) and CH2Cl2 (5
mL), and the mixture was cooled to 0 °C. m-CPBA (70% dispersion in
H2O, 0.19 g, 0.76 mmol, 1.60 equiv) was added in one portion, and
the mixture was stirred until complete consumption of the starting
material was observed by TLC analysis, typically 20 min. The reaction
was quenched via saturated Na2S2O3 (5 mL), and the mixture was
transferred to a separatory funnel. The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL), and the combined organic extracts were
dried with sodium sulfate and concentrated in vacuo to give the crude
epoxide as a 2:1 mixture of diastereomers. The diastereomeric ratio
was determined by 1H NMR spectroscopic analysis of the crude
reaction mixture by comparison of the integration of the resonances at
δ 1.13 (major diastereomer) and δ 1.12 (minor diastereomer). The
product was purified via flash chromatography (60:40 to 50:50 to
40:60 hexanes/EtOAc) to afford epoxide 41 (0.10 g, 93% yield) as a
clear oil in an inseparable mixture of diastereomers. Analytical data:
(2R,3S)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)-
cyclohexan-1-one (36). A 1000 mL round-bottomed flask was
charged with H2O (320 mL), and YSC-2 (77 g, purchased from
Sigma-Aldrich) was added portionwise with vigorous stirring.
Diketone 35 (2.00 g, 9.60 mmol, 1.00 equiv) was dissolved in
DMSO (32 mL) and added to the YSC-2 suspension, and the mixture
was warmed to 30 °C and vigorously stirred for 24 h. The reaction
mixture was then cooled to rt, diluted with Et2O (50 mL), and Celite
(10 g) was added. The stirring was stopped, and the mixture was
allowed to let stand at rt for 12 h. The resulting mixture was then
filtered through a pad of Celite in a Buchner funnel. Once the filter
cake was dry, the Celite pad was then washed with Et2O (100 mL),
CH2Cl2 (100 mL), acetone (100 mL), Et2O (100 mL), and EtOAc
(100 mL), ensuring that the filter cake was loosened with a spatula
between each wash. The filtrate was transferred to a separatory funnel,
and the organic layer was separated. The aqueous layer was extracted
with EtOAc (50 mL), and the combined organic extracts were dried
with sodium sulfate and concentrated in vacuo, giving crude alcohol 36
as a 10:1 mixture of diastereomers. The diastereomeric ratio was
25
1
[α]D +1.9 (c = 1.25, CHCl3); H NMR (600 MHz, CDCl3) δ 3.83
(dd, J = 4.2, 3.0 Hz, 1H), 2.68 (m, 1H), 2.33 (m, 2H), 2.01 (m, 2H),
1.84−1.54 (m, 5H), 1.48−1.40 (m, 1H), 1.27 (m, 3H), 1.23 (m, 3H),
1.09 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 214.2, 214.1, 75.6,
74.4, 64.7, 64.3, 59.1, 58.7, 54.3, 54.0, 37.6, 37.5, 32.0, 31.7, 28.4, 28.3,
24.8, 23.6, 23.5, 20.4, 20.3, 18.6, 18.5, 18.0, 17.1; HRMS (ESI+) calcd
for C13H22O3+Na, 249.1467; found 249.1459; IR (thin film, cm−1)
3446, 3054, 2982, 2874, 1732, 1702, 1497, 1422, 1266, 1156, 1016,
895; TLC (80:20 hexanes/EtOAc) Rf = 0.07.
1
determined by H NMR spectroscopic analysis of the crude reaction
mixture by comparison of the integration of the resonances at δ 1.15
(minor diastereomer) and δ 1.10 (major diastereomer). The product
was purified via flash chromatography (80:20 to 70:30 hexanes/
EtOAc) to afford alcohol 36 (1.32 g, 67% yield) as a yellow, viscous
oil. (Note: for purposes of material throughput, the crude residue may
be stored indefinitely with no deleterious effects to yield. In practice,
up to 8 iterations of this procedure were carried out, and the crude
(4aR,8aS)-2-(2-Hydroxypropan-2-yl)-4a-methyloctahydro-5H-
chromen-5-one (42) and (4aR,5S)-2-(2-hydroxypropan-2-yl)-4a-
methyloctahydro-2H-chromen-5-ol (43). A 20 mL scintillation vial
was charged with keto-epoxide 41 (0.05 g, 0.22 mmol, 1.00 equiv) and
N
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The Journal of Organic Chemistry
Article
CH2Cl2 (2 mL), and PPTS (0.01 g, 0.04 mmol, 0.20 equiv) was added.
The mixture was allowed to stir at rt until TLC analysis indicated
complete consumption of the starting material, typically 30 min. The
reaction mixture was diluted with saturated NaHCO3(aq) (5 mL) and
transferred to a separatory funnel. The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL), and the combined organic extracts were
dried with sodium sulfate and concentrated in vacuo. Crude 1H NMR
analysis revealed an inseparable ∼1:5 mixture of diastereomeric
tetrahydropyrans 42 and diastereomeric vinyl ethers 43. The crude 1H
NMR spectrum is included in the Supporting Information: HRMS
(ESI+) calcd for +Na, 249.1467; found 249.1459.
N′-((2S,3S,E)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)-
cyclohexylidene)-4-methylbenzenesulfonohydrazide (44). The alco-
hol 40 (8.20 g, 38.99 mmol, 1.00 equiv) was dissolved in wet C7H8
(195 mL) in a 500 mL round-bottomed flask, and p-toluenesulfo-
nylhydrazine (8.71 g, 46.79 mmol, 1.20 equiv) was added with
magnetic stirring. The mixture was placed in a preheated oil bath at 70
°C and allowed to stir for 50 min. (Note: product decomposition was
observed if the reaction was allowed to stir for longer than this time
period.) The resulting mixture was cooled to rt and concentrated on a
rotary evaporator. The product was purified via flash chromatography
(70:30 to 60:40 to 50:50 hexanes/EtOAc) to provide the hydrazone
44 (14.75 g, > 99% yield) as a pale yellow, viscous foam. Analytical
data: [α]D28 −144.6 (c = 0.50, CHCl3); 1H NMR (600 MHz, CDCl3)
δ 7.82 (d, J = 8.4 Hz, 2H), 7.64 (br s, 1H), 7.28 (d, J = 7.8 Hz, 2H),
4.93 (t, J = 6.6 Hz, 1H), 3.63 (dd, J = 3.0, 2.4 Hz, 1H), 2.39 (s, 3H),
2.35 (m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 1.75−1.66 (m, 3H), 1.64
(s, 3H), 1.57−1.49 (m, 2H), 1.46 (s, 3H), 1.37 (m, 2H), 1.04 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 163.3, 143.9, 135.1, 131.5, 129.3,
complete consumption of the starting material. The suspension was
filtered through a pad of Celite and concentrated on a rotary
evaporator to afford hydrazone 46 (0.05 g, > 99% crude yield) as a
1
single diastereomer (as determined by H NMR analysis of the crude
mixture, which revealed a single stereoisomer). When this material was
subjected to the reaction conditions used in the conversion of 44 to
45, no reaction was observed, and the starting material was recovered
28
1
quantitatively. Analytical data: [α]D −51.9 (c = 1.25, CHCl3); H
NMR (600 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.65 (br s, 1H),
7.28 (d, J = 7.8 Hz, 2H), 3.63 (dd, J = 3.0, 1.8 Hz, 1H), 2.40 (s, 3H),
2.36 (m, 1H), 1.93 (m, 2H), 1.79−1.64 (m, 3H), 1.56 (m, 1H), 1.46
(m, 1H), 1.34 (m, 1H), 1.27 (m, 1H), 1.02 (s, 3H), 1.00−0.98 (m,
3H), 0.77 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 163.5, 143.8, 135.2, 129.3, 128.2, 75.6, 47.6,
39.5, 36.8, 27.7, 27.6, 22.6, 22.5, 21.5, 21.1, 19.7, 19.2; HRMS (ESI+)
calcd for C20H32N2O3S+Na, 403.2031; found 403.2022; IR (thin film,
cm−1) 3503. 3214, 2951, 2868, 1670, 1470, 1329, 1165, 1092, 1001,
924; TLC (80:20 hexanes/EtOAc) Rf = 0.07.
N′-((2S,4aS,8aS,E)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4 a - m e t h y l o c t a h y d r o - 5 H - c h r o m e n - 5 - y l i d e n e ) - 4 -
methylbenzenesulfonohydrazide(49). A flame-dried, 150 mL round-
bottomed flask was charged with pyran 45 (9.41 g, 23.88 mmol, 1.00
equiv) and CH2Cl2 (120 mL) under an atmosphere of N2. The
reaction mixture was cooled to −50 °C (CO2(s)/acetonitrile bath), and
2,6-lutidine (5.50 mL, 47.46 mmol, 2.00 equiv) and TBSOTf (9.87
mL, 42.99 mmol, 1.8 equiv) were added sequentially. The reaction was
allowed to stir at this temperature until TLC analysis confirmed
complete consumption of the starting material, typically 30 min. The
reaction was quenched via addition of saturated NaHCO3(aq) (40 mL),
and the mixture was warmed to rt and partitioned in a separatory
funnel. The aqueous layer was extracted with EtOAc (3 × 30 mL), and
the combined organic extracts were washed with brine (40 mL), dried
with magnesium sulfate, and concentrated in vacuo. The product was
purified via flash chromatography (100:0 to 95:5 to 90:10 to 80:20
hexanes/EtOAc) to remove silanol byproducts then purified a second
time (90:10 to 80:20 hexanes/EtOAc) to afford silyl ether 49 (9.46 g,
128.2, 124.1, 75.4, 47.6, 36.5, 25.6, 22.0, 21.5, 19.8, 19.1, 17.5; HRMS
(ESI+) calcd for C20H30N2O3S+Na, 401.1875; found 401.1892; IR
(thin film, cm−1) 3516, 3212, 2933, 2872, 1914, 1725, 1598, 1447,
1329, 1185, 1165, 1091, 736; TLC (80:20 hexanes/EtOAc) Rf = 0.17.
N′-((2S,4aS,8aS,E)-2-(2-Hydroxypropan-2-yl)-4a-methyloctahy-
dro-5H-chromen-5-ylidene)-4-methylbenzenesulfonohydrazide(45).
Hydrazone 44 (14.76 g, 38.99 mmol, 1.00 equiv) was dissolved in
CH2Cl2 (320 mL) in a 1000 mL round-bottomed flask with stirring.
The mixture was cooled to 0 °C, and m-CPBA (14.42 g, 70%
dispersion in H2O, 58.49 mmol, 1.50 equiv) was added. The reaction
was allowed to stir at this temperature until TLC analysis showed full
conversion of the starting material, typically 10 min. The reaction was
quenched via addition of saturated Na2S2O3(aq) (70 mL), and the
mixture was partitioned in a separatory funnel. The mixture was
extracted with CH2Cl2 (3 × 50 mL), and the combined organic
extracts were washed with brine (50 mL), dried with magnesium
sulfate, and concentrated to a volume of ∼300 mL on a rotary
evaporator. A stir bar was added followed by PPTS (0.98 g, 3.90
mmol, 0.10 equiv), and the mixture was allowed to stir 12 h at rt. The
reaction mixture was then concentrated in vacuo to give the crude
28
79% yield) as a pale yellow, viscous foam. Analytical data: [α]D
−75.5 (c = 0.35, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J =
8.4 Hz, 2H), 7.57 (br s, 1H), 7.31 (d, J = 7.8 Hz, 2H), 3.04 (dd, J =
7.8, 3.6 Hz, 1H), 2.99 (d, J = 11.4 Hz, 1H), 2.50 (d, J = 14.4 Hz, 1H),
2.43 (s, 3H), 1.93 (m, 1H), 1.83−1.76 (m, 2H), 1.68−1.50 (m, 6H),
1.19 (s, 3H), 1.15 (s, 3H), 0.95 (s, 3H), 0.84 (s, 9H), 0.07 (s, 3H),
0.04 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 165.0, 143.8, 135.2,
129.3, 128.1, 85.3, 82.0, 76.8, 74.7, 42.5, 32.4, 27.2, 25.1, 21.6, 21.3,
17.3, −2.1, −2.2; HRMS (ESI+) calcd for C26H44N2O4SSi+Na,
531.2689; found 531.2704; IR (thin film, cm−1) 3433, 3054, 2985,
2855, 2305, 1630, 1422, 1167, 1092, 835, 739; TLC (80:20 hexanes/
EtOAc) Rf = 0.37.
(2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-4a-
methyl-3,4,4a,7,8,8a-hexahydro-2H-chromene-5-carbaldehyde
(50). A flame-dried, 100 mL round-bottomed flask was charged with
hydrazone 49 (2.00 g, 3.93 mmol, 1.00 equiv) and THF (39 mL)
under an atmosphere of N2. The mixture was cooled to −50 °C, and
nBuLi (1.64 M in hexane, 12.0 mL, 19.7 mmol, 5.00 equiv) was added
1
tetrahydropyran 45 as a single diastereomer (as determined by H
NMR spectroscopic analysis of the crude reaction mixture, which
revealed a single stereoisomer). The product was purified via flash
chromatography (60:40 to 50:50 to 40:60 hexanes/EtOAc) to afford
pyran 45 (11.63 g, 76% yield) as a pale yellow, viscous foam. Analytical
data: [α]D28 −63.2 (c = 0.40, CHCl3); 1H NMR (600 MHz, CDCl3) δ
7.82 (d, J = 7.8 Hz, 2H), 7.73 (br s, 1H), 7.30 (d, J = 7.8 Hz, 2H), 3.11
(t, J = 3.6 Hz, 1H), 3.09 (t, J = 2.4 Hz, 1H), 2.52 (dd, J = 12.0, 3.0 Hz,
1H), 2.45−2.40 (m, 4H), 1.94 (m, 1H), 1.82 (m, 2H), 1.67 (m, 2H),
1.59−1.50 (m, 3H), 1.33−1.26 (m, 2H), 1.15 (s, 3H), 1.14 (s, 3H),
0.96 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 164.5, 143.9, 135.1,
129.3, 128.1, 84.5, 82.0, 71.8, 42.4, 32.1, 26.3, 21.6, 17.2; HRMS
(ESI+) calcd for C20H30N2O4S+Na, 417.1824; found 417.1840; IR
(thin film, cm−1) 3451, 3216, 2946, 2870, 1630, 1598, 1450, 1333,
1166, 1089, 925; TLC (80:20 hexanes/EtOAc) Rf = 0.11.
N′-((2S,3S,E)-3-Hydroxy-2-methyl-2-(4-methylpentyl)-
cyclohexylidene)-4-methylbenzenesulfonohydrazide (46). A 20 mL
scintillation vial was charged with alkene 44 (0.05 g, 0.13 mmol, 1.00
equiv) and MeOH (4 mL). Pd/C (0.025 g, 0.50 mass equiv) was
added, and the resulting suspension was placed under 1 atm H2
(balloon) and allowed to stir 1 h, whereupon TLC analysis indicated
dropwise, producing a dark orange color. The mixture was allowed to
stir 30 min at −50 °C. The flask was fitted with a venting needle, and
the mixture was warmed to 0 °C and stirred 5 min, then warmed to rt
and stirred until complete consumption of the starting material was
observed by TLC analysis, typically 20 min (scale dependent). The
venting needle was removed, and DMF (3.02 mL, 39.3 mmol, 10.0
equiv) was added. Following this addition, the reaction was stirred 20
min, diluted with H2O (20 mL) and Et2O (20 mL) and transferred to
a separatory funnel. The organic layer was separated, and the aqueous
layer was extracted with Et2O (3 × 20 mL). The combined organic
extracts were washed with brine (20 mL), dried with magnesium
sulfate, and concentrated in vacuo. The product was purified via flash
chromatography (100:0 to 95:5 to 90:10 hexanes/EtOAc) to afford
unsaturated aldehyde 50 (0.92 g, 66% yield) as a yellow, viscous oil.
28
1
Analytical data: [α]D −138.0 (c = 0.55, CHCl3); H NMR (600
MHz, CDCl3) δ 9.38 (s, 1H), 6.55 (t, J = 3.0 Hz, 1H), 3.22 (dd, J =
O
DOI: 10.1021/acs.joc.5b01844
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The Journal of Organic Chemistry
Article
8.4, 3.6 Hz, 1H), 3.15 (dd, J = 9.0, 3.0 Hz, 1H), 2.70 (m, 1H), 2.46 (m,
2H), 1.68 (m, 2H), 1.57 (m, 2H), 1.28 (m, 1H), 1.23 (s, 3H), 1.18 (s,
3H), 1.14 (s, 3H), 0.84 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 193.8, 151.0, 148.3, 85.9, 80.9, 74.9, 35.4, 32.6,
27.2, 26.4, 25.8, 25.1, 23.2, 21.3, 17.9, −2.2; HRMS (ESI+) calcd for
C20H36O3Si+Na, 375.2331; found 375.2323; IR (thin film, cm−1)
3435, 2955, 2855, 1692, 1635, 1472, 1376, 1251, 1173, 1042; TLC
(90:10 hexanes/EtOAc) Rf = 0.49.
added drop-by-drop until the reaction pH reached <1 (scale-
dependent, ∼2 mL was required in this iteration), resulting in the
formation of a white suspension. The resulting mixture was warmed to
rt and stirred vigorously for 1 h, whereupon the mixture was
neutralized with saturated NaHCO3(aq) (20 mL). The mixture was
transferred to a separatory funnel, the layers were separated, and the
aqueous layer was extracted with Et2O (3 × 15 mL). The combined
organic extracts were washed with brine (15 mL), dried with
magnesium sulfate, and concentrated in vacuo to give the crude
nonconjugated enone, which was used in the next step without further
purification.
tert-Butyldimethyl-((2-((2S,4aS,8aS)-4a-methyl-5-vinyl-
3,4,4a,7,8,8a-hexahydro-2H-chromen-2-yl)propan-2-yl)oxy)silane
(51). A flame-dried, 100 mL round-bottomed flask was charged with
methyltriphenylphosphonium bromide (4.90 g, 13.7 mmol, 6.00
equiv) and THF (20 mL) under an atmosphere of N2. The mixture
The crude ketone was transferred to a flame-dried, 50 mL round-
bottomed flask and dissolved in CH2Cl2 (18 mL) under an
atmosphere of N2. DBU (0.52 mL, 3.60 mmol, 2.00 equiv) was
added, and the mixture was allowed to stir at rt until complete
conversion of the starting material was observed by TLC analysis,
typically 3 h. The reaction was diluted with H2O (15 mL) and
transferred to a separatory funnel. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were dried with sodium sulfate and
concentrated in vacuo. The product was purified via flash
chromatography (100:0 to 97.5:2.5 to 95:5 to 90:10 hexanes/
EtOAc) to afford conjugated enone 53 (0.38 g, 54% yield) as a
n
was cooled to 0 °C and BuLi (1.65 M in hexanes, 7.63 mL, 12.6
mmol, 5.50 equiv) was added dropwise. The deep yellow mixture was
allowed to stir 1 h at 0 °C upon which the aldehyde 50 (0.81 g, 2.29
mmol, 1.00 equiv) was added as a solution in THF (3 mL). The
reaction was allowed to stir until complete consumption of the starting
material was observed by TLC analysis, typically 15 min. The reaction
was diluted with H2O (15 mL) and transferred to a separatory funnel.
The layers were separated, and the aqueous layer was extracted with
Et2O (3 × 15 mL). The combined organic extracts were washed with
brine (15 mL), dried with magnesium sulfate, and concentrated in
vacuo. The product was purified via flash chromatography (100:0 to
99:1 to 97.5:2.5 hexanes/EtOAc) to afford diene 51 (0.69 g, 86%
yield) as a clear oil. Analytical data: [α]D28 −167.4 (c = 0.35, CHCl3);
1H NMR (600 MHz, CDCl3) δ 6.24 (dd, J = 10.8, 6.0 Hz, 1H), 5.61
28
yellow solid. Analytical data: mp 85−89 °C; [α]D −118.8 (c = 0.85,
1
CHCl3); H NMR (600 MHz, CDCl3) δ 3.19 (dd, J = 9.6, 3.0 Hz,
1H), 3.08 (dd, J = 4.2, 4.2 Hz, 1H), 2.44 (m, 2H), 2.34−2.20 (m, 4H),
2.01 (m, 1H), 1.93 (dt, J = 6.0, 3.0 Hz, 1H), 1.84 (m, 1H), 1.76 (m,
1H), 1.65−1.59 (m, 3H), 1.40 (m, 1H), 1.24 (s, 3H), 1.19 (s, 3H),
1.10 (s, 3H), 0.84 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 199.8, 162.7, 129.8, 85.1, 80.4, 74.8, 38.0, 37.7, 33.3,
27.5, 25.8, 25.2, 24.9, 23.3, 22.9, 22.4, 21.4, 18.1, 18.0, −2.1, −2.2;
HRMS (ESI+) calcd for C23H40O3Si+Na, 415.2644; found 415.2636;
IR (thin film, cm−1) 3053, 2954, 2887, 2855, 1683, 1616, 1576, 1472,
1362, 1265, 1172, 1045; TLC (90:10 hexanes/EtOAc) Rf = 0.34.
(3S,4aS,6aR,10aS,10bS)-3-(2-((tert-Butyldimethylsilyl)oxy)-
propan-2-yl)-6a,10b-dimethyldodecahydro-7H-benzo[f ]chromen-
7-one (54). An oven-dried, 50 mL two-neck round-bottomed flask was
fitted with a stir bar and an oven-dried coldfinger condenser and
placed under an atmosphere of Ar. The flask and condenser were
cooled to −78 °C, and liq. NH3 (5 mL) was allowed to condense into
the flask. Freshly cut Li0 (0.01 g, 1.43 mmol, 14.3 equiv) was washed
with hexanes and added to the flask, resulting in the formation of a
dark blue color. After being stirred 5 min at −78 °C, a solution of
ketone 53 (0.04 g, 0.10 mmol, 1.00 equiv) in THF (3 mL) was added,
and the reaction was warmed to −33 °C and stirred 15 min. The
reaction was the cooled to −78 °C, diluted with THF (5 mL), and a
solution of MeI (0.38 mL, 6.0 mmol, 60.0 equiv) in THF (2 mL) was
added dropwise. The mixture was allowed to warm to rt and stirred
until liq. NH3 had completely evaporated. The residue was quenched
with saturated NH4Cl(aq) (10 mL), diluted with Et2O (10 mL) and
transferred to a separatory funnel. The organic layer was separated,
and the aqueous layer was extracted with Et2O (3 × 10 mL). The
combined organic extracts were dried with magnesium sulfate and
concentrated in vacuo to give the crude ketone 54 as a single
diastereomer (as determined by 1H NMR spectroscopic analysis of the
crude reaction mixture, which revealed a single compound). The
product was purified via flash chromatography (100:0 to 98:2 to 95:5
to 90:10 hexanes/EtOAc) to afford ketone 54 (0.025 g, 61% yield) as
a clear, viscous oil. Analytical data: [α]D28 −38.2 (c = 0.75, CHCl3); 1H
NMR (600 MHz, CDCl3) δ 2.98 (dd, J = 8.4, 3.0 Hz, 1H), 2.84 (dd, J
= 7.8, 3.6 Hz, 1H), 2.64 (m, 1H), 2.44 (dt, J = 7.2, 3.0 Hz, 1H), 2.25
(dd, J = 10.2, 6.0 Hz, 1H), 2.08 (m, 2H), 1.95−1.87 (m, 3H), 1.52−
1.44 (m, 5H), 1.25 (m, 1H), 1.24 (s, 3H), 1.20 (s, 3H), 1.14 (s, 3H),
1.06 (m, 1H), 0.83 (s, 9H), 0.82 (s, 3H) 0.06 (s, 3H), 0.04 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 216.0, 84.9, 84.3, 74.8, 54.4, 47.9,
(t, J = 3.6 Hz, 1H), 5.26 (d, J = 17.4 Hz, 1H), 4.93 (d, J = 10.8 Hz,
1H), 3.23 (dd, J = 5.4, 4.8 Hz, 1H), 3.12 (m, 1H), 2.20 (m, 1H), 1.93
(dt, J = 6.0, 3.0 Hz, 1H), 1.66 (m, 2H), 1.60 (m, 2H), 1.35 (m, 1H),
1.24 (s, 3H), 1.18 (s, 3H), 1.07 (s, 3H), 0.85 (s, 9H), 0.09 (s, 3H),
0.06 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.5, 135.4, 121.6,
113.5, 85.5, 81.5, 74.9, 36.1, 34.3, 27.4, 25.9, 25.0, 23.8, 21.8, 18.9,
18.2, −2.1, −2.2; HRMS (ESI+) calcd for C21H38O2Si+Na, 373.2539;
found 373.2529; IR (thin film, cm−1) 3053, 2985, 2956, 2854, 2685,
1716, 1636, 1456, 1265, 1143; TLC (90:10 hexanes/EtOAc) Rf = 0.91.
tert-Butyldimethyl-((2-((3S,4aS,10bS)-10b-methyl-7-nitro-
2,3,4a,5,6,6a,7,8,9,10b-decahydro-1H-benzo[f ]chromen-3-yl)-
propan-2-yl)oxy)silane (52). A 20 mL scintillation vial was charged
with diene 51 (0.66 g, 1.88 mmol, 1.00 equiv) and CH2Cl2 (9 mL).
Nitroethylene49 (10 M solution in CH2Cl2, 0.75 mL, 7.50 mmol, 4.00
equiv) was added, and the vial was sealed with a screw-cap. The
mixture was heated to 65 °C and stirred until complete conversion of
the starting material was observed by TLC analysis, typically 12 h. The
mixture was cooled to rt and concentrated on a rotary evaporator. The
product was purified via flash chromatography (100:0 to 97.5:2.5 to
95:5 to 90:10 hexanes/EtOAc) to afford alkene 52 (0.75 g, 95% yield)
as a clear, viscous oil in an inseparable mixture of diastereomers.
Analytical data: [α]D −4.7 (c = 0.75, CHCl3); H NMR (600 MHz,
CDCl3) δ 5.51 (br s, 1H), 5.45 (d, J = 4.8 Hz, 1H), 4.79−4.66 (m,
1H), 4.32−4.20 (m, 1H), 3.45 (dd, J = 7.8, 3.0 Hz, 1H), 3.06−3.01
(m, 4H), 2.96−2.87 (m, 3H), 2.27−1.89 (m, 13H), 1.76−1.72 (m,
3H), 1.66−1.37 (m, 17H), 1.25 (m, 2H), 1.21−1.19 (m, 8H), 1.17−
1.15 (m, 3H), 1.05−1.03 (m, 8H), 0.84 (br s, 25H), 0.07 (s, 8H), 0.05
(s, 8H); 13C NMR (150 MHz, CDCl3) δ 144.8, 143.9, 143.2, 118.4,
117.9, 117.7, 90.6, 89.8, 85.6, 85.4, 85.1, 84.9, 83.4, 82.2, 74.8, 39.6,
37.5, 36.8, 36.4, 36.1, 34.4, 28.0 27.3, 27.1, 27.0, 25.5, 25.2, 25.0, 24.4,
24.0, 23.0, 22.7, 21.9, 21.8, 21.6, 21.5, 18.1, 17.0, −2.2; HRMS (ESI+)
calcd for C23H41NO4Si+Na, 446.2703; found 446.2692; IR (thin film,
cm−1) 3054, 2954, 2930, 2855, 1732, 1670, 1546, 1488, 1362, 1265,
1167, 1046; TLC (90:10 hexanes/EtOAc) Rf = 0.66.
28
1
(3S,4aS,10bS)-3-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
10b-methyl-1,2,3,4a,5,6,8,9,10,10b-decahydro-7H-benzo[f ]-
chromen-7-one (53). A 100 mL round-bottomed flask was charged
with alkene 52 (0.753 g, 1.78 mmol, 1.00 equiv) and a 1:1 mixture of
THF/MeOH (35 mL). The solution was cooled to 0 °C, and KOH (1
M in H2O, 5.34 mL, 5.34 mmol, 3.00 equiv) was added dropwise,
subsequently warming to rt. The mixture was stirred until complete
conversion of the starting material was observed by TLC analysis,
typically 45 min. The mixture was cooled to 0 °C, and MsOH was
37.9, 37.3, 36.4, 32.6, 29.9, 27.3, 25.8, 25.1, 25.1, 23.8, 21.5, 19.1, 18.2,
16.0, −2.1, −2.2; HRMS (ESI+) calcd for C24H44O3Si+Na, 431.2957;
found 431.2949; IR (thin film, cm−1) 3421, 2954, 2855, 1792, 1698,
1377, 1265, 1215, 1058; TLC (90:10 hexanes/EtOAc) Rf = 0.54.
P
DOI: 10.1021/acs.joc.5b01844
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The Journal of Organic Chemistry
Article
(3S,4aS,6aS,10aR,10bS)-3-(2-((tert-Butyldimethylsilyl)oxy)-
propan-2-yl)-10b-methyldodecahydro-7H-benzo[f ]chromen-7-one
(55). An oven-dried, 50 mL two-neck round-bottomed flask was fitted
with a stir bar and an oven-dried coldfinger condenser and placed
under an atmosphere of Ar. The flask and condenser were cooled to
−78 °C, and liq. NH3 (5 mL) was allowed to condense into the flask.
Freshly cut Li0 (0.005 g, 0.714 mmol, 14.3 equiv) was washed with
hexanes and added to the flask, resulting in the formation of a dark
blue color. After being stirred 5 min at −78 °C, a solution of ketone 53
(0.02 g, 0.05 mmol, 1.00 equiv) in THF (2 mL) was added, and the
reaction was warmed to −33 °C and stirred 15 min. The reaction was
carefully quenched via portionwise addition of NH4Cl(s), and the
mixture was allowed to warm to rt and stirred until liq. NH3 had
completely evaporated. The residue was diluted with H2O (10 mL)
and Et2O (10 mL) and transferred to a separatory funnel. The organic
layer was separated, and the aqueous layer was extracted with Et2O (3
× 10 mL). The combined organic extracts were dried with magnesium
sulfate and concentrated in vacuo to afford the crude ketone as a 1:1
mixture of diastereomers, which was taken on directly to the next step
without further purification. A crude 1H NMR spectrum of this
reaction is included in the Supporting Information.
This crude residue was transferred to a flame-dried, 20 mL
scintillation vial and dissolved in C7H8 under an atmosphere of N2.
DBU (0.01 mL, 0.05 mmol, 1.00 equiv) was added, and the mixture
was warmed to 65 °C and stirred 12 h. The reaction was cooled to rt,
diluted with H2O (10 mL) and CH2Cl2 (5 mL) and transferred to a
separatory funnel. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic
extracts were dried with magnesium sulfate and concentrated in vacuo.
At this juncture, crude 1H NMR analysis revealed complete
epimerization to a single diastereomer. The product was purified via
flash chromatography (100:0 to 97.5:2.5 to 90:10 hexanes/EtOAc) to
afford ketone 55 (0.015 g, 75% yield) as a clear, viscous oil. Analytical
data: [α]D28 −72.0 (c = 0.75, CHCl3); 1H NMR (600 MHz, CDCl3) δ
3.03 (dd, J = 7.2, 3.6 Hz, 1H), 2.87 (dd, J = 7.8, 3.6 Hz, 1H), 2.36 (m,
1H), 2.26 (m, 2H), 2.10 (m, 1H), 1.91−1.83 (m, 3H), 1.63 (m, 1H),
1.57−1.52 (m, 4H), 1.43−1.36 (m, 3H), 1.21 (s, 3H), 1.16 (br s, 4H),
0.91 (s, 3H), 0.84 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 213.2, 85.1, 83.2, 74.8, 52.3, 49.2, 41.8, 36.7, 36.6,
27.4, 26.5, 26.2, 25.8, 24.9, 24.3, 23.6, 21.8, 18.1, 12.1, −2.1, −2.2;
HRMS (ESI+) calcd for C23H42O3Si+Na, 417.2801; found 417.2793;
IR (thin film, cm−1) 3420, 2951, 2854, 1715, 1652, 1472, 1376, 1251,
1155, 1051, 835; TLC (90:10 hexanes/EtOAc) Rf = 0.40.
1396, 1265, 1173, 1072, 835, 739; TLC (90:10 hexanes/EtOAc) Rf =
0.25.
(3S,4aS,7S,10bS)-3-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
10b-methyl-2,3,4a,5,6,7,8,9,10,10b-decahydro-1H-benzo[f ]-
chromen-7-ol (57). A flame-dried, 20 mL scintillation vial was charged
with ketone 53 (0.06 g, 0.15 mmol, 1.0 equiv) and THF (2 mL) under
an atmosphere of N2. The reaction mixture was cooled to −78 °C, and
LiAl(OtBu)3H (1 M solution in THF, 0.31 mL, 0.31 mmol, 2.00
equiv) was added in one portion. The reaction mixture was allowed to
stir for 12 h, slowly warming to rt during this time period at which
point TLC analysis confirmed complete consumption of the starting
material. The reaction was quenched via saturated NH4Cl(aq) (5 mL)
and transferred to a separatory funnel. The organic layer was
separated, and the aqueous layer was extracted with Et2O (3 × 7
mL). The combined organic extracts were dried with magnesium
sulfate and concentrated in vacuo to give the crude alcohol as a 10:1
mixture of diastereomers. The diastereomeric ratio was determined by
1H NMR spectroscopic analysis of the crude reaction mixture by
comparison of the integration of the resonances at δ 3.99 (major
diastereomer) and δ 3.82 (minor diastereomer). The product was
purified via flash chromatography (90:10 to 80:20 hexanes/EtOAc) to
afford alcohol 57 (0.054 g, 90% yield) as a clear, viscous oil. Analytical
data: [α]D28 −92.7 (c = 1.00, CHCl3); 1H NMR (600 MHz, CDCl3) δ
3.99 (m, 1H), 3.20 (dd, J = 8.4, 3.6 Hz, 1H), 3.08 (dd, J = 7.2, 3.6 Hz,
1H), 2.49 (m, 1H), 1.98 (m, 2H), 1.88 (m, 2H), 1.82 (m, 1H), 1.71
(m, 2H), 1.65 (m, 2H), 1.57 (m, 2H), 1.52 (m, 2H), 1.29 (m, 1H),
1.23 (s, 3H), 1.17 (s, 3H), 0.99 (s, 3H), 0.84 (s, 9H), 0.08 (s, 3H),
0.06 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 139.7, 128.2, 85.1, 81.2,
74.9, 70.6, 34.5, 34.0, 32.6, 27.3, 26.8, 25.9, 25.1, 24.0, 23.8, 21.8, 19.8,
18.4, 18.2, −2.1, −2.2; HRMS (ESI+) calcd for C23H42O3Si+Na,
417.2801; found 417.2791; IR (thin film, cm−1) 3420, 2930, 2855,
1683, 1636, 1507, 1456, 1361, 1264, 1046, 835; TLC (90:10 hexanes/
EtOAc) Rf = 0.25.
N′-((2S,4aS,8aS,E)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyloctahydro-5H-chromen-5-ylidene)-4-methylbenzene-
sulfonohydrazide (59). A flame-dried, 500 mL round-bottomed flask
was charged with hydrazone 49 (6.21 g, 12.2 mmol, 1.00 equiv) and
THF (122 mL) under an atmosphere of N2. The mixture was cooled
n
to −50 °C, and BuLi (2.60 M in hexanes, 16.4 mL, 42.7 mmol, 3.50
equiv) was added over a period of ∼2 min, producing a dark orange
color. The reaction mixture was allowed to stir 40 min, whereupon
MeI (1.90 mL, 30.5 mmol, 2.50 equiv) was added, resulting in a color
change from orange to yellow. The reaction was allowed to stir until
complete consumption of the starting material was observed by TLC
analysis, typically 20 min. The reaction was quenched via saturated
NH4Cl(aq) (40 mL) and allowed to warm to rt. The mixture was
transferred to a separatory funnel, the organic layer was separated, and
the aqueous layer was extracted with Et2O (3 × 40 mL). The
combined organic extracts were washed with brine (40 mL), dried
with magnesium sulfate and concentrated in vacuo. The product was
purified via flash chromatography (90:10 to 80:20 hexanes/EtOAc) to
afford hydrazone 59 (6.37 g, 98% yield) as a white foam in a 7:1
diastereomeric ratio. Analytical data: [α]D28 −121.0 (c = 0.60, CHCl3);
1H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 2H), 7.72 (br s,
(3S,4aS,6aS,10aR,10bR)-3-(2-((Butyldimethylsilyl)oxy)propan-2-
yl)-10b-methyloctahydro-1H-6a,10a-epoxybenzo[f ]chromen-
7(8H)-one (56). A 20 mL scintillation vial was charged with enone 53
(0.10 g, 0.26 mmol, 1.00 equiv) and (CH2Cl)2 (5 mL). p-NPBA32
(0.19 g, 0.89 mmol, 3.50 equiv) was added, and the vial was sealed
with a screw-cap. The mixture was warmed to 65 °C and stirred until
complete consumption of the starting material was observed by TLC
analysis, typically 3 h. The reaction mixture was warmed to rt,
quenched via saturated Na2S2O3(aq) (5 mL), and transferred to a
separatory funnel. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 7 mL). The combined organic
extracts were dried with sodium sulfate and concentrated in vacuo to
afford the crude epoxide as a single diastereomer (as determined by 1H
NMR spectroscopic analysis of the crude reaction mixture, which
revealed a single compound). The product was purified via flash
chromatography (100:0 to 97.5:2.5 to 95:5 hexanes/EtOAc) to afford
keto-epoxide 56 (0.05 g, 47% yield) as a clear, viscous oil. Slow
evaporation of 56 from HPLC grade methanol afforded crystals
1H), 7.30 (d, J = 7.8 Hz, 2H), 3.05 (m, 1H), 3.00 (s, 1H), 2.73 (q, J =
7.8 Hz, 1H), 2.43 (s, 3H), 2.01 (d, J = 13.2 Hz, 1H), 1.69 (m, 1H),
1.57−1.54 (m, 5H), 1.45 (m, 1H), 1.34 (m, 1H), 1.20 (s, 3H), 1.15 (s,
3H), 1.07 (d, J = 7.2 Hz, 3H), 0.95 (s, 3H), 0.84 (s, 9H), 0.07 (s, 3H),
0.04 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 167.1, 143.8, 135.3,
129.3, 128.0, 127.9, 85.2, 82.0, 74.7, 41.9, 33.3, 28.3, 27.7, 27.2, 25.8,
25.0, 22.8, 21.6, 21.2, 19.1, 18.3, 18.1, −2.1, −2.2; HRMS (ESI+) calcd
for C27H46N2O4SSi+Na, 545.2845; found 545.2840; IR (thin film,
cm−1) 3225, 2954, 2855, 1472, 1396, 1265, 1168, 1090, 1038, 812,
773; TLC (90:10 hexanes/EtOAc) Rf = 0.35.
(2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-4a,6-
dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromene-5-carbaldehyde
(60). A flame-dried, 25 mL round-bottomed flask was charged with
hydrazone 59 (0.48 g, 0.92 mmol, 1.00 equiv) and THF (9.5 mL)
under an atmosphere of N2. The solution was cooled to −50 °C, and
nBuLi (1.70 M in hexanes, 3.25 mL, 5.52 mmol, 6.00 equiv) was added
28
suitable for X-ray crystallographic analysis. Analytical data: [α]D
−105.2 (c = 0.70, CHCl3); 1H NMR (600 MHz, CDCl3) δ 3.43 (dd, J
= 8.4, 4.2 Hz, 1H), 3.06 (m, 1H), 2.58 (m, 1H), 2.08 (m, 2H), 1.91−
1.85 (m, 3H), 1.64 (m, 3H), 1.55−1.49 (m, 3H), 1.37 (m, 1H), 1.20
(s, 3H), 1.15 (s, 3H), 1.03 (s, 3H), 0.84 (s, 9H), 0.07 (s, 3H), 0.05 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 207.2, 84.8, 75.4, 74.7, 64.3,
36.4, 36.2, 32.0, 27.4, 25.8, 24.9, 22.3, 21.6, 21.3,18.9, 18.8, 18.1, 15.9,
−2.1, −2.2; HRMS (ESI+) calcd for C23H40O4Si+Na, 431.2594; found
431.2585; IR (thin film, cm−1) 3420, 2955, 2856, 1704, 1646, 1488,
Q
DOI: 10.1021/acs.joc.5b01844
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
28
over a period of ∼2 min, producing a dark orange color. The reaction
was allowed to stir 30 min, whereupon a venting needle was added,
and the mixture was warmed to 0 °C and stirred 5 min. The reaction
was then warmed to rt and stirred until complete consumption of the
starting material was observed by TLC analysis, typically 20 min. The
venting needle was removed, DMF (0.71 mL, 9.2 mmol, 10.0 equiv)
was added, and the reaction was stirred 20 min. The mixture was
diluted with H2O (15 mL) and Et2O (10 mL) and transferred to a
separatory funnel. The organic layer was separated, and the aqueous
layer was extracted with Et2O (3 × 15 mL). The combined organic
extracts were washed with brine (15 mL), dried with magnesium
sulfate and concentrated in vacuo. The product was purified via flash
chromatography (95:5 to 90:10 hexanes/EtOAc) to afford aldehyde
yield) as a clear oil. Analytical data: [α]D −49.8 (c = 1.25, CHCl3);
1H NMR (600 MHz, CDCl3) δ 6.37 (m, 1H), 6.05 (m, 2H), 5.15 (d, J
= 16.8 Hz, 1H), 5.03 (d, J = 10.2 Hz, 1H), 3.19 (dd, J = 7.2, 4.8 Hz,
1H), 2.20 (m, 1H), 2.11 (dd, J = 12.6, 5.4 Hz, 1H), 1.88 (dt, J = 6.0,
3.0 Hz, 1H), 1.68 (br s, 5H), 1.56 (m, 2H), 1.27 (m, 1H), 1.23 (s,
3H), 1.17 (s, 3H), 1.04 (s, 3H), 0.84 (s, 9H), 0.08 (s, 3H), 0.06 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 137.7, 137.1, 133.9, 130.7,
128.7, 115.4, 85.2, 81.4, 74.9, 36.6, 35.3, 31.8, 27.3, 25.8, 25.0, 24.2,
21.8, 20.8, 18.9, 18.2, −2.1, −2.2; HRMS (ESI+) calcd for C24H42O2Si
+Na, 413.2852; found 413.2843; IR (thin film, cm−1) 3420, 2929,
2855, 1670, 1497, 1457, 1387, 1265, 1165, 1040, 835; TLC (90:10
hexanes/EtOAc) Rf = 0.94.
((2-((2S,4aS,8aS,E)-5-(But-3-en-1-ylidene)-4a-methyl-6-methyle-
neoctahydro-2H-chromen-2-yl)propan-2-yl)oxy)(tert-butyl)-
dimethylsilane (65). The triene 63 (0.017 g, 0.043 mmol, 1.00 equiv)
was taken up into hexanes and transferred to a toroidal photochemical
reactor equipped with a water-cooled Pyrex immersion well. A 450 W
Hanovia medium pressure mercury vapor lamp was lowered inside the
immersion well, and the triene solution was irradiated for 1 h. The
solution was subsequently concentrated in vacuo. The product was
purified via flash chromatography to give rearrangement product 65
28
60 (0.21 g, 62% yield) as a yellow, viscous oil. Analytical data: [α]D
−151.8 (c = 0.80, CHCl3); 1H NMR (600 MHz, CDCl3) δ 10.05 (br s,
1H), 3.16 (m, 1H), 3.11 (dd, J = 9.0, 3.0 Hz, 1H), 2.65 (m, 1H), 2.38
(m, 1H), 2.28 (m, 1H), 2.06 (s, 3H), 1.69 (m, 2H), 1.62−1.53 (m,
3H), 1.22 (s, 3H), 1.17 (s, 3H), 1.14 (s, 3H), 0.84 (s, 9H), 0.08 (s,
3H), 0.05 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.9, 153.9,
140.3, 85.8, 80.6, 74.9, 35.7, 34.3, 33.5, 27.1, 25.8, 25.1, 23.7, 21.6,
18.8, 18.2, 18.1, −2.1, −2.2; HRMS (ESI+) calcd for C21H38O3Si+Na,
389.2488; found 389.2481; IR (thin film, cm−1) 2954, 2928, 2855,
1733, 1674, 1472, 1376, 1251, 1095, 1005, 835; TLC (90:10 hexanes/
EtOAc) Rf = 0.50.
28
(0.009 g, 53% yield) as a clear, viscous oil. Analytical data: [α]D
−11.8 (c = 0.10, CHCl3); H NMR (600 MHz, CDCl3) δ 5.83 (m,
1
1H), 5.20 (t, J = 7.8 Hz, 1H), 5.01 (m, 1H), 4.97 (m, 1H), 4.66 (t, J =
1.8 Hz, 1H), 3.10 (dd, J = 7.8, 4.2 Hz, 1H), 3.05 (m, 1H), 2.90 (m,
2H), 2.33 (m, 1H), 2.06 (m, 1H), 1.70 (m, 2H), 1.66−1.55 (m, 6H),
1.22 (s, 3H, 1.17 (s, 3H), 0.94 (s, 3H), 0.85 (s, 9H), 0.08 (s, 3H), 0.05
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 148.0, 144.1, 138.3, 119.1,
114.3, 112.8, 85.2, 82.5, 74.9, 39.8, 34.5, 33.8, 33.2, 28.5, 27.2, 25.8,
25.1, 21.9, 18.2, 17.9, −2.1, −2.2; HRMS (ESI+) calcd for C24H42O2Si
+Na, 413.2852; found 413.2843; IR (thin film, cm−1) 3053, 2956,
2855, 1749, 1670, 1540, 1456, 1265, 1046, 835; TLC (90:10 hexanes/
EtOAc) Rf = 0.97.
tert-Butyl((2-((2S,4aS,8aS)-4a,6-dimethyl-5-vinyl-3,4,4a,7,8,8a-
hexahydro-2H-chromen-2-yl)propan-2-yl)oxy)dimethylsilane (61).
A flame-dried, 25 mL round-bottomed flask was charged with
methyltriphenylphosphonium bromide (1.90 g, 5.28 mmol, 8.00
equiv) and THF (7 mL) under an atmosphere of N2. The mixture was
n
cooled to 0 °C and BuLi (1.69 M in hexanes, 2.94 mL, 4.95 mmol,
7.50 equiv) was added dropwise. The deep yellow mixture was allowed
to stir 1 h at 0 °C upon which the aldehyde 60 (0.24 g, 0.66 mmol,
1.00 equiv) was added as a solution in THF (2 mL). The reaction was
allowed to stir until complete consumption of the starting material was
observed by TLC analysis, typically 15 min. The reaction was diluted
with H2O (15 mL) and transferred to a separatory funnel. The layers
were separated, and the aqueous layer was extracted with Et2O (3 × 15
mL). The combined organic extracts were washed with brine (15 mL),
dried with magnesium sulfate, and concentrated in vacuo. The product
was purified via flash chromatography (100:0 to 99:1 to 97.5:2.5
hexanes/EtOAc) to afford diene 61 (0.20 g, 82% yield) as a clear oil.
Analytical data: [α]D28 −94.4 (c = 1.50, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 6.13 (dd, J = 12.0, 6.0 Hz, 1H), 5.23 (dd, J = 8.4, 3.0 Hz,
1H), 4.96 (dd, J = 15.6, 2.4 Hz, 1H), 3.19 (dd, J = 7.2, 4.8 Hz, 1H),
3.08 (dd, J = 6.6, 4.2 Hz, 1H), 2.18 (m, 1H), 2.08 (dd, J = 11.4, 6.6 Hz,
1H), 1.84 (dt, J = 6.0, 4.2 Hz, 1H), 1.66 (br s, 4H), 1.55 (br s, 3H),
1.28 (m, 1H), 1.23 (s, 3H), 1.17 (s, 3H), 1.02 (s, 3H), 0.84 (s, 9H),
0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 138.1,
134.3, 127.5, 118.0, 85.2, 81.4, 75.0, 36.2, 35.2, 31.6, 27.3, 25.9, 25.1,
24.3, 21.8, 20.5, 18.7, 18.2; HRMS (ESI+) calcd for C22H40O2Si+Na,
387.2695; found 387.2688; IR (thin film, cm−1) 2954, 2855, 1717,
1471, 1376, 1253, 1167, 1039, 880, 741; TLC (90:10 hexanes/EtOAc)
Rf = 0.93.
Synthesis of Enol Silane 66. 1-((2S,4aS,8aS)-2-(2-((tert-
Butyldimethylsilyl)oxy)propan-2-yl)-4a,6-dimethyl-3,4,4a,7,8,8a-
hexahydro-2H-chromen-5-yl)ethan-1-one (S4). A flame-dried, 25
mL round-bottomed flask was charged with hydrazone 59 (0.30 g, 0.57
mmol, 1.00 equiv) and THF (6 mL) under an atmosphere of N2. The
n
solution was cooled to −50 °C, and BuLi (2.64 M in hexanes, 1.30
mL, 3.44 mmol, 6.00 equiv) was added over a period of ∼2 min,
producing a dark orange color. The reaction was allowed to stir 30
min, whereupon a venting needle was added, and the mixture was
warmed to 0 °C and stirred 5 min. The reaction was then warmed to rt
and stirred until complete consumption of the starting material was
observed by TLC analysis, typically 20 min. The venting needle was
removed, the mixture was cooled to −78 °C, and acetaldehyde (0.32
mL, 5.74 mmol, 10.0 equiv) was added dropwise. The reaction was
allowed to stir 25 min, whereupon H2O (5 mL) and Et2O (5 mL)
were added, and the mixture was warmed to rt and transferred to a
separatory funnel. The organic layer was separated, and the aqueous
layer was extracted with Et2O (3 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried with magnesium
sulfate, and concentrated in vacuo to give the crude alcohol, which was
taken on to the next step without further purification.
((2-((2S,4aS,8aS)-5-((Z)-Buta-1,3-dien-1-yl)-4a,6-dimethyl-
3,4,4a,7,8,8a-hexahydro-2H-chromen-2-yl)propan-2-yl)oxy)(tert-
butyl)dimethylsilane (63). A flame-dried, 20 mL scintillation vial was
charged with allyltriphenylphosphonium bromide (1.31 g, 3.43 mmol,
8.00 equiv) and THF (5 mL) under an atmosphere of N2. The mixture
The crude residue was taken up into CH2Cl2 (5 mL) and
transferred to a 20 mL scintillation vial. Dess-Martin periodinane (0.29
g, 0.68 mmol, 2.00 equiv) was added to the vial, and the mixture was
allowed to stir until TLC analysis indicated complete consumption of
the starting material, typically 15 min. The mixture was then quenched
via a 1:1 solution of saturated NaHCO3(aq) and saturated Na2S2O3(aq)
(5 mL), and the mixture was stirred 5 min. The reaction mixture was
then diluted with Et2O (10 mL) and partitioned in a separatory funnel.
The organic layer was separated, and the aqueous layer was extracted
with Et2O (3 × 10 mL). The combined organic extracts were dried
with magnesium sulfate and concentrated in vacuo. The product was
purified via flash chromatography (100:0 to 97.5:2.5 to 95:5 hexanes/
EtOAc) to afford ketone S4 (0.09 g, 43% yield) as a yellow, viscous oil.
Analytical data: [α]D28 −31.6 (c = 0.50, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 3.21 (dd, J = 6.0, 3.6 Hz, 1H), 3.09 (dd, J = 5.4, 3.6 Hz, 1H),
2.25 (s, 3H), 2.16 (m, 1H), 2.08 (m, 1H), 1.67 (m, 2H), 1.56−1.54
n
was cooled to 0 °C and BuLi (2.64 M in hexanes, 1.22 mL, 3.21
mmol, 7.50 equiv) was added dropwise. The deep yellow mixture was
allowed to stir 1 h at 0 °C, whereupon the aldehyde 60 (0.16 g, 0.43
mmol, 1.00 equiv) was added as a solution in THF (2 mL). The
reaction was allowed to stir until complete consumption of the starting
material was observed by TLC analysis, typically 12 h. The reaction
was diluted with H2O (15 mL) and transferred to a separatory funnel.
The layers were separated, and the aqueous layer was extracted with
Et2O (3 × 15 mL). The combined organic extracts were washed with
brine (15 mL), dried with magnesium sulfate, and concentrated in
vacuo. The product was purified via flash chromatography (100:0 to
99:1 to 97.5:2.5 hexanes/EtOAc) to afford triene 63 (0.06 g, 36%
R
DOI: 10.1021/acs.joc.5b01844
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The Journal of Organic Chemistry
Article
(m, 6H), 1.44 (m, 1H), 1.21 (s, 3H), 1.17−1.15 (m, 6H), 0.83 (s, 9H),
0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 208.2,
143.5, 128.5, 85.4, 80.4, 74.8, 35.4, 34.4, 33.3, 30.6, 27.3, 25.8, 25.0,
23.8, 21.3, 20.1, 19.6, 18.1, −2.1, −2.2; HRMS (ESI+) calcd for
C22H40O3Si+Na, 403.2644; found 403.2636; IR (thin film, cm−1)
2955, 2854, 1829, 1686, 1488, 1361, 1249, 1095, 835, 739; TLC
(90:10 hexanes/EtOAc) Rf = 0.38.
6.6, 5.4 Hz, 1H), 3.09 (dd, J = 7.8, 1.8 Hz, 1H), 2.21 (m, 1H), 2.11
(dd, J = 11.4, 6.6 Hz, 1H), 1.93 (dd, J = 5.4, 1.8 Hz, 3H), 1.74−1.70
(m, 2H), 1.51−1.47 (m, 6H), 1.38 (m, 1H), 1.22 (s, 3H), 1.15 (s, 3H),
1.14 (s, 3H), 0.83 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 200.7, 146.4, 140.2, 134.6, 130.2, 85.4, 80.4, 74.9,
35.7, 34.5, 30.5, 27.2, 25.8, 25.0, 23.9, 21.4, 20.7, 19.7, 18.4, 18.1, −2.1,
−2.2; HRMS (ESI+) calcd for C24H42O3Si+Na, 429.2801; found
429.2792; IR (thin film, cm−1) 2955, 2855, 1671, 1472, 1361, 1265,
1165, 1041, 835, 739; TLC (90:10 hexanes/EtOAc) Rf = 0.56.
tert-Butyl((2-((2S,4aR,8aS)-5-iodo-4a,6-dimethyl-3,4,4a,7,8,8a-
hexahydro-2H-chromen-2-yl)propan-2-yl)oxy)dimethylsilane (68).
A flame-dried, 20 mL scintillation vial was charged with hydrazone
59 (0.30 g, 0.57 mmol, 1.00 equiv) and THF (6 mL) under an
tert-Butyl((1-((2S,4aS,8aS)-2-(2-((tert-butyldimethylsilyl)oxy)-
propan-2-yl)-4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-
5-yl)vinyl)oxy)dimethylsilane (66). A flame-dried, 20 mL scintillation
vial was charged with ketone S4 (0.06 g, 0.16 mmol, 1.00 equiv) and
THF (2 mL) under an atmosphere of N2. The reaction was cooled to
0 °C, and NEt3 (0.07 mL, 0.47 mmol, 3.00 equiv) and TBSOTf (0.075
mL, 0.32 mmol, 2.00 equiv) were added sequentially. The reaction
mixture was warmed to rt and stirred until TLC analysis showed
complete consumption of the starting material, typically 3 h. The
reaction was quenched via addition of saturated NaHCO3(aq) (2 mL)
and transferred to a separatory funnel. The organic layer was
separated, and the aqueous layer was extracted with pentane (3 × 5
mL). The combined organic extracts were dried with magnesium
sulfate and concentrated in vacuo. The product was purified via flash
chromatography (100:0 to 98:2 to 97.5:2.5 hexanes/EtOAc) to afford
silyloxydiene 66 (0.077 g, 99% yield) as a clear, viscous oil. Analytical
data: [α]D28 −20.8 (c = 0.33, CHCl3); 1H NMR (600 MHz, CDCl3) δ
4.27 (s, 1H), 3.90 (s, 1H), 3.15 (dd, J = 7.2, 4.8 Hz, 1H), 3.08 (dd, J =
7.8, 3.0 Hz, 1H), 2.15 (m, 1H), 2.06 (dd, J = 11.4, 6.6 Hz, 1H), 1.81
(d, J = 13.2 Hz, 1H), 1.66 (br s, 5H), 1.54 (m, 2H), 1.39 (m, 1H), 1.23
(s, 3H), 1.16 (s, 3H), 1.07 (s, 3H), 0.92 (s, 9H), 0.84 (s, 9H), 0.20 (s,
3H), 0.17 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 155.6, 138.9, 128.6, 85.3, 81.1, 75.0, 34.7, 30.5, 27.2, 25.9,
25.8, 25.7, 25.2, 24.1, 21.9, 20.8, 18.2, 18.1, −2.1, −2.2, −4.5, −4.6;
HRMS (ESI+) calcd for C28H54O3Si2+Na, 517.3509; found 517.3499;
IR (thin film, cm−1) 2930, 2896, 1611, 1497, 1376, 1265, 1165, 1038,
835, 775; TLC (90:10 hexanes/EtOAc) Rf = 0.94.
n
atmosphere of N2. The solution was cooled to −50 °C, and BuLi
(1.70 M in hexanes, 2.00 mL, 3.42 mmol, 6.00 equiv) was added over a
period of ∼2 min, producing a dark orange color. The reaction was
allowed to stir 30 min, whereupon a venting needle was added, and the
mixture was warmed to 0 °C and stirred 5 min. The reaction was then
warmed to rt and stirred until complete consumption of the starting
material was observed by TLC analysis, typically 20 min. The venting
needle was removed, the mixture was cooled to 0 °C, and I2 (0.43 g,
1.71 mmol, 3.00 equiv) was added portionwise. The reaction was
allowed to stir 20 min, whereupon H2O (5 mL) and Et2O (5 mL)
were added, and the mixture was warmed to rt and transferred to a
separatory funnel. The organic layer was separated, and the aqueous
layer was extracted with Et2O (3 × 10 mL). The combined organic
extracts were washed with brine (10 mL) and saturated Na2S2O3(aq)
,
dried with magnesium sulfate, and concentrated in vacuo. The product
was purified via flash chromatography (100:0 to 99:1 to 98:2) to afford
iodide 68 (0.18 g, 67% yield) containing 17% of the inseparable vinyl
C−H compound (arising from protic quenching of the transient
vinyllithium) by 1H NMR analysis. Analytical data: [α]D28 −248.0 (c =
1
1.00, CHCl3); H NMR (600 MHz, CDCl3) δ 3.32 (dd, J = 7.8, 4.2
Hz, 1H), 3.07 (dd, J = 9.0, 3.0 Hz, 1H), 2.30 (m, 1H), 2.22 (dd, J =
11.4, 6.0 Hz, 1H), 1.90 (m, 1H), 185 (s, 3H), 1.70 (m, 1H), 1.60 (br s,
1H), 1.55 (m, 2H), 1.28 (m, 1H), 1.24 (s, 3H), 1.18 (s, 3H), 0.99 (s,
3H), 0.84 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 136.2, 131.2, 114.8, 85.5, 81.1, 74.6, 41.5, 41.3, 32.3, 29.8,
27.4, 25.8, 25.0, 24.2, 22.7, 18.5, 18.1, −2.1, −2.2; HRMS (ESI+) calcd
for C20H37IO2Si+Na, 487.1505; found 487.1497; IR (thin film, cm−1)
2954, 2854, 1771, 1670, 1488, 1376, 1264, 1162, 1040, 834; TLC
(90:10 hexanes/EtOAc) Rf = 0.91.
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methanol
(69). A flame-dried, 50 mL round-bottomed flask was charged with
hydrazone 59 (0.58 g, 1.10 mmol, 1.00 equiv) and THF (11 mL)
under an atmosphere of N2. The solution was cooled to −50 °C, and
nBuLi (1.55 M in hexanes, 4.27 mL, 6.62 mmol, 6.00 equiv) was added
(E)-1-((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-
yl)-4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)but-2-
en-1-one (67). A flame-dried, 25 mL round-bottomed flask was
charged with hydrazone 59 (0.30 g, 0.57 mmol, 1.00 equiv) and THF
(6 mL) under an atmosphere of N2. The solution was cooled to −50
n
°C, and BuLi (2.64 M in hexanes, 1.30 mL, 3.44 mmol, 6.00 equiv)
was added over a period of ∼2 min, producing a dark orange color.
The reaction was allowed to stir 30 min, whereupon a venting needle
was added, and the mixture was warmed to 0 °C and stirred 5 min.
The reaction was then warmed to rt and stirred until complete
consumption of the starting material was observed by TLC analysis,
typically 20 min. The venting needle was removed, the mixture was
cooled to −78 °C, and (E)-crotonaldehyde (0.48 mL, 5.74 mmol, 10.0
equiv) was added dropwise. The reaction was allowed to stir 25 min,
whereupon H2O (5 mL) and Et2O (5 mL) were added, and the
mixture was warmed to rt and transferred to a separatory funnel. The
organic layer was separated, and the aqueous layer was extracted with
Et2O (3 × 10 mL). The combined organic extracts were washed with
brine (10 mL), dried with magnesium sulfate, and concentrated in
vacuo to give the crude alcohol, which was taken on to the next step
without further purification
The crude residue was taken up into CH2Cl2 (5 mL) and
transferred to a 20 mL scintillation vial. Dess-Martin periodinane (0.29
g, 0.68 mmol, 2.00 equiv) was added to the vial, and the mixture was
allowed to stir until TLC analysis indicated complete consumption of
the starting material, typically 15 min. The mixture was then quenched
via a 1:1 solution of saturated NaHCO3(aq) and saturated Na2S2O3(aq)
(5 mL), and the mixture was stirred 5 min. The reaction mixture was
then diluted with Et2O (10 mL) and partitioned in a separatory funnel.
The organic layer was separated, and the aqueous layer was extracted
with Et2O (3 × 10 mL). The combined organic extracts were dried
with magnesium sulfate and concentrated in vacuo. The product was
purified via flash chromatography (100:0 to 97.5:2.5 to 95:5 hexanes/
EtOAc) to afford ketone 67 (0.10 g, 46% yield) as a yellow, viscous oil.
Analytical data: [α]D28 −72.2 (c = 0.48, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 6.73 (m, 1H), 6.14 (dd, J = 13.8, 1.8 Hz, 1H), 3.26 (dd, J =
over a period of ∼2 min, producing a dark orange color. The reaction
was allowed to stir 30 min, whereupon a venting needle was added,
and the mixture was warmed to 0 °C and stirred 5 min. The reaction
was then warmed to rt and stirred until complete consumption of the
starting material was observed by TLC analysis, typically 20 min. The
venting needle was removed, (HCHO)n (0.35 g, 11.0 mmol, 10.0
equiv) was added to the mixture in one portion, and the reaction was
allowed to stir 40 min at rt. H2O (10 mL) and Et2O (5 mL) were
added, and the mixture was transferred to a separatory funnel. The
organic layer was separated, and the aqueous layer was extracted with
Et2O (3 × 10 mL). The combined organic extracts were washed with
brine (10 mL), dried with magnesium sulfate and concentrated in
vacuo. The product was purified via flash chromatography (100:0 to
95:5 to 90:10 to 80:20 hexanes/EtOAc) to afford alcohol 69 (0.26 g,
28
65% yield) as a yellow, viscous oil. Analytical data: [α]D −53.7 (c =
1
0.70, CHCl3); H NMR (600 MHz, CDCl3) δ 4.20 (d, J = 11.4 Hz,
1H), 4.07 (d, J = 11.4 Hz, 1H), 3.18 (dd, J = 6.0, 4.2 Hz, 1H), 3.09
(dd, J = 6.6, 3.6 Hz, 1H), 2.17 (m, 1H), 2.06 (m, 1H), 1.98 (dt, J = 6.0,
3.6 Hz, 1H), 1.71 (s, 3H), 1.66 (m, 2H), 1.60 (m, 2H), 1.44 (m, 1H),
1.23 (s, 3H), 1.17 (s, 3H), 1.00 (s, 3H), 0.84 (s, 9H), 0.80 (s, 3H),
0.05 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 137.4, 132.2, 85.2, 81.3,
74.9, 58.2, 31.5, 25.8, 25.0, 24.2, 21.7, 19.4, 19.0, 18.1, −2.16, −2.21;
S
DOI: 10.1021/acs.joc.5b01844
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The Journal of Organic Chemistry
Article
HRMS (ESI+) calcd for C21H40O3Si+Na, 391.2645; found 391.2652;
IR (thin film, cm−1) 3409, 2953, 2855, 1641, 1461, 1377, 1252, 1168,
1092, 834; TLC (85:15 hexanes/EtOAc) Rf = 0.29.
Procedure for One-Pot Synthesis of 69 from Alcohol 49.
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-4a,6-
dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methanol (69).
A flame-dried, 250 mL round-bottomed flask was charged with
hydrazone 49 (1.50 g, 2.95 mmol, 1.00 equiv) and THF (30 mL)
under an atmosphere of N2. The solution was cooled to −50 °C, and
nBuLi (3.97 mL, 2.6 M in hexanes, 10.32 mmol, 3.50 equiv) was added
in vacuo. The product was purified via flash chromatography (100:0 to
98:2 to 95:5 hexanes/EtOAc) to afford ester 70b (0.05 g, 86% yield)
as a clear, viscous oil. Analytical data: [α]D28 −51.4 (c = 1.25, CHCl3);
1H NMR (600 MHz, CDCl3) δ 4.60 (dd, J = 12.0, 7.8 Hz, 2H), 3.19
(dd, J = 5.4, 5.4 Hz, 1H), 3.08 (dd, J = 6.0, 4.2 Hz, 1H), 2.32 (q, J =
7.2 Hz, 2H), 2.19 (m, 1H), 2.09 (dd, J = 12.6, 4.8 Hz, 1H), 1.82 (dt, J
= 6.0, 3.6 Hz, 1H), 1.67 (br s, 5H), 1.56 (m, 1H), 1.37 (m, 1H), 1.23
(s, 3H), 1.17 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H), 0.99 (s, 3H), 0.84 (s,
9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
174.6, 134.6, 132.3, 85.1, 81.0, 74.9, 60.3, 36.3, 34.0, 27.7, 27.3, 25.8,
25.0, 24.2, 21.7, 19.3, 19.2, 18.2, 9.2, −2.1, −2.2; HRMS (ESI+) calcd
for C24H44O4Si+Na, 447.2907; found 447.2897; IR (thin film, cm−1)
3053, 2955, 2855, 1731, 1540, 1472, 1322, 1265, 1179, 1071, 835;
TLC (90:10 hexanes/EtOAc) Rf = 0.68.
dropwise, producing a dark orange color. The reaction mixture was
allowed to stir 40 min at this temperature, then MeI (0.46 mL, 7.37
mmol, 2.50 equiv) was added. The reaction was allowed to stir at −50
°C until TLC analysis confirmed complete conversion of 49, typically
n
20 min. An additional charge of BuLi (9.07 mL, 2.6 M in hexanes,
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methyl 2-
(1H-indol-2-yl)propanoate (70d). A 20 mL scintillation vial was
charged with ethyl 2-(1H-indol-2-yl)propanoate50 (0.2 g, 0.92 mmol,
1.00 equiv) and a 3:1 mixture of MeOH/THF (5 mL). LiOH (4 M in
H2O, 0.7 mL, 2.76 mmol, 3.00 equiv) was added, and the mixture was
allowed to stir at rt until complete consumption of the starting
material was observed by TLC analysis, typically 6 h. The reaction
mixture was concentrated on a rotary evaporator, and the residue was
diluted with H2O (10 mL) and transferred to a separatory funnel. The
aqueous layer was extracted with EtOAc (2 × 10 mL), and the
aqueous layer was then acidified to pH = 0 with 1 M HCl(aq) and
extracted with CH2Cl2 (3 × 10 mL). The combined CH2Cl2 extracts
were dried with magnesium sulfate and concentrated in vacuo to give
the crude carboxylic acid. This material could not be isolated due to
spontaneous decarboxylation, but could be carried forward directly to
the next step without further purification.
23.6 mmol, 8.00 equiv) was added to the reaction, and the resulting
mixture was stirred 30 min. The flask was fitted with a venting needle,
and the reaction mixture was then warmed to 0 °C, stirred 5 min, then
warmed to rt and stirred until complete consumption of the
intermediate hydrazone was observed by TLC analysis, typically 15−
25 min (scale dependent). The septum was partially removed, and
(HCHO)n (0.89 g, 29.5 mmol, 10.0 equiv) was added in one portion
with vigorous stirring. The reaction was allowed to stir 30 min at rt, at
which time the mixture was diluted with H2O (25 mL) and Et2O (20
mL) and transferred to a separatory funnel. The organic layer was
separated and the aqueous layer was extracted with Et2O (3 × 20 mL).
The combined organic extracts were washed with brine (30 mL), dried
with magnesium sulfate, and concentrated in vacuo. The product was
purified via flash chromatography (100:0 to 95:5 to 90:10 to 80:20
hexanes/EtOAc) to afford alcohol 69 (0.76 g, 66% yield).
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methyl
acetate (70a). A flame-dried, 20 mL scintillation vial was charged with
alcohol 69 (0.05 g, 0.14 mmol, 1.00 equiv) and CH2Cl2 under an
atmosphere of N2. The mixture was cooled to 0 °C, and NEt3 (0.04
mL, 0.27 mmol, 2.00 equiv), DMAP (0.002 g, 0.014 mmol, 0.1 equiv),
and last Ac2O (0.03 mL, 0.27 mmol, 2.00 equiv) were added
sequentially. The mixture was allowed to stir at this temperature until
TLC analysis showed complete consumption of the starting material,
typically 3 h. The mixture was diluted with H2O (7 mL) and
transferred to a separatory funnel. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 7 mL), dried
with magnesium sulfate, and concentrated in vacuo. The product was
purified via flash chromatography (100:0 to 98:2 to 95:5 to 90:10
hexanes/EtOAc) to afford acetate 70a (0.046 g, 83% yield) as a clear,
viscous oil. Analytical data: [α]D28 −59.0 (c = 1.35, CHCl3); 1H NMR
(600 MHz, CDCl3) δ 4.59 (dd, J = 12.0, 5.4 Hz, 2H), 3.19 (dd, J = 6.0,
4.8 Hz, 1H), 3.08 (dd, J = 6.0, 4.2 Hz, 1H), 2.20 (m, 1H), 2.11 (m,
1H), 2.05 (s, 3H), 1.82 (m, 1H), 1.67 (br s, 5H), 1.57 (m, 1H), 1.36
(m, 1H), 1.23 (s, 3H), 1.17 (s, 3H), 0.99 (s, 3H), 0.84 (s, 9H), 0.08 (s,
3H), 0.05 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 171.3, 134.8,
132.2, 85.1, 81.0, 74.9, 60.4, 36.3, 33.9, 31.6, 27.3, 25.8, 25.0, 24.1,
21.6, 21.2, 19.3, 19.2, 18.1, −2.1, −2.2; HRMS (ESI+) calcd for
C23H42O4Si+Na, 433.2750; found 433.2741; IR (thin film, cm−1)
2955, 2856, 1771, 1730, 1472, 1377, 1249, 1092, 1039, 835, 759; TLC
(90:10 hexanes/EtOAc) Rf = 0.54.
The crude acid (∼4.00 equiv) was dissolved in CH2Cl2 (3 mL) and
transferred to a flame-dried, 20 mL scintillation vial under an
atmosphere of N2. DCC (0.095 g, 0.46 mmol, 2.00 equiv) was added
followed by DMAP (0.003 g, 0.023 mmol, 0.10 equiv) and last a
solution of alcohol 69 (0.085 g, 0.23 mmol, 1.00 equiv) in CH2Cl2 (1
mL). The reaction was allowed to stir until TLC analysis confirmed
complete consumption of the starting material, typically 20 min. The
reaction mixture was filtered through cotton into a separatory funnel,
and H2O (10 mL) and EtOAc (10 mL) were added. The mixture was
extracted with EtOAc (3 × 10 mL), and the combined organic extracts
were washed with saturated NaHCO3(aq) (10 mL), dried with
magnesium sulfate, and concentrated in vacuo. The product was
purified via flash chromatography (100:0 to 95:5 to 90:10 hexanes/
EtOAc) to afford an inseparable mixture of diastereomeric esters 70d
28
(0.14 g, 99% yield) as a brown, viscous oil. Analytical data: [α]D
1
−68.4 (c = 0.43, CHCl3); H NMR (600 MHz, CDCl3) δ 8.59 (m,
1H), 7.56 (m, 1H), 7.32 (m, 1H), 7.15 (m, 1H), 7.09 (m, 1H), 6.37
(br s, 1H), 4.66 (m, 2H), 3.95 (m, 1H), 3.17 (m, 1H), 3.06−2.98 (m,
1H), 2.21 (m, 1H), 2.10 (m, 1H), 1.68−1.66 (m, 4H), 1.64−1.62 (m,
4H), 1.46 (m, 2H), 1.32 (m, 2H), 1.23−1.21 (m, 3H), 1.16−1.14 (m,
3H), 0.97−0.96 (m, 3H), 0.86 (s, 9H), 0.10−0.09 (m, 3H), 0.07 (m,
3H); 13C NMR (150 MHz, CDCl3) δ 173.6, 136.7, 136.6, 136.0,
135.4, 131.9, 128.0, 121.7, 120.2, 119.7, 110.6, 100.1, 85.1, 85.0, 80.9,
74.8, 61.3, 61.2, 41.5, 39.3, 39.2, 36.2, 33.9, 31.6, 27.2, 27.1, 26.1, 25.8,
25.2, 25.1, 24.1, 23.3, 21.5, 19.2, 18.1, 17.4, 17.2, 14.1, −2.2, −2.3;
HRMS (ESI+) calcd for C32H49NO4Si+Na, 562.3329; found 562.3320;
IR (thin film, cm−1) 3392, 2954, 2855, 1716, 1471, 1377, 1250, 1172,
1069, 835; TLC (90:10 hexanes/EtOAc) Rf = 0.41.
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methyl
propionate (70b). A flame-dried, 20 mL scintillation vial was charged
with CH2Cl2 (3 mL) and propionic acid (0.02 g, 0.27 mmol, 2.00
equiv) at rt under an atmosphere of N2. DCC (0.06 g, 0.27 mmol, 2.00
equiv) and DMAP (0.002 g, 0.014 mmol, 0.10 equiv) were added
followed last by a solution of alcohol 69 (0.05 g, 0.14 mmol, 1.00
equiv) in CH2Cl2 (1 mL), and the reaction was allowed to stir at rt
until TLC analysis confirmed complete conversion of the starting
material, typically 3.5 h. The reaction mixture was filtered through
cotton into a separatory funnel, and H2O (10 mL) and EtOAc (10
mL) were added. The mixture was extracted with EtOAc (3 × 10 mL),
and the combined organic extracts were washed with saturated
NaHCO3(aq) (10 mL), dried with magnesium sulfate, and concentrated
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methyl 3-
((tert-butyldimethylsilyl)oxy)-2-methylpropanoate (70e). A flame-
dried, 20 mL scintillation vial was charged with CH2Cl2 (3 mL) and 3-
((tert-butyldimethylsilyl)oxy)-2-methylpropanoic acid51 (0.05 g, 0.22
mmol, 2.00 equiv) at rt under an atmosphere of N2. DCC (0.04 g, 0.22
mmol, 2.00 equiv) and DMAP (0.002 g, 0.014 mmol, 0.10 equiv) were
added followed last by a solution of alcohol 69 (0.04 g, 0.11 mmol,
1.00 equiv) in CH2Cl2 (1 mL), and the reaction was allowed to stir at
rt until TLC analysis confirmed complete conversion of the starting
material, typically 3.5 h. The reaction mixture was filtered through
T
DOI: 10.1021/acs.joc.5b01844
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The Journal of Organic Chemistry
Article
cotton into a separatory funnel, and H2O (10 mL) and EtOAc (10
mL) were added. The mixture was extracted with EtOAc (3 × 10 mL),
and the combined organic extracts were washed with saturated
NaHCO3(aq) (10 mL), dried with magnesium sulfate, and concentrated
in vacuo. The product was purified via flash chromatography (100:0 to
98:2 to 95:5 hexanes/EtOAc) to afford an inseparable mixture of
diastereomeric esters 70e (0.047 g, 76% yield) as a clear, viscous oil.
Analytical data: [α]D28 −42.1 (c = 1.20, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 4.58 (m, 2H), 3.79 (m, 1H), 3.64 (m, 1H), 3.18 (m, 1H),
3.08 (dd, J = 7.2, 3.6 Hz, 1H), 2.62 (m, 1H), 2.19 (m, 1H), 2.09 (m,
1H), 1.82 (m, 1H), 1.67−1.66 (m, 5H), 1.57 (m, 2H), 1.37 (m, 1H),
1.23 (s, 3H), 1.17 (s, 3H), 1.14−1.12 (m, 3H), 0.99 (m, 3H), 0.87 (s,
9H), 0.84 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H), 0.03 (br s, 6H), 13C
NMR (150 MHz, CDCl3) δ 175.1, 134.6, 134.5, 132.3, 85.1, 81.0, 74.9,
65.3, 65.2, 60.4, 60.3, 42.7, 36.3, 34.1, 34.0, 31.7, 27.4, 27.3, 25.9, 25.8,
25.0, 24.2, 21.7, 21.6, 19.3, 19.2, 18.2, 13.6, −2.1, −2.2, −5.5; HRMS
(ESI+) calcd for C31H60O5Si2+Na, 591.3877; found 591.3867; IR (thin
film, cm−1) 3053, 2955, 2884, 2857, 1727, 1471, 1377, 1265, 1179,
1049, 836; TLC (90:10 hexanes/EtOAc) Rf = 0.73.
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methyl
(S)-2-Bromopropanoate (70f). A flame-dried, 20 mL scintillation vial
was charged with CH2Cl2 (3 mL) and (S)-2-bromopropanoic acid52
(0.04 g, 0.27 mmol, 2.00 equiv) at rt under an atmosphere of N2. DCC
(0.06 g, 0.27 mmol, 2.00 equiv) and DMAP (0.002 g, 0.014 mmol,
0.10 equiv) were added followed last by a solution of alcohol 69 (0.05
g, 0.14 mmol, 1.00 equiv) in CH2Cl2 (1 mL), and the reaction was
allowed to stir at rt until TLC analysis confirmed complete conversion
of the starting material, typically 3.5 h. The reaction mixture was
filtered through cotton into a separatory funnel, and H2O (10 mL) and
EtOAc (10 mL) were added. The mixture was extracted with EtOAc
(3 × 10 mL), and the combined organic extracts were washed with
saturated NaHCO3(aq) (10 mL), dried with magnesium sulfate, and
concentrated in vacuo. The product was purified via flash
chromatography (100:0 to 98:2 to 95:5 hexanes/EtOAc) to afford
ester 70f (0.062 g, 90% yield) as a clear, viscous oil. Analytical data:
[α]D28 −49.2 (c = 1.50, CHCl3); 1H NMR (600 MHz, CDCl3) δ 4.68
(br s, 1H), 4.36 (q, J = 6.6 Hz, 1H), 3.19 (dd, J = 6.0, 4.2 Hz, 1H),
3.08 (dd, J = 6.6, 3.6 Hz, 1H), 2.20 (m, 1H), 2.10 (m, 1H), 1.83−1.81
(m, 5H), 1.69−1.66 (m, 5H), 1.58 (m, 1H), 1.38 (m, 1H), 1.23 (s,
3H), 1.17 (s, 3H), 1.01 (s, 3H), 0.84 (s, 9H), 0.08 (s, 3H), 0.05 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 170.4, 135.7, 131.6, 85.1, 80.9,
74.9, 62.0, 40.3, 36.2, 34.1, 31.7, 27.3, 25.8, 25.0, 24.1, 21.7, 21.6, 19.4,
19.3, 18.1, −2.1, −2.2; HRMS (ESI+) calcd for C24H43BrO4Si+Na,
525.2012; found 525.2004; IR (thin film, cm−1) 2929, 2856, 1732,
1472, 1378, 1329, 1217, 1159, 1070, 835; TLC (90:10 hexanes/
EtOAc) Rf = 0.62.
3H), 1.16 (s, 3H), 1.01 (s, 3H), 0.84 (s, 9H), 0.08 (s, 3H), 0.05 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 168.3, 137.4, 136.9, 134.3,
132.4, 128.8, 85.1, 81.0, 74.9, 60.4, 36.2, 34.1, 31.7, 31.6, 27.2, 25.8,
25.0, 24.2, 21.7, 19.4, 19.2, 14.4, 12.1, −2.1, −2.2; HRMS (ESI+) calcd
for C26H46O4Si+Na, 473.3063; found 473.3055; IR (thin film, cm−1)
2955, 2855, 1731, 1703, 1636, 1487, 1361, 1263, 1070, 835, 758; TLC
(90:10 hexanes/EtOAc) Rf = 0.65.
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methyl 3-
(dimethyl(phenyl)silyl)-2-methylpropanoate (70h). A flame-dried, 20
mL scintillation vial was charged with CH2Cl2 (5 mL) and 3-
(dimethyl(phenyl)silyl)-2-methylpropanoic acid53 (0.18 g, 0.81 mmol,
2.00 equiv) at rt under an atmosphere of N2. DCC (0.17 g, 0.81 mmol,
2.00 equiv) and DMAP (0.005 g, 0.04 mmol, 0.10 equiv) were added
followed last by a solution of alcohol 69 (0.15 g, 0.41 mmol, 1.00
equiv) in CH2Cl2 (2 mL), and the reaction was allowed to stir at rt
until TLC analysis confirmed complete conversion of the starting
material, 5 h. The reaction mixture was filtered through cotton into a
separatory funnel, and H2O (10 mL) and EtOAc (10 mL) were added.
The mixture was extracted with EtOAc (3 × 10 mL), and the
combined organic extracts were washed with saturated NaHCO3(aq)
(10 mL), dried with magnesium sulfate, and concentrated in vacuo.
The product was purified via flash chromatography (100:0 to 98:2 to
98:2 to 95:5 hexanes/EtOAc) to afford ester 70h (0.21 g, 91% yield)
as a clear, viscous oil. Analytical data: [α]D28 −42.5 (c = 1.30, CHCl3);
1H NMR (600 MHz, CDCl3) δ 7.51 (br s, 2H), 7.36 (br s, 3H), 4.56
(dd, J = 7.8, 4.2 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H), 3.20 (dd, J = 6.0,
4.2 Hz, 1H), 3.10 (dd, J = 6.0, 3.6 Hz, 1H), 2.54 (m, 1H), 2.20 (m,
1H), 2.10 (m, 1H), 1.79 (d, J = 12.6 Hz, 1H), 1.68−1.66 (m, 5H),
1.58 (m, 2H), 1.32 (m, 2H), 1.25 (s, 3H), 1.19 (s, 3H), 1.15 (d, J = 6.6
Hz, 3H), 1.00 (s, 3H), 0.94−0.89 (m, 2H), 0.87 (s, 9H), 0.31 (br s,
6H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
177.6, 138.8, 134.5, 133.5, 132.3, 129.1, 128.9, 127.9, 127.785.1, 81.0,
74.9, 60.3, 36.6, 36.3, 36.2, 34.1, 31.6, 27.3, 27.2, 25.8, 25.1, 24.1, 21.7,
20.7, 20.6, 20.5, 19.8, 19.3, 19.2, 19.2, 18.1, −2.1, −2.2, −2.3, −2.4,
−2.6; HRMS (ESI+) calcd for C33H56O4Si2+Na, 595.3615; found
595.3604; IR (thin film, cm−1) 3052, 2956, 2856, 1809, 1718, 1487,
1457, 1361, 1265, 1198, 1047, 835; TLC (90:10 hexanes/EtOAc) Rf =
0.78.
2-((2S,4aS,6S,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-
yl)-4a,6-dimethyl-5-methyleneoctahydro-2H-chromen-6-yl)-3-
(dimethyl(phenyl)silyl)-2-methylpropanoic acid (71b). A flame-
dried, 20 mL scintillation vial was charged with THF (2 mL) under
an atmosphere of N2. The mixture was cooled to −78 °C, and a
premade solution of LDA (0.5 M in THF/hexanes, 0.52 mL, 0.26
mmol, 3.00 equiv) was added followed by a solution of ester 70h (0.05
g, 0.087 mmol, 1.00 equiv) in THF (1 mL). The reaction was allowed
to stir 45 min at this temperature at which point TMSCl (0.04 mL,
0.26 mmol, 3.00 equiv) was added, and the mixture was warmed to rt
and stirred 5 min. The septum was replaced with a screw cap, the vial
was sealed, and the mixture was warmed to 75 °C and stirred until
TLC analysis indicated complete consumption of the starting material,
typically 12 h. The mixture was cooled to rt and quenched via addition
of 1 M HCl(aq) (4 mL). The mixture was transferred to a separatory
funnel and diluted with Et2O (10 mL). The organic layer was
separated, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic extracts were washed with brine (10 mL)
and concentrated in vacuo to give the crude rearrangement product in
a 6.6:1.1:1 diastereomeric ratio. The diastereomeric ratio was
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methyl
(Z)-2-Methylbut-2-enoate (70g). A flame-dried, 20 mL scintillation
vial was charged with CH2Cl2 (3 mL) and angelic acid (0.03 g, 0.27
mmol, 2.00 equiv) at rt under an atmosphere of N2. DCC (0.06 g, 0.27
mmol, 2.00 equiv) and DMAP (0.002 g, 0.014 mmol, 0.10 equiv) were
added followed last by a solution of alcohol 69 (0.05 g, 0.14 mmol,
1.00 equiv) in CH2Cl2 (1 mL), and the reaction was allowed to stir at
rt until TLC analysis confirmed complete conversion of the starting
material, 30 h. In some cases, an additional 2.00 equiv of angelic acid
and DCC were added after 12 h to aide starting material conversion.
The reaction mixture was filtered through cotton into a separatory
funnel, and H2O (10 mL) and EtOAc (10 mL) were added. The
aqueous layer was extracted with EtOAc (3 × 10 mL), and the
combined organic extracts were washed with saturated NaHCO3(aq)
(10 mL), dried with magnesium sulfate, and concentrated in vacuo.
The product was purified via flash chromatography (100:0 to 98:2 to
95:5 hexanes/EtOAc) to afford ester 70g (0.040 g, 59% yield) as a pale
1
determined by H NMR spectroscopic analysis of the crude reaction
mixture by comparison of the integration of the resonances at δ 5.25
(minor diastereomer), δ 5.10 (major diastereomer), and δ 5.04 (minor
diastereomer, overlapping signals). The product was purified via flash
chromatography (100:0 to 95:5 to 90:10 hexanes/EtOAc) to afford
carboxylic acid 71b (0.032 g, 62% yield) as a clear viscous oil.
Analytical data: [α]D28 −18.3 (c = 1.25, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 7.51 (m, 2H), 7.34 (m, 3H), 5.10 (s, 1H), 5.01 (s, 1H), 3.11
(dd, J = 6.0, 4.8 Hz, 1H), 3.01 (m, 1H), 1.97−1.90 (m, 2H), 1.74 (m,
1H), 1.66−1.54 (m, 6H), 1.38 (s, 3H), 1.27 (m, 2H), 1.22 (s, 3H),
1.17 (s, 3H), 1.16 (s, 3H), 1.15 (m, 1H), 1.07 (s, 3H), 1.05 (m, 1H),
28
yellow, viscous oil. Analytical data: [α]D −53.1 (c = 1.00, CHCl3);
1H NMR (600 MHz, CDCl3) δ 6.83 (q, J = 6.6 Hz, 1H), 4.65 (br s,
2H), 3.19 (dd, J = 5.4, 5.4 Hz, 1H), 3.09 (dd, J = 6.0, 3.6 Hz, 1H), 2.19
(m, 1H), 2.10 (m, 1H), 1.97 (m, 1H), 1.88−1.83 (m, 4H), 1.79 (d, J =
6.6 Hz, 3H), 1.67 (br s, 4H), 1.56 (m, 2H), 1.37 (m, 1H), 1.23 (s,
U
DOI: 10.1021/acs.joc.5b01844
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The Journal of Organic Chemistry
Article
0.84 (s, 9H), 0.37 (s, 3H), 0.29 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H); 13
C
3406, 2955, 2856, 1693, 1641, 1471, 1378, 1252, 1170, 1094, 1042,
835, 760; TLC (85:15 hexanes/EtOAc) Rf = 0.40.
NMR (150 MHz, CDCl3) δ 184.0, 160.8, 140.3, 133.5, 128.8, 127.7,
111.7, 84.7, 80.4, 74.8, 52.5, 46.5, 39.3, 36.8, 36.6, 32.7, 30.2, 27.3,
25.9, 25.0, 24.7, 24.5, 23.3, 23.1, 22.1, 22.1, 18.2, −1.2, −1.4, −2.1,
−2.2; HRMS (ESI+) calcd for C33H56O4Si2+Na, 595.3615; found
595.3605; IR (thin film, cm−1) 3420, 3053, 2956, 2956, 2855, 1716,
1689, 1487, 1377, 1265, 1093, 896, 835; TLC (90:10 hexanes/EtOAc)
Rf = 0.46.
((2S,4aS,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-
4a,6-dimethyl-3,4,4a,7,8,8a-hexahydro-2H-chromen-5-yl)methyl
Isobutyrate (70c). A flame-dried, 500 mL round-bottomed flask was
charged with CH2Cl2 (110 mL) and isobutyric acid (2.22 mL, 24.47
mmol, 2.00 equiv) at rt under an atmosphere of N2. DCC (5.05 g,
24.47 mmol, 2.00 equiv) and DMAP (0.15 g, 1.22 mmol, 0.10 equiv)
were added followed last by a solution of alcohol 69 (4.51 g, 12.23
mmol, 1.00 equiv) in CH2Cl2 (10 mL), and the reaction was allowed
to stir at rt until TLC analysis confirmed complete conversion of the
starting material, typically 2.5 h. The reaction mixture was filtered
through cotton into a separatory funnel, and H2O (40 mL) and EtOAc
(100 mL) were added. The mixture was extracted with EtOAc (3 × 30
mL), and the combined organic extracts were washed with saturated
NaHCO3(aq) (2 × 30 mL), dried with magnesium sulfate, and
concentrated in vacuo. The product was purified via flash
chromatography (100:0 to 97.5:2.5 to 95:5 hexanes/EtOAc) to afford
Synthesis of Ketone 72. Methyl 2-((2S,4aS,6S,8aS)-2-(2-((tert-
Butyldimethylsilyl)oxy)propan-2-yl)-4a,6-dimethyl-5-methyleneoc-
tahydro-2H-chromen-6-yl)-2-methylpropanoate (S5). The acid 71a
(3.14 g, 7.16 mmol, 1.00 equiv) was dissolved in MeOH/C7H8 (2:1,
75 mL) in a 250 mL round-bottomed flask with magnetic stirring at rt.
TMSCHN2 (2 M in Et2O, 10.00 mL, 20 mmol, 2.79 equiv) was added
dropwise until the yellow color of excess TMSCHN2 in solution
persisted. AcOH (1.50 g, 24.98 mmol, 3.50 mmol) was added
dropwise, giving a clear solution. The resulting mixture was
concentrated in vacuo and purified via flash chromatography (100:0
to 97.5:2.5 to 95:5 hexanes/EtOAc) to afford ester S5 (3.06 g, 94%
yield) as a clear, viscous oil in an inseparable 6.3:1 diastereomeric ratio
(as determined by integration of the resonances at δ 3.64 (minor
diastereomer) and δ 3.62 (major diastereomer)). Analytical data:
[α]D28 −89.7 (c = 0.60, CHCl3); 1H NMR (600 MHz, CDCl3) δ 5.01
(s, 1H), 5.00 (s, 1H), 3.62 (s, 3H), 3.08 (m, 1H), 3.03 (dd, J = 6.0, 2.4
Hz, 1H), 2.08 (m, 1H), 1.95 (dt, J = 5.4, 3.6 Hz, 1H), 1.65 (m, 2H),
1.59 (m, 2H), 1.57 (br s, 1H), 1.50 (m, 1H), 1.39 (m, 1H), 1.29 (s,
3H), 1.28 (s, 3H), 1.22 (s, 3H), 1.21 (s, 3H), 1.16 (s, 3H), 1.08 (s,
3H), 0.84 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 178.7, 161.4, 110.0, 84.8, 81.0, 74.9, 51.4, 50.3, 44.3, 39.5,
36.9, 33.1, 28.5, 27.3, 25.6, 25.0, 24.6, 23.9, 23.7, 22.4, 22.1, 18.2, −2.1,
−2.2; HRMS (ESI+) calcd for C26H48O4Si+Na, 475.3220; found
475.3221; IR (thin film, cm−1) 2954, 2855, 1722, 1601, 1451, 1378,
1169, 1051, 835, 741; TLC (85:15 hexanes/EtOAc) Rf = 0.66.
3-((2S,4aS,6S,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-
yl)-4a,6-dimethyl-5-methyleneoctahydro-2H-chromen-6-yl)-3-
methylbutan-2-one (72). A flame-dried, 500 mL round-bottomed
flask was charged with ester S5 (3.82 g, 8.44 mmol, 1.00 equiv) and
Et2O (84 mL) under an atmosphere of N2. The mixture was cooled to
0 °C, and MeLi (1.6 M in Et2O, 21.09 mL, 33.75 mmol, 4.00 equiv)
was added. The mixture was warmed to rt, whereupon TLC analysis
showed incomplete conversion of the starting material. A second
addition of MeLi (4.00 equiv) was carried out, upon which TLC
analysis showed remaining starting material. A third addition of MeLi
(4.00 equiv) was carried out, upon which TLC analysis showed
complete conversion of the starting material. The reaction mixture was
cooled to 0 °C and quenched carefully with saturated NH4Cl(aq) (25
mL). The mixture was partitioned in a separatory funnel, and the
aqueous layer was extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried with magnesium sulfate and concentrated
in vacuo. The product was purified via flash chromatography (100:0 to
97.5:2.5 to 95:5 hexanes/EtOAc) to afford ketone 72 (3.52 g, 86%
yield) as a clear, viscous oil in an inseparable 7:1 ratio of diastereomers
(as determined by integration of the resonances at δ 5.05 (major
diastereomer) and δ 5.03 (minor diastereomer)). Analytical data:
[α]D28 −92.2 (c = 0.60, CHCl3); 1H NMR (600 MHz, CDCl3) δ 5.05
(s, 1H), 4.90 (s, 1H), 3.15 (dd, J = 5.4, 4.8 Hz, 1H), 3.04 (m, 1H),
2.18 (s, 3H), 1.96 (m, 1H), 1.66 (m, 1H), 1.61−1.59 (m, 3H), 1.53
(m, 1H), 1.44 (m, 1H), 1.30 (s, 3H), 1.23 (s, 3H), 1.22 (s, 3H), 1.16
(br s, 6H), 1.08 (s, 3H), 0.84 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 215.1, 161.4, 111.1, 84.7, 80.5, 74.8, 54.7,
44.9, 39.4, 36.8, 33.0, 29.7, 29.4, 27.4, 25.8, 25.0, 24.6, 23.6, 23.5, 22.7,
22.0, 18.1, −2.1, −2.2; HRMS (ESI+) calcd for C26H48O3Si+Na,
459.3271; found 459.3267; IR (thin film, cm−1) 2955, 2856, 1694,
1620, 1470, 1377, 1251, 1094, 835; TLC (85:15 hexanes/EtOAc) Rf =
0.54.
28
ester 70c (4.01 g, 75%) as a clear, viscous oil. Analytical data: [α]D
1
−73.0 (c = 0.75, CHCl3); H NMR (600 MHz, CDCl3) δ 4.58 (br s,
2H), 3.19 (dd, J = 5.4, 4.8 Hz, 1H), 3.08 (dd, J = 5.4, 4.2 Hz, 1H), 2.54
(m, 1H), 2.19 (m, 1H), 2.09 (m, 1H), 1.82 (dt, J = 6.0, 3.0 Hz, 1H),
1.67−1.65 (m, 5H), 1.57 (m, 2H), 1.37 (m, 1H), 1.23 (s, 3H), 1.17
(br s, 6H), 1.15 (d, J = 2.4 Hz, 3H), 0.99 (s, 3H), 0.84 (s, 3H), 0.08 (s,
3H), 0.05 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 177.3, 134.5,
132.3, 85.1, 81.0, 74.9, 60.3, 25.8, 24.2, 21.7, 19.3, 19.2, 19.1, 19.0,
18.2, −2.1, −2.2; HRMS (ESI+) calcd for C25H46O4Si+Na, 461.3063;
found 461.3062; IR (thin film, cm−1) 2955, 2856, 1721, 1470, 1378,
1215, 1092, 835, 756; TLC (85:15 hexanes/EtOAc) Rf = 0.66.
2-((2S,4aS,6S,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-
yl)-4a,6-dimethyl-5-methyleneoctahydro-2H-chromen-6-yl)-2-
methylpropanoic acid (71a). A flame-dried, 250 mL round-bottomed
flask was charged with THF (80 mL) and diisopropylamine (3.84 mL,
27.42 mmol, 3.00 equiv) under an atmosphere of N2. The mixture was
n
cooled to 0 °C and BuLi (1.85 M solution in hexanes, 14.82 mL,
27.42 mmol, 3.00 equiv) was added slowly. After being stirred for 30
min at 0 °C, the mixture was cooled to −78 °C, and isobutyrate 70c
(4.01 g, 9.14 mmol, 1.00 equiv) was added as a solution in THF (15
mL). The mixture was allowed to stir for 45 min at which time TMSCl
(3.52 mL, 27.42 mmol, 3.00 equiv) was added. The reaction mixture
was then allowed to warm to rt, stirred for 5 min, and subsequently
warmed to 75 °C and stirred until TLC analysis indicated complete
conversion of the starting material, typically 12h. The reaction mixture
was cooled to rt and quenched via 1 M HCl(aq) (25 mL). The mixture
was then partitioned in a separatory funnel and extracted with Et2O (3
× 20 mL). The combined organic extracts were washed with 6 M HCl
(2 × 30 mL), dried with magnesium sulfate, and concentrated in vacuo
to provide the crude acid as a 6:1 mixture of diastereomers. The
diastereomeric ratio was determined by 1H NMR spectroscopic
analysis of the crude reaction mixture by comparison of the integration
of the resonances at δ 5.13 (minor diastereomer) and δ 5.12 (major
diastereomer). The product was purified via flash chromatography
(100:0 to 90:10 to 80:20 hexanes/EtOAc) to afford acid 71a (3.14 g,
78% yield) as a clear, viscous oil in an inseparable 6:1 diastereomeric
ratio. Analytical data: [α]D28 −43.5 (c = 0.70, CHCl3); 1H NMR (600
MHz, CDCl3) δ 5.12 (s, 1H), 5.04 (s, 1H), 3.12 (dd, J = 6.6, 2.4 Hz,
1H), 3.04 (m, 1H), 2.09 (m, 1H), 1.95 (m, 1H), 1.66 (m, 2H), 1.59
(m, 2H), 1.54 (m, 1H), 1.41 (m, 1H), 1.33 (s, 3H), 1.31 (s, 3H), 1.25
(s, 3H), 1.23 (s, 3H), 1.17 (s, 3H), 1.09 (s, 3H), 0.84 (s, 9H), 0.08 (s,
3H), 0.06 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 184.5, 161.1,
110.4, 84.7, 81.0, 74.8, 50.2, 44.4, 39.5, 36.9, 33.2, 28.3, 27.4, 25.6,
25.0, 24.6, 23.7, 23.6, 22.4, 22.1, 18.2, −2.2; HRMS (ESI+) calcd for
C25H46O4Si+Na, 461.3063; found 461.3063; IR (thin film, cm−1)
3-((2S,4aS,5R,6S,8aS)-2-(2-((tert-Butyldimethylsilyl)oxy)propan-2-
yl)-5-(hydroxymethyl)-4a,6-dimethyloctahydro-2H-chromen-6-yl)-
3-methylbutan-2-ol (73). A flame-dried, 250 mL round-bottomed
flask was charged with ketone 72 (1.63 g, 3.74 mmol, 1.00 equiv) and
THF (70 mL) under an atmosphere of N2. BH3·THF (1 M in THF,
16.82 mL, 4.50 equiv) was added, and the mixture was warmed to 50
°C and stirred until complete conversion of the starting material was
observed by TLC analysis, typically 12 h. The reaction mixture was
then cooled to 0 °C, and 3 M NaOH(aq) (7.5 mL) was added slowly
followed by H2O2 (30% w/w in H2O, 7.5 mL). The resulting mixture
was warmed to rt and stirred for 2.5 h, upon which the mixture was
V
DOI: 10.1021/acs.joc.5b01844
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The Journal of Organic Chemistry
Article
partitioned in a separatory funnel, diluted with H2O (30 mL), and
extracted with Et2O (3 × 20 mL). The combined organic extracts were
dried with magnesium sulfate and concentrated in vacuo to afford the
crude diol as an inseparable mixture of diastereomers at C12c and C6a.
chromen-8(4aH)-one O-Benzyl Oxime (76). The enone 75 (1.61 g,
3.70 mmol, 1.00 equiv) was dissolved in EtOAc (60 mL) in a 250 mL
round-bottomed flask and charged with Pd/C (2.40 g, 1.50 mass
equiv). The reaction mixture was placed under 1 atm (balloon) of H2
and stirred until full conversion of the starting material was observed
by TLC analysis, typically 30 min. The mixture was then filtered
through a pad of Celite, and the filter cake was washed with two 20 mL
portions of EtOAc. The solution was then concentrated in vacuo to
afford the crude ketone, which was carried to the next step without
further purification.
1
The diastereoselection of this reaction at C4b was determined via H
NMR analysis of the subsequent intermediate 74. The product was
purified via flash chromatography (80:20 to 70:30 hexanes/EtOAc) to
afford diol 73 (1.27 g, 74% yield) as a white, viscous foam. This
diastereomeric mixture was carried on to the next step without further
separation. Analytical data: [α]D28 −83.9 (c = 0.60, CHCl3); 1H NMR
(600 MHz, CDCl3) δ 4.18 (m, 2H), 3.88 (t, J = 12.6 Hz, 2H), 3.68
(dd, J = 9.0, 3.0 Hz, 1H), 3.56 (d, J = 12.0 Hz, 1H), 3.06 (m, 2H), 2.93
(dd, J = 6.0, 4.8 Hz, 1H), 2.86 (dd, J = 7.2, 4.2 Hz, 1H), 1.98 (m, 3H),
1.76 (s, 1H), 1.59−1.49 (m, 11H), 1.42−1.36 (m, 3H), 1.25 (d, J = 6.0
Hz, 5H), 1.21 (s, 6H), 1.15 (s, 7H), 1.01 (s, 2H), 0.95 (br s, 9H), 0.90
(br s, 4H), 0.89 (s, 3H), 0.86 (s, 2H), 0.83 (br s, 22H), 0.07 (s, 7H),
0.05 (s, 7H); 13C NMR (150 MHz, CDCl3) δ 85.1, 84.9, 84.2, 83.7,
74.9, 68.7, 61.5, 61.0, 54.2, 52.9, 45.8, 45.1, 42.5, 42.4, 39.0, 38.5, 37.9,
37.8, 34.0, 33.5, 27.4, 27.3, 25.8, 25.2, 25.0, 24.9, 24.6, 21.5, 21.4, 21.2,
19.8, 18.1, 17.8, 17.5, 14.7, 14.2, −2.1, −2.2; HRMS (ESI+) calcd for
C26H52O4Si+Na, 479.3533; found 479.3549; IR (thin film, cm−1)
3320, 2955, 2855, 1471, 1379, 1251, 1172, 1100, 834, 759; TLC
(85:15 hexanes/EtOAc) Rf = 0.14.
The residue was dissolved in MeOH/H2O (5:1, 80 mL) in a 250
mL round-bottomed flask. BnONH3Cl (11.84 g, 74.19 mmol, 20.00
equiv) and NaOAc (4.56 g, 55.64 mmol, 15.00 equiv) were added, and
the resulting suspension was fitted with a reflux condenser and heated
to 85 °C with stirring until TLC analysis confirmed complete
consumption of the starting material, typically 16 h. The reaction
mixture was cooled to rt and concentrated on a rotary evaporator. The
residue was taken up into H2O (30 mL) and CH2Cl2 (30 mL), and the
mixture was partitioned in a separatory funnel and extracted with
CH2Cl2 (3 × 20 mL). The combined organic extracts were washed
with H2O (30 mL), dried with magnesium sulfate, and concentrated in
vacuo. The product was purified via flash chromatography (100:0 to
98:2 to 97.5:2.5 to 95:5 hexanes/EtOAc) to afford oxime 76 (1.66 g,
28
(3S,4aS,6aS,10aR,10bS)-3-(2-((tert-Butyldimethylsilyl)oxy)-
propan-2-yl)-6a,7,7,10b-tetramethyl-2,3,5,6,6a,7,10a,10b-octahy-
dro-1H-benzo[f ]chromen-8(4aH)-one (75). A flame-dried, 250 mL
round-bottomed flask was charged with CH2Cl2 (70 mL) and
(COCl)2 (1.71 mL, 19.92 mmol, 5.00 equiv) under an atmosphere
of N2. The mixture was cooled to −78 °C, and DMSO (2.83 mL,
39.84 mmol, 10.00 equiv) was added slowly. The mixture was allowed
to stir 30 min at −78 °C then the diol 73 (1.82 g, 3.98 mmol, 1.00
equiv) was added as a solution in CH2Cl2 (10 mL). The reaction
mixture was stirred at this temperature for 2 h then DIPEA (13.88 mL,
79.69 mL, 20.0 equiv) was added. The reaction was stirred 30 min at
−78 °C then warmed to 0 °C and stirred 15 min. At this time TLC
analysis confirmed complete conversion of the starting material. The
reaction was quenched with saturated NH4Cl(aq) (25 mL), and the
mixture was partitioned in a separatory funnel. The mixture was
extracted with CH2Cl2 (3 × 20 mL), and the combined organic
extracts were washed with brine (20 mL), dried with magnesium
sulfate and concentrated in vacuo to afford the crude ketoaldehyde 74,
which was carried to the next step without further purification. (Note:
at this stage, a single diastereomer was observed in the 1H NMR
spectrum of the crude aldehyde, thereby establishing complete control
of the C4b methine stereocenter in the hydroboration/oxidation step.
This crude spectrum is provided in the Supporting Information.)
The crude ketoaldehyde 74 was dissolved in MeOH/THF (1:1, 80
mL) in a 250 mL round-bottomed flask and cooled to 0 °C with
magnetic stirring. KOH(aq) (2 M, 8 mL) was added, and the reaction
was warmed to rt and stirred for 12 h. The resulting mixture was
concentrated on a rotary evaporator and partitioned with EtOAc (30
mL) and H2O (30 mL) in a separatory funnel. The mixture was
extracted with EtOAc (3 × 20 mL), and the combined organic extracts
were dried with magnesium sulfate and concentrated in vacuo. The
product was purified via flash chromatography (100:0 to 97.5:2.5 to
95:5 to 90:10 hexanes/EtOAc) to afford the enone 75 (1.29 g, 75%
yield) as a yellow, viscous oil. Analytical data: [α]D28 −109.0 (c = 0.85,
83% yield) as a clear, viscous oil. Analytical data: [α]D −112.8 (c =
1
0.45, CHCl3); H NMR (600 MHz, CDCl3) δ 7.37−7.28 (m, 5H),
5.08 (br s, 2H), 3.35 (dd, J = 9.6, 4.2 Hz, 1H), 3.10 (dd, J = 8.4, 3.0
Hz, 1H), 2.88 (dd, J = 6.0, 4.2 Hz, 1H), 1.82 (m, 2H), 1.66−1.45 (m,
7H), 1.36 (m, 1H), 1.23 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 1.01 (s,
3H), 0.85 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 165.2, 138.7, 128.1, 128.0, 127.4, 85.4, 85.3, 75.1, 74.9, 45.9,
45.5, 41.1, 38.2, 36.2, 31.3, 27.3, 25.8, 25.0, 24.5, 23.3, 21.4, 20.9, 20.0,
19.0, 18.1, 16.8, 13.3, −2.2; HRMS (ESI+) calcd for C33H55NO3Si+Na,
564.3849; found 564.3862; IR (thin film, cm−1) 2951, 2855, 1626,
1470, 1378, 1250, 1173, 1040, 898, 835, 757; TLC (85:15 hexanes/
EtOAc) Rf = 0.77.
((3S,4aS,6aS,7R,10aR,10bS,E)-8-((Benzyloxy)imino)-3-(2-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-6a,7,10b-trimethyldodecahy-
dro-1H-benzo[f ]chromen-7-yl)methyl acetate (78). A 100 mL
round-bottomed flask was charged with oxime 76 (1.66 g, 3.06
mmol, 1.00 equiv) and AcOH:Ac2O (1:1, 31 mL) with magnetic
stirring at rt. Pd(OAc)2 (0.10 g, 0.46 mmol, 0.15 equiv) and
PhI(OAc)2 (1.48 g, 4.60 mmol, 1.50 equiv) were added sequentially,
and the reaction mixture was warmed to 100 °C. This temperature was
maintained until TLC analysis showed complete conversion of the
starting material, typically 1 h. The mixture was cooled to rt, diluted
with pentane (30 mL) and H2O (20 mL), and transferred to a
separatory funnel. Saturated NaHCO3(aq) (30 mL) was added
dropwise into the separatory funnel, and the mixture was allowed to
stand 10 min upon completion of the addition. The layers were
separated, and the aqueous layer was extracted with pentane (3 × 20
mL). The combined organic extracts were dried with magnesium
sulfate and concentrated in vacuo to afford the crude acetate 78 as a
single diastereomer (as determined by 1H NMR spectroscopic analysis
of the crude reaction mixture, which revealed a single compound). The
product was purified via flash chromatography (100:0 to 95:5 to 90:10
hexanes/EtOAc) to afford the acetate 78 (1.49 g, 81% yield) as a
28
1
reddish-brown, viscous oil. Analytical data: [α]D −66.2 (c = 0.70,
CHCl3); H NMR (500 MHz, CDCl3) δ 6.73 (d, J = 12.6 Hz, 1H),
CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.34−7.27 (m, 5H), 5.04 (br
s, 2H), 4.55 (d, J = 10.8 Hz, 1H), 4.03 (d, J = 11.4 Hz, 1H), 3.36 (dd, J
= 10.8, 13.6 Hz, 1H), 3.09 (dd, J = 8.4, 3.0 Hz, 1H), 2.88 (dd, J = 5.4,
4.8 Hz, 1H),1.94 (s, 3H), 1.82−1.74 (m, 2H), 1.63−1.52 (m, 8H),
1.35 (m, 1H), 1.22 (s, 3H), 1.21 (s, 3H), 1.15 (s, 3H), 0.91 (s, 3H),
0.84 (s, 12H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 171.1, 161.6, 128.2, 128.0, 127.4, 85.3, 85.1, 75.4, 74.8, 65.6,
48.4, 46.0, 42.1, 38.2, 36.3, 32.0, 27.3, 25.8, 25.0, 24.4, 21.4, 21.1, 20.8,
20.1, 18.1, 17.3, 17.0, 13.5, −2.2; HRMS (ESI+) calcd for
C35H57NO5Si+Na, 622.3904; found 622.3908; IR (thin film, cm−1)
2953, 2884, 1732, 1470, 1380, 1249, 1038, 835, 756; TLC (60:40
hexanes/EtOAc) Rf = 0.80.
5.99 (dd, J = 7.0, 3.5 Hz, 1H), 3.14 (dd, J = 9.0, 3.0 Hz, 1H), 2.97 (dd,
J = 5.0, 5.0 Hz, 1H), 2.29 (br s, 1H), 1.96 (d, J = 9.0 Hz, 1H), 1.70−
1.58 (m, 6H), 1.43 (m, 1H), 1.23 (s, 3H), 1.17 (s, 3H), 1.07 (s, 3H),
1.00 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.84 (s, 9H), 0.08 (s, 3H),
0.06 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 204.9, 146.2, 129.0,
85.6, 85.0, 74.8, 51.5, 49.7, 43.8, 37.3, 35.5, 30.5, 27.4, 25.8, 24.9, 23.8,
21.2, 20.3, 18.1, 16.9, 16.6, 14.7, −2.1, −2.2; HRMS (ESI+) calcd for
C26H46O3Si+Na, 457.3114; found 457.3129; IR (thin film, cm−1)
2954, 2855, 1677, 1461, 1389, 1251, 1174, 1103, 1041, 834, 756; TLC
(85:15 hexanes/EtOAc) Rf = 0.43.
(3S,4aS,6aS,10aR,10bS,E)-3-(2-((tert-Butyldimethylsilyl)oxy)-
propan-2-yl)-6a,7,7,10b-tetramethyldecahydro-1H-benzo[f ]-
W
DOI: 10.1021/acs.joc.5b01844
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Synthesis of Ketoaldehyde 83. (3S,4aS,6aS,7S,10aR,10bS)-7-
(Hydroxymethyl)-3-(2-hydroxypropan-2-yl)-6a,7,10b-trimethylde-
cahydro-1H-benzo[f ]chromen-8(4aH)-one (S6). A 50 mL round-
bottomed flask was charged with acetate 78 (0.71 g, 1.18 mmol, 1.00
equiv) and 2 M HCl(aq)/MeOH/THF/acetone (10:10:10:1, 12 mL).
The mixture was warmed to 85 °C and stirred until full convergence to
a single product was observed by TLC analysis, typically 5 h. The
mixture was cooled to rt and concentrated on a rotary evaporator, and
the residue was taken up into H2O (15 mL) and CH2Cl2 (15 mL) and
partitioned in a separatory funnel. The mixture was extracted with
CH2Cl2 (3 × 10 mL), and the combined organic extracts were dried
with magnesium sulfate and concentrated in vacuo. The product was
purified via flash chromatography (60:40 EtOAc:hexanes) to afford
hydroxy ketone S6 (0.28 g, 71% yield) as a reddish-brown, viscous oil.
Analytical data: [α]D −159.6 (c = 0.30, CHCl3); H NMR (600
MHz, CDCl3) δ 4.12 (dd, J = 8.4, 3.0 Hz, 1H), 3.22 (m, 2H), 3.02 (dd,
J = 6.0, 3.0 Hz, 1H), 2.64 (dd, J = 7.2, 3.0 Hz, 1H), 2.59 (br s, 1H),
2.55 (m, 1H), 2.29 (m, 1H), 1.89−1.86 (m, 2H), 1.80 (m, 1H), 1.70−
1.60 (m, 6H), 1.46 (m, 1H), 1.40 (dt, J = 6.0, 3.6 Hz, 1H), 1.31 (s,
3H), 1.23 (m, 1H), 1.18 (s, 3H), 1.15 (s, 3H), 0.99 (s, 3H), 0.91 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 219.3, 85.0, 84.6, 71.8, 63.6,
57.4, 45.3, 42.1, 37.9, 37.6. 36.4, 30.7, 26.1, 23.9, 23.7, 21.7, 21.2, 18.2,
16.9, 13.5; HRMS (ESI+) calcd for C20H34O4+Na, 361.2355; found
361.2360; IR (thin film, cm−1) 3450, 2950, 1692, 1425, 1166, 1102,
735, 685; TLC (60:40 hexanes/EtOAc) Rf = 0.12.
separatory funnel, diluted with H2O (15 mL) and extracted with Et2O
(3 × 15 mL). The combined organic extracts were washed with
saturated NaHCO3(aq) (10 mL), dried with magnesium sulfate and
concentrated in vacuo. The product was purified via flash
chromatography (80:20 to 70:30 to 60:40 hexanes/EtOAc) to afford
an inseparable 2.6:1 mixture of diol diastereomers 84 (0.14 g, 99%
yield) as a pale white, viscous foam. Analytical data: [α]D28 −182.8 (c =
1
0.25, CHCl3); H NMR (600 MHz, CDCl3) δ 6.30 (dd, J = 10.8, 6.0
Hz, 1H), 6.14 (m, 1H), 5.24 (d, J = 17.4 Hz, 1H), 5.08 (d, J = 10.8 Hz,
1H), 5.03−4.99 (m, 2H), 4.40 (d, J = 8.4 Hz, 1H), 3.16 (m, 1H), 2.88
(m, 1H), 1.83 (m, 3H), 1.72 (m, 2H), 1.59 (m, 3H), 1.53 (s, 3H),
1.45−1.36 (m, 5H), 1.15 (s, 3H), 1.14 (s, 3H), 1.03 (m, 1H), 0.90 (s,
3H), 0.87 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 145.8, 140.7,
116.4, 112.6, 85.7, 84.5, 80.0, 79.6, 72.0, 49.4, 47.3, 43.1, 38.0, 36.3,
35.9, 32.4, 26.0, 24.3, 23.6, 21.9, 19.5, 18.6, 17.0, 13.3; HRMS (ESI+)
calcd for C24H40O4+Na, 415.2825; found 415.2829; IR (thin film,
cm−1) 3303, 2949, 2877, 1621, 1461, 1301, 1089, 920, 737; TLC
(60:40 hexanes/EtOAc) Rf = 0.32.
(2S,4aS,4bR,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-4a,9a,9b-
trimethyl-3,4,4a,4b,5,6,9,9a,9b,10,11,11a-dodecahydroindeno[5,4-
f ]chromene-6a,9(2H)-diol (85). A flame-dried, 20 mL scintillation vial
was charged with Grubbs’ second generation catalyst (0.99 g, 0.12
mmol, 0.20 equiv) and a stir bar in a nitrogen-filled glovebox. The vial
was removed from the glovebox and charged with CH2Cl2 (12 mL)
under an atmosphere of N2. Diol 84 (0.23 g, 0.59 mmol, 1.00 equiv)
was added as a solution in CH2Cl2 (3 mL), and the mixture was
allowed to stir at rt until complete conversion of the starting material
was observed by TLC analysis, typically 3 h. The reaction mixture was
concentrated in vacuo, and the product was purified via flash
chromatography (80:20 to 70:30 to 60:40 hexanes/EtOAc) to afford
allylic alcohol 85 (0.16 g, 73% yield) as a pale-brown viscous foam.
Analytical data: [α]D28 −62.8 (c = 0.75, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 6.22 (d, J = 5.4 Hz, 1H), 6.14 (dd, J = 3.0, 2.4 Hz, 1H), 4.42
(br s, 1H), 3.18 (dd, J = 9.0, 3.0 Hz, 1H), 2.95 (dd, J = 7.8, 3.6 Hz,
1H), 2.69 (br s, 1H), 2.26 (d, J = 5.4 Hz, 1H), 2.22 (br s, 1H), 1.83−
1.75 (m, 8H), 1.63 (s, 3H), 1.56−1.54 (m, 3H), 1.42 (m, 2H), 1.17 (s,
3H), 1.16 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 143.2, 137.2, 87.3, 86.0, 84.6, 83.3, 71.9, 52.5, 47.9, 41.8,
38.3, 36.3, 32.9, 30.4, 26.8, 26.1, 23.9, 23.6, 21.9, 20.2, 17.7, 13.2;
HRMS (ESI+) calcd for C22H36O4+Na, 387.2512; found 387.2519; IR
(thin film, cm−1) 3400, 2951, 2675, 1729, 1449, 1384, 1256, 1097,
1023, 910, 754; TLC (60:40 hexanes/EtOAc) Rf = 0.25.
(2S,4aS,4bR,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-4a,9a,9b-
trimethyl-3,4,4a,4b,5,6,8,9a,9b,10,11,11a-dodecahydroindeno[5,4-
f ]chromen-9(2H)-one (86). A flame-dried, 20 mL scintillation vial was
charged with diol 85 (0.15 g, 0.40 mmol, 1.00 equiv) and CH2Cl2 (9
mL) under and atmosphere of N2. The mixture was cooled to 0 °C,
and TFA (0.15 mL, 2.02 mmol, 5.00 equiv) was added. The reaction
mixture was warmed to rt and allowed to stir until complete
conversion of the starting material was observed by TLC analysis,
typically 30 min. The reaction was quenched with saturated
NaHCO3(aq) (5 mL), and the mixture was partitioned in a separatory
funnel. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL), and
the combined organic extracts were dried with Na2SO4 and
concentrated in vacuo. The product was purified via flash
chromatography (90:10 to 80:20 to 70:30 hexanes/EtOAc) to afford
the nonconjugated enone 86 (0.10 g, 71% yield) as a pale brown,
viscous oil. Analytical Data: [α]D28 −77.7 (c = 0.50, CHCl3); 1H NMR
(600 MHz, CDCl3) δ 5.64 (m, 1H), 3.17 (dd, J = 9.0, 2.4 Hz, 1H),
2.95 (dd, J = 5.4, 4.8 Hz, 1H), 2.83 (m, 1H), 2.69 (m, 1H), 2.61 (br
s,1H), 2.40 (m, 1H), 2.10 (br s, 1H), 1.84 (m, 2H), 1.64 (m, 3H), 1.55
(m, 2H), 1.43−1.33 (m, 3H), 1.16 (s, 3H), 1.13 (br s, 4H), 1.12 (s,
3H), 0.91 (s, 3H), 0.83 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
223.0, 148.2, 116.3, 85.5, 84.4, 71.8, 59.3, 46.6, 43.0, 41.1, 37.9, 36.5,
30.9, 27.6, 26.1, 24.0, 23.7, 21.8, 21.7, 17.6, 17.4, 13.4; HRMS (ESI+)
calcd for C22H34O3+Na, 369.2406; found 369.2398; IR (thin film,
cm−1) 3053, 2979, 2977, 1734, 1558, 1472, 1373, 1265, 1139, 1086,
971, 921, 704; TLC (80:20 hexanes/EtOAc) Rf = 0.23.
28
1
(3S,4aS,6aS,7S,10aR,10bS)-3-(2-Hydroxypropan-2-yl)-6a,7,10b-
trimethyl-8-oxododecahydro-1H-benzo[f ]chromene-7-carbalde-
hyde (83). A 20 mL scintillation vial was charged with alcohol S6 (0.29
g, 0.84 mmol, 1.00 equiv) and CH2Cl2 (8 mL). Dess-Martin
periodinane (0.71 g, 1.68 mmol, 2.00 equiv) was added at rt with
stirring. The reaction mixture was allowed to stir at room temperature
until TLC analysis confirmed complete conversion of the starting
material, typically 20 min. The mixture was then quenched via a 1:1
solution of saturated NaHCO3(aq) and saturated Na2S2O3(aq) (10 mL),
and the mixture was stirred 5 min. The reaction mixture was then
diluted with Et2O (15 mL) and partitioned in a separatory funnel. The
aqueous layer was extracted with Et2O (3 × 10 mL), and the
combined organic extracts were dried with magnesium sulfate and
concentrated in vacuo. The product was purified via flash
chromatography (60:40 to 50:50 hexanes/EtOAc) to afford the
ketoaldehyde 83 (0.28 g, 99% yield) as a pale white powder. Analytical
28
1
data: mp 121−125 °C; [α]D −223.7 (c = 0.50, CHCl3); H NMR
(600 MHz, CDCl3) δ 10.06 (s, 1H), 3.22 (dd, J = 9.0, 3.0 Hz, 1H),
3.02 (dd, J = 6.0, 2.4 Hz, 1H), 2.52−2.46 (m, 2H), 1.94−1.82 (m,
3H), 1.57−1.70 (m, 5H), 1.47 (m, 1H), 1.26 (s, 3H), 1.24 (s, 3H),
1.22 (m, 1H), 1.18 (s, 3H), 1.15 (s, 3H), 0.94 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 214.0, 204.2, 84.9, 84.6, 71.9, 64.7, 45.1, 43.4, 37.8,
37.6, 36.5, 31.6, 26.1, 23.7, 23.5, 21.6, 20.9, 19.5, 14.8, 13.6; HRMS
(ESI+) calcd for C20H32O4+Na, 359.2199; found 359.2198; IR (thin
film, cm−1) 3019, 2955, 2857, 2400, 1721, 1388, 1265, 1215, 1098;
TLC (60:40 hexanes/EtOAc) Rf = 0.24.
(3S,4aS,6aS,7S,10aR,10bS)-7-(1-Hydroxyallyl)-3-(2-hydroxypro-
pan-2-yl)-6a,7,10b-trimethyl-8-vinyldodecahydro-1H-benzo[f ]-
chromen-8-ol (84). A flame-dried, 20 mL scintillation vial was charged
with LiCl (0.30 g, 7.13 mmol, 20.00 equiv equiv), anhydrous CeCl3
(0.88 g, 3.57 mmol, 10.00 equiv), and a stir bar in a nitrogen-filled
glovebox. The vial was removed from the glovebox and placed under
an N2 atmosphere. THF (5 mL) was added, and this mixture was
stirred at rt for 2.5 h. A separate flame-dried, 20 mL scintillation vial
was charged with aldehyde 83 (0.12 g, 0.36 mmol, 1.00 equiv) and
THF (2 mL) under an atmosphere of N2. The CeCl3·2LiCl suspension
was added to the solution of 83 at rt, and the resulting mixture was
stirred 2.5 h. The reaction was subsequently cooled to −78 °C, and
vinylmagnesium bromide (1 M in THF, 3.57 mL, 3.57 mmol, 10
equiv) was added. The reaction mixture was allowed to stir at this
temperature until TLC analysis confirmed complete consumption of
the starting material, typically 20 min. The reaction was quenched with
MeOH (3 mL), and the mixture was immediately warmed to rt upon
which 5% AcOH(aq) (2 mL) and Et2O (2 mL) were added with
stirring. Once the vial had reached rt, the solution was transferred to a
(2S,4aS,4bR,6aR,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-
4a,9a,9b-trimethyltetradecahydroindeno[5,4-f ]chromen-9(2H)-one
X
DOI: 10.1021/acs.joc.5b01844
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(87). A 20 mL scintillation vial was charged with ketone 86 (0.008 g,
0.02 mmol, 1.00 equiv) and EtOH (2 mL), and Pd/C (0.013 g, 1.50
mass equiv) was added. The reaction mixture was placed under 1 atm
H2 (balloon), and the mixture was allowed to stir overnight. The
reaction was filtered through a Celite plug, and the filtrate was
concentrated on a rotary evaporator to give the crude ketone as a
single diastereomer (as determined by 1H NMR spectroscopic analysis
of the crude reaction mixture, which revealed a single compound). The
product was purified via flash chromatography (90:10 to 80:20 to
70:30 hexanes/EtOAc) to afford ketone 87 as a clear, viscous oil.
Analytical data: [α]D28 −45.2 (c = 0.35, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 3.18 (dd, J = 9.0, 3.0 Hz, 1H), 2.92 (d, J = 6.6, 4.2 Hz, 1H),
2.60 (br s, 1H), 2.33 (m, 1H), 2.21 (m, 1H), 2.03 (m, 1H), 1.92−1.82
(m, 3H), 1.74 (m, 2H), 1.64−1.41 (m, 11H), 1.17 (s, 3H), 1.14 (s,
3H), 1.10 (s, 3H), 1.04 (s, 3H), 0.85 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 224.9, 85.4, 84.4, 71.8, 54.5, 47.5, 46.2, 39.3, 38.8, 37.8, 36.3,
32.5, 26.8, 26.2, 26.1, 23.7, 23.5, 21.8, 20.9, 19.5, 17.3, 13.5; HRMS
(ESI+) calcd for C22H36O3+Na, 371.2562; found 371.2554; IR (thin
film, cm−1) 3446, 2955, 2852, 1731, 1636, 1520, 1473, 1396, 1085,
754; TLC (80:20 hexanes/EtOAc) Rf = 0.20.
resulting mixture was concentrated in vacuo to afford the crude alcohol
90, which was carried forward to the next step without purification.
Although this material was not isolated, the diastereomeric ratio was
1
determined by H NMR spectroscopic analysis of the crude reaction
mixture, which revealed a single compound. This crude 1H NMR
spectrum is included in the Supporting Information.
A 20 mL scintillation vial was charged with the crude alcohol 90 and
CH2Cl2 (3 mL) with magnetic stirring. Dess-Martin periodinane
(0.045 g, 0.11 mmol, 1.50 equiv) was added, and the reaction mixture
was allowed to stir at rt until complete conversion of the starting
materal was observed by TLC analysis, typically 20 min. The reaction
was then quenched via a 1:1 solution of saturated NaHCO3(aq) and
saturated Na2S2O3(aq) (3 mL), and the mixture was stirred 5 min. The
reaction mixture was then diluted with Et2O (5 mL) and partitioned in
a separatory funnel. The aqueous layer was extracted with Et2O (3 × 5
mL), and the combined organic extracts were dried with magnesium
sulfate and concentrated in vacuo. The product was purified via flash
chromatography (90:10 to 80:20 to 70:30 hexanes/EtOAc) to afford
ketone 91 (0.022 g, 89% yield) as a clear semisolid. Slow evaporation
from HPLC-grade hexanes provided crystals suitable for X-ray
27
(2S,4aS,4bR,9S,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-
4a,9a,9b-trimethyl-2,3,4,4a,4b,5,6,8,9,9a,9b,10,11,11a-
tetradecahydroindeno[5,4-f ]chromen-9-ol (88). A flame-dried, 20
mL scintillation vial was charged with diol 86 (0.16 g, 0.43 mmol, 1.00
equiv) and CH2Cl2 (9 mL) under and atmosphere of N2. The mixture
was cooled to 0 °C, and TFA (0.17 mL, 2.14 mmol, 5.00 equiv) was
added. The reaction mixture was warmed to rt and allowed to stir until
complete conversion of the starting material was observed by TLC
analysis, typically 30 min. The reaction was quenched with saturated
NaHCO3(aq) (5 mL), and the mixture was partitioned in a separatory
funnel. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL), and
the combined organic extracts were dried with Na2SO4 and
concentrated in vacuo to afford the crude nonconjugated enone 86,
which was carried to the next step without further purification.
A flame-dried, 20 mL scintillation vial was charged with the crude
ketone 86 and THF (5 mL) under an atmosphere of N2. The reaction
mixture was cooled to 0 °C, and LiAlH4 (1 M in THF, 2.00 mL, 2.00
mmol, 4.70 equiv) was added dropwise. The reaction mixture was
allowed to stir at this temperature until TLC analysis indicated
complete consumption of the starting material, typically 30 min. The
reaction was then carefully quenched with saturated NH4Cl(aq) (4 mL)
and stirred 5 min at rt. The resulting mixture was partitioned in a
separatory funnel and extracted with Et2O (3 × 5 mL). The combined
organic extracts were dried with magnesium sulfate and concentrated
in vacuo to afford the crude alcohol 88 as a single diastereomer (as
crystallographic analysis. Analytical data: mp 125−130 °C; [α]D
−89.3 (c = 0.85, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.16 (dd, J =
9.0, 3.0 Hz, 1H), 2.93 (m, 1H), 2.65 (br s, 1H), 2.32 (dd, J = 11.0, 8.5
Hz, 1H), 2.19−2.14 (m, 2H), 2.00 (m, 1H), 1.78−1.23 (m, 15H), 1.16
(s, 3H), 1.14 (s, 3H), 1.02 (s, 3H), 0.92 (s, 3H), 0.83 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 221.2, 85.7, 84.4, 71.8, 56.1, 46.9, 40.2,
39.9, 37.8, 37.5, 36.5, 31.1, 26.1, 25.8, 24.2, 23.8, 23.7, 21.9, 21.2, 18.9,
12.9, 10.3; HRMS (ESI+) calcd for C22H36O3+Na, 371.2562; found
371.2560; IR (thin film, cm−1) 3566, 3446, 2946, 2876, 1772, 1731,
1472, 1385, 1259, 1158, 1098, 974, 735; TLC (70:30 hexanes/EtOAc)
Rf = 0.60.
Note: The following sequence for conversion of 91 to paspaline was
adapted from the previously published protocol by Smith and co-
workers.12a,d
(2S,4aS,4bR,6aS,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-
4a,9a,9b-trimethyl-8-(methylthio)tetradecahydroindeno[5,4-f ]-
chromen-9(2H)-one (S7). A flame-dried, 20 mL scintillation vial was
cooled to 0 °C and charged with THF (1 mL) and a freshly prepared
solution of lithium diisopropylamide (0.5 M in THF, 0.57 mL, 0.29
mmol, 5.00 equiv) under an atmosphere of N2. The resulting solution
was then charged with a solution of ketone 91 (0.02 g, 0.06 mmol,
1.00 equiv) in THF (0.5 mL), and the reaction mixture was allowed to
stir 15 min at 0 °C. HMPA (0.6 mL) was added followed by Me2S2
(0.031 mL, 0.34 mmol, 6.00 equiv), and the reaction was allowed to
stir until TLC analysis showed complete conversion of the starting
material, typically 10 min. The reaction was quenched via addition of
H2O (5 mL). The resulting mixture was transferred to a separatory
funnel, and the organic layer was separated. The aqueous layer was
extracted with Et2O (3 × 5 mL), and the combined organic extracts
were washed with brine (2 × 10 mL), dried with magnesium sulfate,
and concentrated in vacuo. The product was purified via flash
chromatography (90:10 to 80:20 to 70:30 hexanes/EtOAc) to afford
an inseparable, diastereomeric mixture of thioethers S7 (0.019 g, 84%
yield) as a yellow, viscous oil. Analytical data: [α]D27 −57.9 (c = 0.70,
1
determined by H NMR spectroscopic analysis of the crude reaction
mixture, which revealed a single compound). The crude product was
purified via flash chromatography (80:20 to 70:30 to 60:40 hexanes/
EtOAc) to afford alcohol 88 (0.90 g, 60% yield) as a pale yellow foam.
28
1
Analytical data: [α]D −116.4 (c = 0.50, CHCl3); H NMR (600
MHz, CDCl3) δ 5.22 (s, 1H), 4.37 (t, J = 8.4 Hz, 1H), 3.18 (dd, J =
9.0, 3.0 Hz, 1H), 2.95 (m, 1H), 2.68 (br s, 1H), 2.54 (m, 1H), 2.25 (d,
J = 10.8 Hz, 1H), 2.20 (m, 1H), 1.94 (br s, 1H), 1.80 (d, J = 2.4 Hz,
1H), 1.69−1.59 (m, 6H), 1.50 (m, 1H), 1.42−1.36 (m, 3H), 1.19 (s,
3H), 1.17 (s, 3H), 1.14 (s, 3H), 0.86 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 148.1, 117.5, 85.8, 85.2, 84.4, 71.9, 55.1, 48.1, 43.9, 40.9,
38.0, 36.7, 31.8, 27.0, 26.1, 24.6, 23.8, 23.6, 22.8, 21.9, 16.7, 13.5;
HRMS (ESI+) calcd for C22H36O3+Na, 371.2562; found 371.2570; IR
(thin film, cm−1) 3433, 2979, 2678, 2399, 1452, 1373, 1215, 1093, 955,
755, 668; TLC (60:40 hexanes/EtOAc) Rf = 0.36
1
CHCl3); H NMR (600 MHz, CDCl3) δ 3.16 (dd, J = 9.0, 3.0 Hz,
1H), 2.94 (m, 2H), 2.61 (br s, 1H), 2.25 (br s, 3H), 2.22−2.13 (m,
3H), 1.63−1.57 (m, 11H), 1.47 (m, 10H), 1.17 (s, 3H), 1.14 (s, 3H),
1.02 (s, 3H), 1.01 (s, 3H), 0.83 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 218.4, 85.6, 84.4, 71.8, 56.6, 49.8, 46.6, 40.1, 38.1, 37.8, 36.4, 31.8,
31.1, 26.1, 25.2, 24.2, 23.7, 21.8, 21.1, 19.0, 15.4, 12.9, 11.0; HRMS
(ESI+) calcd for C23H38O3S+Na, 417.2439; found 417.2438; IR (thin
film, cm−1) 3446, 2946, 2874, 1732, 1652, 1519, 1456, 1386, 1232,
1152, 1086, 946; TLC (70:30 hexanes/EtOAc) Rf = 0.63.
(2S,4aS,4bR,6aS,9aS,9bS,11aS)-8-(2-Aminophenyl)-2-(2-hydroxy-
propan-2-yl)-4a,9a,9b-trimethyltetradecahydroindeno[5,4-f ]-
chromen-9(2H)-one (S8). A flame-dried, 20 mL scintillation vial was
charged with a solution of aniline (0.25 M in CH2Cl2, 0.26 mL, 0.07
mmol, 2.00 equiv) under an atmosphere of N2, and the resulting
solution was cooled to −78 °C. The lights in the fume hood were
turned off, and a solution of tBuOCl (0.25 M in CH2Cl2, 0.26 mL, 0.07
(2S,4aS,4bR,6aS,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-
4a,9a,9b-trimethyltetradecahydroindeno[5,4-f]chromen-9(2H)-one
(91). A flame-dried, 20 mL scintillation vial was charged with
Crabtree’s catalyst (0.01 g, 0.01 mmol, 0.15 equiv) in a nitrogen-filled
glovebox. The vial was sealed with a rubber-septum, removed from the
glovebox, and placed under an atmosphere of N2. CH2Cl2 (4 mL,
freshly degassed via N2 bubbling for 30 min) was added followed by a
solution of alcohol 88 (0.025 g, 0.07 mmol, 1.00 equiv) in degassed
CH2Cl2 (2 mL), and the resulting mixture was placed under an
atmosphere of H2 (balloon) and allowed to stir 36 h at rt. The
Y
DOI: 10.1021/acs.joc.5b01844
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mmol, 2.00 equiv) was added dropwise. The reaction mixture was
allowed to stir 15 min, upon which a solution of thioether S8 (0.013 g,
0.03 mmol, 1.00 equiv) in CH2Cl2 (1.5 mL) was added. The mixture
was allowed to stir 50 min, upon which NEt3 (0.02 mL, 0.13 mmol,
4.00 equiv) was added. The reaction was then warmed to rt and
allowed to stir until a bright orange color was observed, typically 5
min. The resulting solution was diluted with H2O (5 mL) and Et2O
(10 mL) and partitioned in a separatory funnel. The organic layer was
separated, and the aqueous layer was extracted with Et2O (3 × 5 mL).
The combined organic extracts were dried with magnesium sulfate and
concentrated in vacuo to afford a crude mixture of diastereomeric
keto-anilines, which was carried directly on to the next step without
further purification.
AUTHOR INFORMATION
Corresponding Author
*Email: jsj@unc.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project described was supported by Award No. R01
GM084927 from the National Institute of General Medical
Sciences. R.J.S. acknowledges an NSF Graduate Research
Fellowship and ACS Division of Organic Chemistry graduate
fellowship. X-ray crystallography was performed by Dr. Peter
White (UNC). The authors thank Dr. Shubin Liu (UNC) for
assistance with DFT structure optimization calculations.
The residue was taken up into EtOH (1 mL) in a 20 mL
scintillation vial, and a slurry of Raney Ni in H2O (150 mg) was added.
The reaction mixture was stirred vigorously at rt until complete
conversion of the intermediate thioether was observed by TLC
analysis, typically 1 h. The reaction mixture was filtered through a
Celite plug, and the resulting solution was concentrated in vacuo. The
crude product was purified via flash chromatography (90:10 to 80:20
to 70:30 to 60:40 hexanes/EtOAc) to afford ketoaniline S8 (0.009 g,
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27
62% yield) as yellow, viscous oil. Analytical data: [α]D +26.6 (c =
0.45, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.06 (m, 2H), 6.77 (m,
2H), 4.21 (br s, 2H), 3.54 (t, J = 9.0 Hz, 1H), 3.16 (dd, J = 9.6, 2.4 Hz,
1H), 2.94 (m, 1H), 2.62 (br s, 1H), 2.35 (m, 1H), 2.14−2.04 (m, 3H),
1.84−1.37 (m, 16H), 1.17 (s, 3H), 1.15 (s, 1H), 1.11 (s, 3H), 0.98 (s,
3H), 0.86 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 221.0, 146.0,
127.6, 125.8, 125.4, 119.1, 117.5, 85.6, 84.5, 71.8, 57.0, 51.5, 46.8, 40.1,
38.0, 37.8, 36.5, 31.3, 28.9, 26.1, 25.4, 24.2, 23.7, 21.9, 21.2, 19.2, 12.9,
10.0; HRMS (ESI+) calcd for C28H41NO3+Na, 462.2984; found
462.2983; IR (thin film, cm−1) 3421, 3053, 2984, 2877, 2305, 1732,
1652, 1456, 1362, 1265, 738; TLC (70:30 hexanes/EtOAc) Rf = 0.30.
Paspaline (1). A 1 mL dram vial was charged with ketone S8 (0.007
g, 0.02 mmol, 1.00 equiv), CH2Cl2 (1.2 mL), and PTSA (0.002 g, 0.01
mmol, 0.66 equiv). The vial was sealed, and the mixture was warmed
to 50 °C and stirred for 16 h. The reaction mixture was cooled to rt,
diluted with H2O (10 mL) and Et2O (10 mL), and transferred to a
separatory funnel. The organic layer was separated, and the aqueous
layer was extracted with Et2O (3 × 5 mL). The combined organic
extracts were dried with magnesium sulfate and concentrated in vacuo.
The product was purified via flash chromatography (90:10 to 80:20
hexanes/EtOAc) to afford paspaline (0.006 g, 89% yield) as a yellow
foam. Slow evaporation from HPLC-grade hexanes provided crystals
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25
suitable for X-ray crystallographic analysis. Analytical data: [α]D
1
−16.4 (c = 0.30, CHCl3); H NMR (600 MHz, CDCl3) δ 7.72 (br s,
1H), 7.42 (m, 1H), 7.30 (m, 1H), 7.07 (m, 2H), 3.21 (dd, J = 9.6, 2.4
Hz, 1H), 3.03 (dd, J = 8.4, 3.6 Hz, 1H), 2.77−2.65 (m, 3H), 2.32 (dd,
J = 10.8, 2.4 Hz, 1H), 1.96 (m, 1H), 1.84−1.77 (m, 3H), 1.70−1.56
(m, 6H), 1.49−1.37 (m, 3H), 1.19 (s, 3H), 1.17 (s, 3H), 1.13 (s, 3H),
1.03 (s, 3H), 0.88 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 150.8,
139.3, 125.1, 120.4, 119.5, 118.4, 118.2, 111.4, 85.7, 84.7, 71.9, 53.0,
48.7, 46.4, 40.0, 37.6, 36.5, 33.9, 27.5, 26.1, 25.2, 24.6, 23.7, 22.0, 21.9,
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2855, 1455, 1386, 1375, 1331, 1265, 1158, 1087, 1037; TLC (70:30
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■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01844.
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X-ray data for 32 (CIF)
X-ray data for 54 (CIF)
X-ray data for 91 (CIF)
X-ray data for 1 (CIF)
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DOI: 10.1021/acs.joc.5b01844
J. Org. Chem. XXXX, XXX, XXX−XXX

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AA
DOI: 10.1021/acs.joc.5b01844
J. Org. Chem. XXXX, XXX, XXX−XXX