A stereoconvergent intramolecular Diels-Alder cycloaddition related to the construction of the decalin core of neo-clerodane diterpenoids

Article abstract of DOI:10.1021/jo400029u

Several examples of a highly specific, stereoconvergent intramolecular Diels-Alder cycloaddition that led to the trans-decalin core of neo-clerodane diterpenoids are described. The relative configuration adjacent to the dienophile, which led to C4 of the decalin system, as well as the electron-withdrawing effects of various substituents and conformational rigidity of the Diels-Alder precursors were explored.

Full text of DOI:10.1021/jo400029u

Article
pubs.acs.org/joc
A Stereoconvergent Intramolecular Diels−Alder Cycloaddition
Related to the Construction of the Decalin Core of neo-Clerodane
Diterpenoids
Sean C. Butler*,† and Craig J. Forsyth‡
†Department of Chemistry, The University of Texas at Tyler, Tyler, Texas 75799, United States
‡Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
S
* Supporting Information
ABSTRACT: Several examples of a highly specific, stereoconvergent intramolecular Diels−Alder cycloaddition that led to the
trans-decalin core of neo-clerodane diterpenoids are described. The relative configuration adjacent to the dienophile, which led to
C4 of the decalin system, as well as the electron-withdrawing effects of various substituents and conformational rigidity of the
Diels−Alder precursors were explored.
Scheme 1. Improvements in DATA Synthesis of Decalin
Core of Salvinorin A
INTRODUCTION
■
In recent years, chemists and biologists around the globe have
shown interest in neo-clerodane diterpenoids1 (NCDs, Figure
1). Much of the synthetic interest2 stems from the unique
Figure 1. Carbon skeletons of neo-clerodane diterpenoids (1) and
salvinorin A (2).
biological activity3,4 of the selective and potent κ-opioid
receptor agonist, salvinorin A (2),5,6 which has led to several
total syntheses7−9 and is of interest to us as well.10 Due to the
inherent structural features of NCDs, including the position of
stereogenic centers and the decalin core motif, there is no
doubt that a Diels−Alder cycloaddition would prove to be a
valuable tool in their construction.1 Since its inception, the
Diels−Alder reaction11 has served as a powerful method for the
synthesis of both large and small organic molecules.12,13
Previously, Burns and Forsyth10 have shown that the decalin
core of 2 could be prepared via an intramolecular Diels−Alder/
Tsuji allylation (DATA) sequence. Since that account, the
overall yield of the sequence has been improved via prolonged
reaction times of the cycloaddition step (Scheme 1). Whereas
the original reaction gave complete lack of apparent endo
versus exo selectivity, the prolonged reaction times had caused
a slight shift in the product distribution where the undesired,
cis-decalin 4 was now favored. This lack of selectivity in the
cycloaddition reaction partly led to the exploration and
determination of how the introduction of certain structural
differences in 3 would affect the outcome of the intramolecular
Diels−Alder reaction.
Received: February 8, 2013
Published: March 19, 2013
© 2013 American Chemical Society
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Synthesis of the methyl carbonate substrates began with the
addition of isopropenylmagnesium bromide to aldehyde 7
(Scheme 3), which was prepared from a derivative14,15 of L-
RESULTS AND DISCUSSION
■
To determine a plan of action with regard to the types of
structural modifications necessary to improve the selectivity of
the cycloaddition reaction, attention was turned toward the
proposed transition states of the Diels−Alder reaction (Scheme
2). As previously noted,10 it was likely that cis-decalin 4 arose
Scheme 3. Synthesis of Diastereomeric Bis-carbonates (S)-
and (R)-13a
Scheme 2. Proposed Transition States in Formation of cis-
and trans-Decalins 4 and 510
from a boatlike endo transition state A (endo-TS-A), whereas
trans-decalin 5 was thought to originate from a chairlike exo
transition state B (exo-TS-B). Apparently endo-TS-A and exo-
TS-B have comparable energies, based on the product
distribution, which offers an explanation of why cis-decalin 4
was not favored significantly over trans-decalin 5. Therefore, it
would be necessary to introduce structural adjustments to 3
that would guide the molecule into a transition state similar to
exo-TS-B to produce a trans-decalin ring system.
Replacement of the dienophile enone carbonyl of 3 by
introduction of a stereogenic center would ultimately allow us
to determine whether configurational differences in the allylic
position would affect the cycloaddition transition states and
generate one product predominantly. Removal of the electron-
withdrawing effect of the ketone moiety entirely would
significantly reduce the reactivity toward annulation. Replace-
ment of the ketone with an alternative electron-withdrawing
group (EWG) at the allylic position would be necessary to
preserve the reactivity of the molecule toward cycloaddition by
retaining comparable energetics of the frontier molecular
orbitals. Therefore, a methyl carbonate was initially chosen to
replace the ketone functionality. It was envisioned that a methyl
carbonate, a stronger EWG than a simple alcohol, would allow
the cycloaddition to proceed without a drastic change in
reaction conditions. This functional group manipulation would
both permit a direct comparison of two diastereomeric
compounds and determine whether the introduction of a
specific epimer at the allylic sp3 center would be advantageous
in favoring an exo-cycloaddition.
(+)-tartaric acid. The secondary alcohols of unknown
configuration were chromatographically separated, and the
less polar isomer was converted into its corresponding (S)- and
(R)-Mosher ester derivatives by use of (S)- and (R)-(−)-α-
methoxy-α-(trifluoromethyl)phenylacetic acids, respec-
tively.16,17 It was determined via advanced Mosher analysis18
that the newly formed stereogenic center of the less polar
isomer possessed the (S) absolute configuration. With the
configurations of both isomeric alcohols established, each
isomer was then functionalized analogously. Due to the
similarities in chemical transformations, only the compounds
that arose through the (S)-series will be discussed. Treatment
of (S)-9 with methyl chloroformate in the presence of pyridine
and 4-dimethylaminopyridine (DMAP) afforded methyl
carbonate (S)-10a, which was followed by the removal of the
tert-butyldiphenylsilyl (TBDPS) group with a buffered solution
of tetrabutylammonium fluoride (TBAF). Dess−Martin period-
inane19 facilitated the oxidation of primary alcohol (S)-11a to
the corresponding aldehyde, which was directly transformed
into enone (S)-12a via Horner−Wadsworth−Emmons (HWE)
olefination with the conjugate base of diethyl (3-oxobutan-2-
yl)phosphonate.20 The Masamune modification21 of the HWE
reaction was used in an attempt to improve the yield of the
olefination step. However, the use of anhydrous lithium
chloride and diisopropylethylamine in acetonitrile only
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Scheme 4. Stereoconvergent IMDA Reaction of (S)- and (R)-13a
permitted isolation of (S)-12a in 46% yield. O-Acylation of the
potassium enolate of (S)-12a with allyl chloroformate in
dimethoxyethane (DME) completed the synthesis of bis-
carbonate (S)-13a in suitable yield.
subsequently oxidized to diastereomeric diones 16, epimeric at
the tertiary α-keto center C9. Gas chromatographic analysis of
16 derived from either 14 or 15 indicated the same 3:1
diastereomeric ratio. Therefore, with the combined chemical
and spectral data, the complete stereochemistry of decalins 14
and 15 was assigned with confidence.
With bis-carbonates (S)- and (R)-13a in hand, focus turned
toward the intramolecular Diels−Alder (IMDA) reactions of
each isomer. As mentioned above, an electron-withdrawing
carbonate was chosen to replace the ketone functionality on the
dienophile to facilitate the cycloaddition; however, elevated
temperatures were still required for annulation. In the event,
separate heating of each allylic carbonate epimer (S)- and (R)-
13a at 180 °C in 1,2-dichlorobenzene (DCB) in the presence
of butylated hydroxytoluene (BHT) generated 14 and 15,
respectively. Each cycloadduct apparently bore the same trans-
decalin stereochemistry and differed only in configuration at the
original epimeric C422 centers (Scheme 4). This result was in
favorable contrast to the original enone dienophile IMDA
reaction that had shown little endo versus exo selectivity. The
absolute configurations at C1 and C2 were known because the
synthesis of 14 and 15 began from L-(+)-tartaric acid and the
configurations at C4 were elucidated through advanced Mosher
analysis. Consequently, two-dimensional NMR experiments
(correlation and nuclear Overhauser effect spectroscopy, COSY
and NOESY; Scheme 4) in combination with proton splitting
and coupling constant data analyses indicated that the IMDA
reaction of (S)- and (R)-13a led to the assembly of trans-
decalin ring systems in both cases (14 and 15, respectively).
Nevertheless, to further confirm these results, each cycloadduct
was treated separately with lithium aluminum hydride to
convert the bis-carbonates into secondary alcohols, which were
This stereoconvergent result was serendipitous, particularly
in that the stereochemistry of the ring junction corresponded to
that of trans-fused NCDs and 2. To explain the stereospecificity
of each IMDA reaction, transition states were proposed and
examined for each transformation. Axial transition state C (ax-
TS-C) and equatorial transition state D (eq-TS-D)23 are most
closely related to exo-TS-B in that they have been predicted to
adopt chairlike conformations, versus boatlike conformations as
proposed for endo-TS-A. The C4 methyl carbonate undoubt-
edly played a pivotal role in forcing the isopropenyl methyl
group into a pseudoaxial position that ultimately led to the
assembly of trans-decalin 14. The fact that 14 is formed, instead
of a cis-decalin, also suggests that the 1,2-allylic strain between
the methyl carbonate and the isopropenyl methyl group would
be more sterically demanding than the pseudo-1,3-diaxial
interaction among the methyl groups of the [4 + 2] system.
Similarly, the cycloaddition reaction of (R)-13a was also
predicted to have occurred through a related transition state
(eq-TS-D); the only difference was the opposite configuration
at C4. As with ax-TS-C, the placement of the isopropenyl
methyl substituent in a pseudoaxial orientation would also
decrease the amount of 1,2-allylic strain in eq-TS-D, but in
addition, the configuration at C4 also allowed the substituents
among C1−C4 to possess a pseudoequatorial arrangement,
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a
Table 1. Stereoconvergent Intramolecular Diels−Alder Cycloadditions
a
Each substrate was prepared similarly from aldehyde 7. bAll reactions were conducted with 1,2-dichlorobenzene as the solvent and a
c
substoichiometric amount of BHT as a radical inhibitor. Reaction was performed in a sealed tube.
except the C5 methyl group. An increase in the reaction rate for
cycloaddition of (R)-13a over (S)-13a was also observed. This
is also likely due to the spatial arrangement of the C1−C4
substituents. Although both compounds produced trans-
decalins, the higher-energy transition state ax-TS-C would be
disfavored over eq-TS-D solely on the basis of the pseudoaxial
carbonate moiety.
To improve the rate of the cyclization, the next logical step
was to increase the electron-withdrawing power of the C4
substituent. Because the absolute configuration adjacent to the
dienophile did not appear to affect the stereochemical outcome
in the IMDA reaction, the kinetically favored (R)-series was
explored further. The effect of aryl esters in place of the methyl
carbonate substituents (Scheme 3 and Table 1, entries 3 and 4)
were next examined.
The rates of cycloaddition of benzoyl esters (R)-13b and
(R)-13c were similar to the previously observed cycloaddition
of (R)-13a. The use of 1,2-DCB at 180 °C was still beneficial
and the IMDA reactions of diastereomers (R)-13b and (R)-13c
formed only the trans-decalin framework, but in higher yields
than previously observed with (R)-13a. The p-nitrobenzoate of
(R)-13c did not appreciably increase the rate of cyclization
compared to (R)-13b. This observation suggests that the spatial
arrangement of the C4 substituent and the ability of the acyclic
Diels−Alder precursor to adopt the correct conformation had a
greater influence on the rate than the inherent electron-
withdrawing power of a given substituent. Each substituent at
C4 studied thus far is electron-withdrawing. Attention was
turned toward the epimeric mixture of silyl ethers 13d, which
allowed continued investigation of the effect of configuration at
C4 with less electron-withdrawing substituents. Because the
silyl ether was not able to lower the energy of the lowest
unoccupied molecular orbital (LUMO) of the dienophile as
effectively as a carbonate or ester, due to the diminution of
electron-withdrawing power, higher temperatures were used to
induce cyclization. The mixture of silyl ethers 13d was reacted
in a sealed tube at 225−250 °C for 72 h, which afforded trans-
decalins 19 and 20 in 63% overall yield (Table 1, entry 5). By
combining the results highlighted in Table 1, it was shown that
the configuration at C4 does not affect the stereochemical
outcome of decalin formation, but it does, along with the
electron-withdrawing ability of the C4 substituent, have an
effect on the reaction rate.
To more fully explore the reactivity of this IMDA reaction,
we chose to investigate the rotational degrees of freedom of the
Diels−Alder precursor. Each substrate to this point contained a
cyclic isopropylidene moiety that conformationally restricts
each molecule, whereas removal of the isopropylidene would
allow further conformational freedom, which could effictively
increase the reaction rate. It was desired to compare the
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Scheme 5. Synthesis of Diels−Alder Precursor 29
Scheme 6. trans-Decalin-Selective IMDA Cycloaddition
reactivity of an acyclic protected C1−C2 vicinal diol with silyl
ethers 13d, as they were the most unreactive (Table 1, entry 5),
and a large change in rate of cycloaddition of a different
compound would be more evident. For this the isopropylidine
moiety was replaced with two benzyl ethers while the tert-
butyldimethylsilyl (TBS) ether was retained. Dibenzyl ether 29
was also synthesized from a L-(+)-tartaric acid derivative24 in
like manner to the isopropylidene substrates (Scheme 5).
Alcohol 21 was transformed into a mixture of methyl enol
ethers 22 through a Swern oxidation/Wittig olefination
sequence followed by the conversion to aldehyde 23 using
mercuric acetate. The addition of isopropenylmagnesium
bromide afforded 24, at which point protecting group
manipulations gave rise to alcohols 26. The conversion of 26
to enone 27 revealed a complex mixture of diastereomers,
which was not seen before with the HWE olefinations that
yielded enones 12a−d. However, enone 28 could be isolated
from the mixture and was converted to 29 via O-acylation with
the use of potassium bis(trimethylsilyl)amide and allyl
chloroformate. At this point the configuration at C4 was
unknown, but the Diels−Alder cycloaddition of 29 allowed the
elucidation of the C4 stereocenter. When 29 was submitted to
the same reaction conditions as 13d, the cycloaddition was
complete in 20 h, an almost 4-fold increase in rate (Scheme 6).
However, this reaction was less efficient and stereoselective
than had been seen previously, but it did still show trans-decalin
selectivity. The cycloaddition of 29 gave a 40% yield of exo
cycloaddition product 30 and a 12% yield of endo product 31,
compared to 63% combined yield of exo products 19 and 20
from the acetonide precursor 13d (Table 1). This can be
attributed to the acyclic vicinal diol benzyl ether protection
array of 29 significantly lowering the energies, relative to those
of the cyclic acetonide 13d, of both endo and exo transition
states, leading to 30 and 31 via conformational relaxation. The
relative energetic difference between the endo and exo
transition states is greater for the conformationally more rigid
acetonide substrate 13d than it is for the conformationally
relaxed vicinal diol benzyl ether 29.
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Supplemental purification of the mixture via recrystallization from 95%
ethanol facilitated the removal of 4 from 5;
CONCLUSION
■
It has been demonstrated that the customization and tailoring
of organic substrates indeed still has an important role in
organic synthesis. It was determined here that either relative
configuration at C4 would direct the construction of the trans-
fused decalin motif, but it was advantageous to reduce the
conformational freedom of the substrate through the use of a
cyclic isopropylidene to observe complete trans-decalin
formation in the cycloaddition. It was also realized that C4
substituents that occupy a pseudoequatorial position during the
cycloaddition led to an increased rate of reaction. The increased
rate of cycloaddition was even more apparent due to the greater
electron-withdrawing power of the C4 substituent. In
conclusion, the relative configuration adjacent to the
dienophile, the conformational rigidity of the substrate, and
the electron-withdrawing ability of the C4 substituent each
played an integral part in the rate and stereoconvergence of the
IMDA cycloadditions leading to functionalized decalin cores,
which are prominent structural elements in a wide range of
natural and biologically active compounds. The continued
development of this chemistry will enable the synthesis of neo-
clerodane diterpenoids (1), such as salvinorin A (2).
Spectral Data for cis-Fused Decalin 4 (Endo Product). Rf 0.42 (4:1
hexanes/EtOAc, v/v); mp 95−98 °C; [α]2D3 +23.9 (c 1.00, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 5.96 (dddd, J = 16.8, 10.4, 5.6, 5.6 Hz,
1H), 5.42−5.35 (m, 1H), 5.32−5.28 (m, 1H), 4.66 (d, J = 5.6 Hz,
2H), 3.72 (dd, J = 10.4, 9.2 Hz, 1H), 3.60 (ddd, J = 13.6, 8.8, 4.4 Hz,
1H), 2.89 (dd, J = 14.4, 4.8 Hz, 1H), 2.72 (t, J = 14.4 Hz, 1H), 2.44−
2.31 (m, 1H), 2.20 (dd, J = 17.2, 6.4 Hz, 1H), 2.09 (d, J = 10.4 Hz,
1H), 2.00 (ddd, J = 12.4, 12.4, 6.8 Hz, 1H), 1.75 (s, 3H), 1.46 (s, 3H),
1.44 (s, 3H), 1.41−1.36 (m, 1H), 1.18 (s, 3H); 13C NMR (100 MHz,
C6D6) δ 209.1, 153.3, 142.4, 131.9, 121.8, 118.5, 111.0, 83.0, 77.0,
68.6, 47.9, 47.1, 42.8, 29.3, 27.3, 27.2, 23.3, 20.0, 16.2; IR (thin film)
2984, 2934, 1752, 1707, 1380, 1240 cm−1; HRMS (ESI) m/z for
C19H26NaO6 [M + Na]+ calcd 373.1622, obsd 373.1617.
Spectral Data for trans-Fused Decalin 5 (Exo Product). Rf 0.44
1
(4:1 hexanes/EtOAc, v/v); [α]2D3 +49.4 (c 1.00, CHCl3); H NMR
(400 MHz, CDCl3) δ 5.95 (dddd, J = 17.2, 10.4, 6.0, 6.0 Hz, 1H), 5.38
(dddd, J = 17.2, 1.6, 1.6, 1.6 Hz, 1H), 5.29 (dddd, J = 10.4, 0.8, 0.8, 0.8
Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.92 (dd, J = 11.2, 8.4 Hz, 1H), 3.50
(ddd, J = 13.4, 8.4, 5.2 Hz, 1H), 3.02 (t, J = 13.6 Hz, 1H), 2.81 (dd, J =
13.2, 4.8 Hz, 1H), 2.57−2.50 (m, 1H), 2.33−2.24 (m, 2H), 2.00 (ddd,
J = 14.0, 6.4, 2.8 Hz, 1H), 1.79−1.73 (m, 3H), 1.69−1.59 (m, 1H),
1.47 (s, 3H), 1.43 (s, 3H), 1.24 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 209.3, 153.2, 142.3, 131.5, 120.7, 119.2, 111.0, 79.1, 77.4, 68.9, 47.8,
44.3, 41.6, 29.6, 27.12, 27.1, 24.0, 17.7, 14.0; IR (neat) 2987, 2936,
1751, 1718, 1376, 1239 cm−1; HRMS (ESI) m/z for C19H26NaO6 [M
+ Na]+ calcd 373.1622, obsd 373.1627.
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise stated, all oxygen- and
moisture-sensitive reactions were performed under anhydrous
conditions (oven-dried glassware sealed under a dry argon
atmosphere). Solutions and solvents sensitive to moisture were
transferred via standard syringe and cannula techniques. All
commercial reagents were purchased as reagent grade and, unless
otherwise noted, were used without further purification. All organic
solvents were used dry: tetrahydrofuran (THF), diethyl ether (Et2O),
dichloromethane (CH2Cl2), and toluene were purified via a solvent
purification system; triethylamine (Et3N), diisopropylamine, and
diisopropylethylamine (DIPEA) were distilled from CaH2; dimethyl
sulfoxide (DMSO) was stored over freshly activated 4 Å molecular
sieves; and 1,2-dimethoxyethane (DME) was distilled from sodium
benzophenone ketyl. Thin-layer chromatography was performed on
glass-backed thin-layer chromatography (TLC) extra hard layer 60 Å,
250 μm, F-254 plates that were visualized via UV light (254 nm) or by
p-anisaldehyde (PAA), phosphomolybdic acid (PMA), or ceric
ammonium molybdate (CAM) stains and the column chromato-
graphic separations were performed by use of silica gel (40−63 μm).
Melting points were measured on a capillary melting point apparatus.
Optical rotations were measured by a polarimeter at 589 nm with a
sodium lamp and concentrations are reported in grams per 100 mL.
Nuclear magnetic resonance (NMR) spectra were obtained for proton
(1H) and carbon (13C) nuclei on 400 and 500 MHz spectrometers;
residual solvent peak signals for CDCl3 were set at 7.26 and 77.16 ppm
(3aS,5aR,9R,9aS,9bS)-9-Allyl-2,2,5a,9-tetramethylhexahydro-
naphtho[1,2-d][1,3]dioxole-5,8(5aH,9bH)-dione (6). Tris-
(dibenzylideneacetone)dipalladium (12.5 mg, 13.7 μmol) and
triphenylphosphine (35.9 mg, 0.137 mmol) were dissolved in toluene
(13.7 mL) under an argon atmosphere and stirred at room
temperature (rt) until the solution became yellow in color. Enol
carbonate 5 (96.3 mg, 0.275 mmol) in toluene (1.3 mL) was added to
the resultant solution via cannula, and the mixture was stirred for 1 h
at rt. The solvent was removed in vacuo and the crude material was
purified via flash chromatography on silica gel (6:1 hexanes/EtOAc, v/
v) to afford 6 (79.3 mg, 94%); Rf 0.33 (4:1 hexanes/EtOAc, v/v); mp
69−70 °C; [α]2D3 −25.6 (c 0.515, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.55 (dddd, J = 14.8, 9.6, 8.4, 6.4 Hz, 1H), 5.12−4.96 (m,
2H), 3.95 (dd, J = 11.6, 8.8 Hz, 1H), 3.60−3.50 (m, 1H), 2.92−2.82
(m, 2H), 2.54−2.40 (m, 4H), 2.28 (d, J = 11.6 Hz, 1H), 2.00−1.85
(m, 2H), 1.49 (s, 3H), 1.44 (s, 3H), 1.32 (s, 3H), 1.18 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 215.0, 209.1, 134.1, 119.6, 111.2, 77.8,
77.5, 50.3, 47.7, 45.9, 44.7, 42.5, 35.1, 30.6, 27.1, 27.0, 21.7, 19.7; IR
(thin film) 2985, 2935, 1708, 1702, 1382, 1234, 1114 cm−1; HRMS
(ESI) for C18H26NaO4 [M + Na]+ calcd 329.1723, obsd 329.1732.
(R)-1-[(4S,5S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2,2-dimeth-
yl-1,3-dioxolan-4-yl]-3-methylbut-3-en-2-ol [(R)-8] and (S)-1-
[(4S,5S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2,2-dimethyl-1,3-di-
oxolan-4-yl]-3-methylbut-3-en-2-ol [(S)-9]. Freshly prepared isopro-
penylmagnesium bromide (13.2 mL, 5.94 mmol, 0.45 M solution in
THF) was added dropwise to a −78 °C solution of aldehyde 7 (1.22 g,
2.96 mmol) in THF (2 mL) over 2 h. After complete addition, the
reaction mixture was warmed to rt and stirred an additional 1 h before
a saturated solution of NH4Cl (15 mL) was added. The mixture was
partitioned between water (15 mL) and EtOAc (10 mL), and the
layers were separated. The aqueous portion was extracted with EtOAc
(3 × 30 mL) and the organic extracts were combined, dried (MgSO4),
and concentrated. Purification via flash chromatography on silica gel
(9:1 to 7:1 hexanes/EtOAc, v/v) provided a diastereomeric mixture of
alcohols (R)-8 and (S)-9 (1.18 g, 87%) as a colorless oil. In order to
obtain spectral data for each isomer, an analytical sample was purified
(8:1 hexanes/EtOAc, v/v) and the following data were collected.
(Absolute configurations were determined via advanced Mosher ester
analysis.)
1
in the H and 13C spectra, respectively. A Fourier transform infrared
(FT-IR) spectrometer was used to record infrared spectra and
absorptions are reported in reciprocal centimeters. High-resolution
mass spectrometric data were obtained on a time-of-flight (TOF)
electrospray ionization (ESI) mass spectrometer.
Allyl {(3aS,5aS,9aR,9bS)-2,2,5a,9-Tetramethyl-5-oxo-
3a,4,5,5a,6,7,9a,9b-octahydronaphtho[1,2-d][1,3]dioxol-8-yl} Car-
bonate (4) and Allyl {(3aS,5aR,9aR,9bS)-2,2,5a,9-Tetramethyl-5-
oxo-3a,4,5,5a,6,7,9a,9b-octahydronaphtho[1,2-d][1,3]dioxol-8-yl}
Carbonate (5). Enol carbonate 3 (159.3 mg, 0.455 mmol) was
dissolved in toluene (45 mL), and butylated hydroxytoluene (9.9 mg,
0.045 mmol) was added. The reaction mixture was warmed at 110 °C
for 6 days before concentration under reduced pressure. The resulting
residue was purified via flash chromatography on silica gel (10:1
hexanes/EtOAc, v/v) to afford cis-fused isomer 4 (44.6 mg, 28%) as a
white solid and trans-fused isomer 5 (59.4 mg, 37%) as a colorless oil,
as well as a mixture of the two isomers (49.2 mg, 31%, 4:5 = 7.5:1).
Spectral Data for (R)-8. Rf 0.50 (7:1 hexanes/EtOAc, eluted three
1
times); [α]2D3 −2.2 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ
7.72−7.63 (m, 4H), 7.47−7.35 (m, 6H), 5.06−5.02 (m, 1H), 4.88−
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The Journal of Organic Chemistry
Article
4.84 (m, 1H), 4.28 (dd, J = 9.6, 3.2 Hz, 1H), 4.12 (ddd, J = 9.6, 7.2, 2.4
Hz, 1H), 3.87−3.71 (m, 4H), 3.15 (br s, 1H), 1.93 (dt, J = 14.4, 3.2
Hz, 1H), 1.74 (s, 3H), 1.43 (s, 3H), 1.39 (s, 3H), 1.07 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 146.7, 135.74 (2C), 135.73 (2C), 133.20,
133.15, 130.00, 129.97, 127.9 (4C), 111.1, 109.5, 81.4, 79.0, 75.1, 64.1,
39.3, 27.4, 27.1, 27.0 (3C), 19.4, 18.1; IR (neat) 3485, 2930, 2857,
1428, 1379, 1246, 1216, 1112 cm−1; HRMS (ESI) m/z for
C27H38NaO4Si [M + Na]+ calcd 477.2432, obsd 477.2434.
3H), 1.39 (s, 3H), 1.90 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.3, 143.4, 135.8 (2C), 135.75 (2C), 133.2, 133.1, 129.9, 129.8,
127.9 (2C), 127.8 (2C), 113.1, 109.0, 81.0, 78.5, 75.1, 64.1, 54.7, 37.7,
27.5, 27.0, 26.9 (3C), 19.3, 18.1; IR (neat) 3051, 2933, 2860, 1965,
1900, 1755, 1442, 1380, 1266, 1113, 1085 cm−1; HRMS (ESI) m/z for
C29H40NaO6Si [M + Na]+ calcd 535.2486, obsd 535.2497.
(S)-1-[(4S,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-
3-methylbut-3-en-2-yl Methyl Carbonate [(S)-11a]. Silyl ether (S)-
10a (138.5 mg, 0.270 mmol) was taken up in THF (2.7 mL), and a 1:1
equimolar mixture of TBAF/AcOH (0.85 mL, 0.810 mmol, 0.95 M
solution in THF) was added. The reaction mixture was stirred at rt for
2 h before immediate concentration in vacuo. The resulting material
was purified via flash chromatography on silica gel (4:1 to 1:1 hexanes/
EtOAc, v/v) to give alcohol (S)-11a (69.8 mg, 94%) as a slightly
opaque oil; Rf 0.10 (4:1 hexanes/EtOAc, v/v); [α]2D3 −42.5 (c 1.01,
Spectral Data for (S)-9. Rf 0.59 (7:1 hexanes/EtOAc, eluted three
times); [α]2D3 −14.6 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ
1
7.71−7.65 (m, 4H), 7.46−7.36 (m, 6H), 5.07−5.03 (m, 1H), 4.89 (s,
1H), 4.35−4.28 (br m, 1H), 4.23 (ddd, J = 8.4, 8.4, 3.2 Hz, 1H), 3.86−
3.78 (m, 2H), 3.77−3.70 (m, 1H), 2.65 (d, J = 5.2 Hz, 1H), 1.98−1.90
(m, 1H), 1.85−1.77 (m, 1H), 1.73 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H),
1.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 147.2, 135.79 (2C),
135.77 (2C), 133.3, 133.2, 130.0, 129.9, 127.89 (2C), 127.87 (2C),
110.7, 109.0, 80.8, 76.3, 72.8, 64.3, 37.8, 27.5, 27.1, 27.0 (3C), 19.4,
18.7; IR (neat) 3484, 2931, 2858, 1960, 1896, 1845, 1473, 1428, 1379,
1247, 1218, 1113 cm−1; HRMS (ESI) m/z for C27H38NaO4Si [M +
Na]+ calcd 477.2432, obsd 477.2419.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 5.18 (dd, J = 10.0, 3.2 Hz,
1H), 5.04 (m, 1H), 4.94−4.91 (m, 1H), 4.00−3.94 (m, 1H), 3.79−
3.73 (m, 5H), 3.65−3.58 (m, 1H), 2.00 (br s, 1H), 1.95 (ddd, J = 14.4,
10.0, 3.2 Hz, 1H), 1.82 (ddd, J = 14.4, 8.8, 3.2 Hz, 1H), 1.75 (s, 3H),
1.40 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.1,
143.1, 113.3, 109.3, 81.6, 78.5, 73.7, 62.0, 54.8, 37.5, 27.5, 27.2, 18.1;
IR (neat) 3489, 2988, 1752, 1444, 1380, 1270 cm−1; HRMS (ESI) m/z
for C13H22NaO6 [M + Na]+ calcd 297.1309, obsd 297.1298.
(R)-(S)-1-[(4S,5S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2,2-di-
methyl-1,3-dioxolan-4-yl]-3-methylbut-3-en-2-yl-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate [(R)-Mosher Ester of (S)-9] and (S)-
(S)-1-[(4S,5S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2,2-dimethyl-
1,3-dioxolan-4-yl]-3-methylbut-3-en-2-yl-3,3,3-trifluoro-2-methoxy-
2-phenylpropanoate [(S)-Mosher Ester of (S)-9]. Dicyclohexylcarbo-
diimide (28.1 mg, 0.136 mmol) and DMAP (16.6 mg, 0.136 mmol)
were added to a solution of (S)-9 (20.0 mg, 0.044 mmol) and (R)-α-
methoxy-α-trifluoromethylphenylacetic acid [(R)-MTPA-OH] (31.8
mg, 0.136 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred
at rt for 4 days before it was filtered through a cotton plug to remove
the solid byproducts, and the solvent was removed under reduced
pressure. The residue was purified via flash chromatography on silica
gel (20:1 hexanes/EtOAc, v/v) to yield the (R)-Mosher ester of (S)-9
as a colorless oil (27.6 mg, 94%); Rf 0.23 (20:1 hexanes/EtOAc, v/v);
1H NMR (400 MHz, CDCl3) δ 7.67−7.61 (m, 4H), 7.55−7.51 (m,
2H), 7.45−7.39 (m, 3H), 7.38−7.33 (m, 6H), 5.57 (dd, J = 10.8, 2.8
Hz, 1H), 5.04 (s, 1H), 4.95 (t, J = 1.6 Hz, 1H), 4.02 (ddd, J = 10.0,
7.6, 2.4 Hz, 1H), 3.78 (dd, J = 10.0, 4.0 Hz, 1H), 3.74−3.68 (m, 1H),
3.63 (dd, J = 10.0, 6.0 Hz, 1H), 3.54 (d, J = 1.2 Hz, 3H), 2.19 (ddd, J =
14.4, 11.2, 2.4 Hz, 1H), 1.75 (ddd, J = 14.4, 10.4, 3.2 Hz, 1H), 1.66 (s,
3H), 1.41 (s, 3H), 1.34 (s, 3H), 1.02 (s, 9H); HRMS (ESI) m/z for
C37H45F3NaO6Si [M + Na]+ calcd 693.2830, obsd 693.2844.
(S)-1-{(4S,5S)-2,2-Dimethyl-5-[(E)-2-methyl-3-oxobut-1-en-1-yl]-
1,3-dioxolan-4-yl}-3-methylbut-3-en-2-yl Methyl Carbonate [(S)-
12a]. Alcohol (S)-11a (96.4 mg, 0.351 mmol) was dissolved in
CH2Cl2 (3.5 mL) and cooled to 0 °C. Sodium bicarbonate (442.7 mg,
5.27 mmol) was added, followed by Dess−Martin periodinane (223.5
mg, 0.527 mmol) and the reaction mixture was warmed to rt and
stirred for 2.5 h. The reaction was quenched by the addition of
saturated aqueous solutions of NaHCO3 and Na2S2O3. The mixture
was stirred vigorously for 20 min and the layers were separated. The
aqueous layer was extracted with EtOAc (3 × 15 mL), and the
combined extracts were dried over MgSO4 and concentrated. The
residue was used in the next step with no further purification. A
solution of 3-oxobutan-2-ylphosphonate (153.4 mg, 0.737 mmol) in
THF (1.1 mL) was added to a slurry of NaH (28.1 mg, 0.702 mmol,
60% in oil) in THF (1.4 mL) at 0 °C, and the mixture was stirred for 1
h. Freshly prepared aldehyde in THF (1.1 mL) was introduced via
cannula and the reaction mixture was warmed to rt and stirred for 14 h
before being quenching with saturated aqueous NH4Cl (10 mL). The
aqueous layer was extracted with EtOAc (3 × 10 mL), and the
combined extracts were dried and concentrated in vacuo. Purification
via flash chromatography on silica gel (6:1 hexanes/EtOAc, v/v)
furnished enone (S)-12a (58.6 mg, 51% over two steps) as a colorless
In a similar fashion, the (S)-MTPA ester of (S)-9 was prepared with
1
(S)-MPTA-OH; Rf 0.16 (20:1 hexanes/EtOAc, v/v); H NMR (400
1
oil; [α]2D3 −11.6 (c 1.14, CHCl3); H NMR (400 MHz, CDCl3) δ
MHz, CDCl3) δ 7.66−7.61 (m, 4H), 7.55−7.50 (m, 2H), 7.45−7.32
(m, 9H), 5.64 (dd, J = 10.8, 2.8 Hz, 1H), 5.14 (s, 1H), 5.00 (t, J = 1.6
Hz, 1H), 3.75−3.70 (m, 1H), 3.69−3.62 (m, 2H), 3.53 (d, J = 1.2 Hz,
3H), 3.50 (dd, J = 10.4, 6.4 Hz, 1H), 2.18 (ddd, J = 13.2, 10.8, 2.0 Hz,
1H), 1.76−1.71 (m, 4H), 1.38 (s, 3H), 1.29 (s, 3H), 1.03 (s, 9H);
HRMS (ESI) m/z for C37H45F3NaO6Si [M + Na]+ calcd 693.2830,
obsd 693.2828.
6.45−6.40 (m, 1H), 5.17 (dd, J = 9.2, 4.0 Hz, 1H), 5.03 (s, 1H), 4.96−
4.93 (m, 1H), 4.48 (dd, J = 8.0, 8.0 Hz, 1H), 3.89 (ddd, J = 8.4, 8.4, 4.4
Hz, 1H), 3.76 (s, 3H), 2.35 (s, 3H), 1.91−1.86 (m, 2H), 1.85 (d, J =
1.2 Hz, 3H), 1.75 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 199.5, 155.1, 143.0, 141.4, 137.2, 113.5, 109.9, 78.3,
77.9, 77.3, 54.9, 36.2, 27.4, 27.2, 25.8, 18.1, 12.2; IR (neat) 2992, 2928,
1753, 1678, 1443, 1372, 1269, 1049 cm−1; HRMS (ESI) m/z for
C17H26NaO6 [M + Na]+ calcd 349.1622, obsd 349.1631.
(S)-1-[(4S,5S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2,2-dimeth-
yl-1,3-dioxolan-4-yl]-3-methylbut-3-en-2-yl Methyl Carbonate [(S)-
10a]. Methyl chloroformate (1.36 mL, 17.6 mmol) was added
dropwise over 2 h to a 0 °C solution of alcohol (S)-9 (400 mg, 0.880
mmol), pyridine (2.14 mL, 26.4 mmol), and a catalytic amount of
DMAP in CH2Cl2 (8.8 mL), and the mixture was stirred at rt for 18 h.
The reaction mixture was cooled to 0 °C, additional methyl
chloroformate (1.0 mL, 13.2 mmol) was added, and the mixture was
stirred for 2 h. The reaction was quenched by the addition of saturated
aqueous NH4Cl and the mixture was extracted with EtOAc (3 × 15
mL). The combined extracts were dried over MgSO4 and concentrated
under reduced pressure. Purification via flash chromatography on silica
gel (20:1 hexanes/EtOAc, v/v) gave (S)-10a as a colorless oil (383.1
mg, 85%); Rf 0.19 (15:1 hexanes/EtOAc, v/v); [α]2D3 −18.8 (c 1.01,
Dicarbonate (S)-13a. Enone (S)-12a (58.6 mg, 0.180 mmol) in
DME (0.6 mL) was added slowly to a −78 °C solution of potassium
bis(trimethylsilyl)amide (KHMDS; 43.1 mg, 0.216 mmol) in DME
(1.8 mL), and the mixture was stirred for 5 min prior to the
introduction of neat allyl chloroformate (76.5 μL, 0.720 mmol). The
reaction mixture was then warmed to 0 °C and stirred for 1 h before
the addition of saturated aqueous NH4Cl (3 mL). The mixture was
extracted with EtOAc (3 × 5 mL), the combined organic extracts were
dried over MgSO4, and the volatiles were removed under reduced
pressure. Purification via flash chromatography on silica gel (9:1
hexanes/EtOAc, v/v) yielded dicarbonate (S)-13a (56.6 mg, 77%) as a
colorless oil; Rf 0.35 (4:1 hexanes/EtOAc, v/v); [α]2D3 −16.6 (c 1.18,
1
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.75−7.69 (m, 4H), 7.47−
CHCl3); H NMR (400 MHz, CDCl3) δ 5.97 (dddd, J = 17.2, 10.4,
7.38 (m, 6H), 5.27 (dd, J = 10.4, 2.4 Hz, 1H), 5.09 (s, 1H), 4.95 (t, J =
1.6 Hz, 1H), 4.14 (ddd, J = 9.6, 7.2, 2.0 Hz, 1H), 3.83−3.72 (m, 6H),
2.10 (ddd, J = 14.4, 10.4, 2.4 Hz, 1H), 1.83−1.75 (m, 4H), 1.40 (s,
6.0, 6.0 Hz, 1H), 5.73 (d, J = 8.8 Hz, 1H), 5.40 (dd, J = 17.2, 1.2 Hz,
1H), 5.30 (dd, J = 10.4, 0.8 Hz, 1H), 5.20−5.12 (m, 2H), 5.05 (d, J =
2.0 Hz, 1H), 5.02 (s, 1H), 4.92 (m, 1H), 4.69 (m, 2H), 4.41 (dd, J =
3901
dx.doi.org/10.1021/jo400029u | J. Org. Chem. 2013, 78, 3895−3907

The Journal of Organic Chemistry
Article
1
8.4, 8.4 Hz, 1H), 3.82−3.77 (m, 1H), 3.76 (s, 3H), 1.92 (d, J = 0.8 Hz,
3H), 1.89−1.79 (m, 2H), 1.74 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 155.1, 153.9, 153.0, 143.0, 133.7, 131.4,
124.5, 119.4, 113.5, 109.2, 103.7, 78.3, 77.7, 77.3, 69.1, 54.8, 36.0, 27.4,
27.2, 18.1, 14.1; IR (neat) 1754, 1444, 1269, 1223 cm−1; HRMS (ESI)
m/z for C21H30NaO8 [M + Na]+ calcd 433.1833, obsd 433.1820.
(R)-1-[(4S,5S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2,2-dimeth-
yl-1,3-dioxolan-4-yl]-3-methylbut-3-en-2-yl Methyl Carbonate [(R)-
10a]. Methyl chloroformate (1.3 mL, 17.1 mmol) was added dropwise
over 2 h to a 0 °C solution of alcohol (R)-8 (388.9 mg, 0.855 mmol),
pyridine (2.1 mL, 25.7 mmol), and a catalytic amount of DMAP in
CH2Cl2 (8.5 mL). The reaction mixture was stirred for 2 h at 0 °C, the
reaction was quenched by addition of saturated aqueous NH4Cl (5
mL), and the mixture was extracted with CH2Cl2 (3 × 15 mL). The
combined extracts were dried over MgSO4 and the volatiles were
removed in vacuo. The material was purified via flash chromatography
(20:1 to 10:1 hexanes/EtOAc, v/v) to afford methyl carbonate (R)-
10a (369.1 mg, 84%) as a colorless oil; Rf 0.17 (15:1 hexanes/EtOAc,
hexanes/EtOAc, v/v); [α]2D3 −10.4 (c 1.01, CHCl3); H NMR (400
MHz, CDCl3) δ 6.42−6.37 (m, 1H), 5.19 (app t, J = 7.2 Hz, 1H),
5.07−5.04 (m, 1H), 4.99−4.97 (m, 1H), 4.51 (app t, J = 8.4 Hz, 1H),
3.79−3.74 (m, 4H), 2.34 (s, 3H), 2.10−2.02 (m, 1H), 1.87 (d, J = 1.2
Hz, 3H), 1.82 (ddd, J = 11.2, 6.8, 4.0 Hz, 1H), 1.71 (s, 3H), 1.44 (s,
3H), 1.41 (s, 3H); 13C NMR (100 MHz, C6D6) δ 197.8, 155.4, 142.5,
141.1, 137.0, 114.6, 109.7, 78.6, 78.0, 77.8, 54.3, 35.1, 27.4, 27.1, 25.2,
17.7, 12.3; IR (neat) 2982, 2928, 1752, 1678, 1444, 1372, 1269, 1059
cm−1; HRMS (ESI) m/z for C17H26NaO6 [M + Na]+ calcd 349.1622,
obsd 349.1625.
Dicarbonate (R)-13a. Enone (R)-12a (50.0 mg, 0.153 mmol) in
DME (1.5 mL) was added slowly to a −78 °C solution of KHMDS
(36.7 mg, 0.184 mmol) in DME (0.5 mL) and stirred for 5 min prior
to the introduction of neat allyl chloroformate (65.0 μL, 0.612 mmol).
The reaction mixture was then warmed to 0 °C and stirred for 1 h
before the addition of saturated aqueous NH4Cl (5 mL). The mixture
was extracted with EtOAc (3 × 10 mL), and the combined organic
extracts were dried over MgSO4 and the volatiles were removed under
reduced pressure. Purification via flash chromatography on silica gel
(9:1 hexanes/EtOAc, v/v) yielded dicarbonate (R)-13a (43.2 mg,
69%) in the form of a colorless oil; Rf 0.16 (9:1 hexanes/EtOAc, v/v);
1
v/v); [α]2D3 −7.2 (c 1.03, CHCl3); H NMR (400 MHz, CDCl3) δ
7.71−7.65 (m, 4H), 7.47−7.36 (m, 6H), 5.31 (dd, J = 7.2, 7.2 Hz,
1H), 5.13−5.11 (m, 1H), 5.04−5.01 (m, 1H), 4.02 (ddd, J = 7.2, 7.2,
4.4 Hz, 1H), 3.81−3.70 (m, 6H), 2.06−1.99 (m, 2H), 1.76 (s, 3H),
1.42 (s, 3H), 1.35 (s, 3H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 155.1, 142.0, 135.7 (4C), 133.23, 133.2, 129.93, 129.9, 127.9 (2C),
127.8 (2C), 114.9, 109.0, 81.9, 79.5, 75.5, 64.1, 54.7, 36.3, 27.5, 27.0,
26.9 (3C), 19.3, 17.7; IR (neat) 3074, 2933, 2860, 1752, 1442, 1269,
1113, 1080 cm−1; HRMS (ESI) m/z for C29H40NaO6Si [M + Na]+
calcd 535.2486, obsd 535.2490.
(R)-1-[(4S,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]-3-methylbut-3-en-2-yl Methyl Carbonate [(R)-11a]. An equimo-
lar (1:1) mixture of TBAF/AcOH in THF (0.38 mL, 0.360 mmol, 0.95
M solution in THF) was added to a rt solution of silyl ether (R)-10a
(61.4 mg, 0.120 mmol) in THF (1.2 mL), and the mixture was stirred
for 1.5 h. The mixture was concentrated under reduced pressure and
the oil was purified via flash chromatography on silica gel (2:1 to 1:1
hexanes/EtOAc, v/v) to furnish alcohol (R)-11a (31.2 mg, 95%) as a
slightly opaque oil; Rf 0.11 (4:1 hexanes/EtOAc, v/v); [α]2D3 −13.2 (c
1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.24 (t, J = 6.8 Hz, 1H),
5.08 (m, 1H), 5.00−4.97 (m, 1H), 3.89 (ddd, J = 8.0, 8.0, 4.0 Hz, 1H),
3.82−3.74 (m, 5H), 3.65−3.58 (m, 1H), 2.04 (ddd, J = 14.0, 8.0, 6.8
Hz, 1H), 1.97 (br s, 1H), 1.89 (ddd, J = 14.4, 7.6, 4.0 Hz, 1H), 1.74 (s,
3H), 1.41 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
155.0, 141.6, 114.8, 108.9, 81.2, 78.9, 73.7, 61.7, 54.7, 35.8, 27.3, 26.9,
17.6; IR (neat) 3512, 2988, 1752, 1444, 1381, 1271, 1069 cm−1;
HRMS (ESI) m/z for C13H22NaO6 [M + Na]+ calcd 297.1309, obsd
297.1310.
(R)-1-{(4S,5S)-2,2-Dimethyl-5-[(E)-2-methyl-3-oxobut-1-en-1-yl]-
1,3-dioxolan-4-yl}-3-methylbut-3-en-2-yl Methyl Carbonate [(R)-
12a]. A solution of alcohol (R)-11a (182.5 mg, 0.665 mmol) in
CH2Cl2 (6.6 mL) was cooled to 0 °C before addition of NaHCO3
(838.4 mg, 9.98 mmol) and Dess−Martin periodinane (423.3 mg,
0.998 mmol). The cold bath was removed and the reaction mixture
was stirred at rt for 3 h, after which saturated aqueous solutions of
NaHCO3 and Na2S2O3 were added and the mixture was stirred
vigorously for 30 min. The layers were separated, the aqueous layer
was extracted with CH2Cl2 (3 × 20 mL), and the organic extracts were
combined, dried over MgSO4, and concentrated under reduced
pressure. The crude aldehyde was taken to the next step with no
further purification. A solution of 3-oxobutan-2-ylphosphonate (291.5
mg, 1.40 mmol) in THF (2.0 mL) was added dropwise to a 0 °C slurry
of sodium hydride (53.2 mg, 1.33 mmol, 60% in oil) in THF (2.7 mL).
The reaction mixture stirred for 1 h at 0 °C and became transparent as
all the NaH was consumed. A solution of freshly prepared aldehyde in
THF (2.0 mL) was added via cannula and the cold bath was removed.
The reaction mixture was stirred at rt for 14 h and then saturated
aqueous NH4Cl (10 mL) was added, followed by extraction with
EtOAc (3 × 15 mL). The combined organic extracts were dried
(MgSO4) and the solvent was removed in vacuo. Purification via flash
chromatography (6:1 hexanes/EtOAc, v/v) afforded enone (R)-12a
(109.7 mg, 51% over two steps) as a colorless oil; Rf 0.29 (4:1
[α]2D3 −18.5 (c 1.08, CHCl3); H NMR (400 MHz, CDCl3) δ 5.95
1
(dddd, J = 16.4, 10.4, 6.0, 6.0 Hz, 1H), 5.68 (d, J = 8.8 Hz, 1H), 5.39
(dd, J = 17.2, 1.6 Hz, 1H), 5.29 (dd, J = 10.4, 1.2 Hz, 1H), 5.20 (app t,
J = 7.2 Hz, 1H), 5.14 (d, J = 2.4 Hz, 1H), 5.06 (s, 1H), 5.03 (d, J = 2.4
Hz, 1H), 4.99−4.95 (m, 1H), 4.67 (d, J = 6.0 Hz, 2H), 4.44 (dd, J =
8.8, 8.8 Hz, 1H), 3.75 (s, 3H), 3.63 (ddd, J = 8.4, 8.4, 3.6 Hz, 1H),
2.10−1.93 (m, 1H), 1.91 (d, J = 0.8 Hz, 3H), 1.80 (ddd, J = 14.0, 7.6,
3.6 Hz, 1H), 1.70 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 155.0, 153.9, 153.0, 141.8, 133.5, 131.4, 124.4, 119.4,
115.1, 109.3, 103.7, 79.1, 77.6, 77.4, 69.1, 54.8, 34.4, 27.4, 27.1, 17.5,
14.1; IR (neat) 2986, 2928, 1762, 1752, 1270, 1224 cm−1; HRMS
(ESI) m/z for C21H30NaO8 [M + Na]+ calcd 433.1833, obsd 433.1827.
(R)-1-[(4S,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]-3-methylbut-3-en-2-yl Benzoate [(R)-11b]. A solution of alcohol
(R)-8 (389.1 mg, 0.856 mmol) in CH2Cl2 (8.5 mL) was cooled to 0
°C before the addition of benzoic anhydride (386.8 mg, 1.71 mmol),
triethylamine (0.36 mL, 2.57 mmol), and a catalytic amount of DMAP.
The reaction mixture was stirred for 24 h after warming to rt, and an
additional portion of DMAP was added. The mixture was stirred an
additional 2 days before a saturated solution of NaHCO3 (15 mL) was
added, followed by extraction with EtOAc (3 × 15 mL). The
combined organic extracts were dried (MgSO4) and concentrated. The
resulting residue was taken up in THF (8.5 mL), and an equimolar
(1:1) solution of TBAF/AcOH (2.7 mL, 2.57 mmol, 0.95 M) was
added. The reaction mixture was stirred for 3 h at rt before being
concentrated in vacuo. The resulting oil was purified via flash
chromatography on silica gel (4:1 hexanes/EtOAc, v/v) to afford
alcohol (R)-11b (222.4 mg, 81% over two steps) as a colorless oil; Rf
0.27 (2:1 hexanes/EtOAc, v/v); [α]2D3 −24.8 (c 1.01, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 8.06−8.02 (m, 2H), 7.57−7.52 (m, 1H),
7.46−7.40 (m, 2H), 5.63 (dd, J = 6.8, 6.8 Hz, 1H), 5.12 (br s, 1H),
5.00−4.97 (m, 1H), 3.96 (ddd, J = 8.0, 8.0, 4.0 Hz, 1H), 3.83−3.76
(m, 2H), 3.67−3.62 (m, 1H), 2.28−2.24 (br s, 1H), 2.20−2.12 (m,
1H), 2.00 (ddd, J = 14.0, 6.8, 4.4 Hz, 1H), 1.81 (s, 3H), 1.39 (s, 3H),
1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 142.4, 133.0,
130.5, 129.7 (2C), 128.5 (2C), 114.2, 109.0, 81.5, 75.5, 74.2, 62.0,
36.3, 27.4, 27.0, 18.1; IR (neat) 3441, 2986, 2934, 1720, 1602, 1452,
1379, 1314, 1272, 1097 cm−1; HRMS (ESI) m/z for C18H24NaO5 [M
+ Na]+ calcd 343.1516, obsd 343.1514.
(R)-1-{(4S,5S)-2,2-Dimethyl-5-[(E)-2-methyl-3-oxobut-1-en-1-yl]-
1,3-dioxolan-4-yl}-3-methylbut-3-en-2-yl Benzoate [(R)-12b]. A
solution of alcohol (R)-11b (432.8 mg, 1.35 mmol) in CH2Cl2
(13.5 mL) was cooled to 0 °C before addition of NaHCO3 (1.71 g,
20.3 mmol) and Dess−Martin periodinane (861.0 mg, 2.03 mmol).
The cold bath was removed and the reaction mixture was stirred at rt
for 3 h, after which saturated aqueous solutions of NaHCO3 and
Na2S2O3 were added and the mixture was stirred vigorously for 30
min. The layers were separated, the aqueous layer was extracted with
CH2Cl2 (3 × 15 mL), and the organic extracts were combined, dried
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over MgSO4, and concentrated under reduced pressure. The crude
aldehyde was taken to the next step with no further purification. A
solution of 3-oxobutan-2-ylphosphonate (618.3 mg, 1.35 mmol) in
THF (4.2 mL) was added dropwise to a 0 °C slurry of sodium hydride
(64.8 mg, 2.7 mmol, 60% in oil) in THF (5.4 mL). The reaction
mixture stirred for 1 h at 0 °C before a solution of freshly prepared
aldehyde in THF (4.2 mL) was added via cannula and the cold bath
was removed. The reaction mixture was stirred at rt for 14 h and then
saturated aqueous NH4Cl (10 mL) was added, followed by extraction
with EtOAc (3 × 20 mL). The combined organic extracts were dried
(MgSO4) and the solvent was removed in vacuo. Purification via flash
chromatography (4:1 hexanes/EtOAc, v/v) afforded enone (R)-12b
(163.6 mg, 33% over two steps) as a pale yellow oil; Rf 0.56 (4:1
MHz, CDCl3) δ 163.9, 150.6, 141.8, 136.1, 130.8 (2C), 123.6 (2C),
114.8, 109.1, 81.4, 76.9, 74.2, 61.8, 36.3, 27.4, 26.9, 18.0; IR (neat)
2985, 2935, 1716, 1527, 1274 cm−1; HRMS (ESI) m/z for
C18H23NaNO7 [M + Na]+ calcd 388.1367, obsd 388.1363.
(R)-1-{(4S,5S)-2,2-Dimethyl-5-[(E)-2-methyl-3-oxobut-1-en-1-yl]-
1,3-dioxolan-4-yl}-3-methylbut-3-en-2-yl 4-Nitrobenzoate [(R)-12c].
A solution of alcohol (R)-11c (387.6 mg, 1.06 mmol) in CH2Cl2 (10.5
mL) was cooled to 0 °C before addition of NaHCO3 (1.34 g, 15.9
mmol) and Dess−Martin periodinane (674.4 mg, 1.59 mmol). The
cold bath was removed and the reaction mixture was stirred at rt for 3
h, after which saturated aqueous solutions of NaHCO3 and Na2S2O3
were added and the mixture was stirred vigorously for 30 min. The
layers were separated, the aqueous layer was extracted with CH2Cl2,
and the organic extracts were combined, dried over MgSO4, and
concentrated under reduced pressure. The crude aldehyde was taken
to the next step with no further purification. A solution of 3-oxobutan-
2-ylphosphonate (485.5 mg, 2.33 mmol) in THF (3.3 mL) was added
dropwise to a 0 °C slurry of sodium hydride (84.8 mg, 2.12 mmol,
60% in oil) in THF (4.2 mL). The reaction mixture was stirred for 1 h
at 0 °C before a solution of freshly prepared aldehyde in THF (3.3
mL) was added via cannula and the cold bath was removed. The
reaction mixture was stirred at 14 h at rt before a solution of saturated
aqueous NH4Cl (10 mL) was added, followed by extraction with
EtOAc (3 × 20 mL). The combined organic extracts were dried
(MgSO4) and the solvent was removed in vacuo. Purification via flash
chromatography (4:1 hexanes/EtOAc, v/v) afforded enone (R)-12c
(168.5 mg, 38% over two steps) as a pale yellow oil; Rf 0.48 (4:1
hexanes/EtOAc, v/v); [α]2D3 −25.6 (c 1.02, CHCl3); H NMR (400
1
MHz, CDCl3) δ 8.15−8.00 (m, 2H), 7.58−7.52 (m, 1H), 7.46−7.40
(m, 2H), 6.41−6.36 (m, 1H), 5.56 (dd, J = 7.2, 7.2 Hz, 1H), 5.10 (s,
1H), 5.00−4.96 (m, 1H), 4.52 (dd, J = 8.4, 8.4 Hz, 1H), 3.84 (ddd, J =
8.0, 8.0, 4.0 Hz, 1H), 2.29 (s, 3H), 2.20 (ddd, J = 14.0, 8.0, 8.0 Hz,
1H), 1.92 (ddd, J = 14.0, 6.8, 4.4 Hz, 1H), 1.87 (d, J = 1.2 Hz, 3H),
1.78 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 199.5, 165.6, 142.3, 141.3, 137.2, 133.1, 130.5, 129.7 (2C), 128.5
(2C), 114.3, 109.8, 77.6 (2C), 75.3, 35.1, 27.3, 26.9, 25.7, 18.0, 12.3;
IR (neat) 2985, 2934, 1719, 1676, 1271, 1113 cm−1; HRMS (ESI) m/z
for C22H28NaO5 [M + Na]+ calcd 395.1829, obsd 395.1833.
(R)-1-{(4S,5S)-5-[(E)-3-{[(Allyloxy)carbonyl]oxy}-2-methylbuta-
1,3-dien-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}-3-methylbut-3-en-2-
yl Benzoate [(R)-13b]. Enone (R)-12b (163.0 mg, 0.438 mmol) in
DME (2.0 mL) was added dropwise to a −78 °C solution of KHMDS
(104.8 mg, 0.526 mmol) in DME (5.5 mL), and the mixture was
stirred for 15 min prior to the introduction of neat allyl chloroformate
(0.23 mL, 2.19 mmol). The reaction mixture was then warmed to −50
°C and stirred for 1 h before the addition of saturated aqueous NH4Cl
(5 mL). The mixture was extracted with EtOAc (3 × 10 mL), and the
combined organic extracts were dried over MgSO4 and concentrated
under reduced pressure. Purification via flash chromatography on silica
gel (8:1 hexanes/EtOAc, v/v) yielded enol carbonate (R)-13b (141.2
mg, 71%) as a colorless oil; Rf 0.45 (4:1 hexanes/EtOAc, v/v); [α]D23
−37.5 (c 1.01, CDCl3); 1H NMR (400 MHz, CDCl3) δ 8.06−8.00 (m,
2H), 7.58−7.51 (m, 1H), 7.46−7.39 (m, 2H), 5.95 (dddd, J = 16.0,
10.4, 5.6, 5.6 Hz, 1H), 5.72 (d, J = 8.8 Hz, 1H), 5.61 (dd, J = 7.2, 7.2
Hz, 1H), 5.43−5.35 (m, 1H), 5.33−5.27 (m, 1H), 5.14 (d, J = 2.4 Hz,
1H), 5.12 (s, 1H), 5.04 (d, J = 2.4 Hz, 1H), 5.00−4.97 (m, 1H), 4.69−
4.64 (m, 2H), 4.44 (dd, J = 8.4, 8.4 Hz, 1H), 3.72 (ddd, J = 8.4, 8.4, 3.2
Hz, 1H), 2.08 (ddd, J = 13.6, 8.4, 6.8 Hz, 1H), 1.95−1.92 (m, 1H),
1.91 (d, J = 0.8 Hz, 3H), 1.78 (s, 3H), 1.39 (s, 3H), 1.34 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 165.7, 153.9, 153.0, 142.3, 133.7, 133.0,
131.4, 130.7, 129.7 (2C), 128.4 (2C), 124.4, 119.4, 114.5, 109.2, 103.7,
77.9, 77.5, 75.7, 69.1, 34.7, 27.4, 27.0, 17.9, 14.1; IR (neat) 2986, 2933,
1763, 1719, 1450, 1379, 1369, 1273, 1224, 1112, cm−1; HRMS (ESI)
m/z for C26H32NaO7 [M + Na]+ calcd 479.2040, obsd 479.2037.
(R)-1-[(4S,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]-3-methylbut-3-en-2-yl 4-Nitrobenzoate [(R)-11c]. A solution of
alcohol (R)-8 (1.20 g, 2.64 mmol) in CH2Cl2 (26.5 mL) was cooled to
0 °C before the addition of p-nitrobenzoyl chloride (1.47 g, 7.92
mmol), triethylamine (1.5 mL, 10.6 mmol), and a catalytic amount of
DMAP. The reaction mixture was stirred for 18 h after warming to rt
before saturated solution of NaHCO3 (15 mL) was added, followed by
extraction with EtOAc. The combined organic extracts were dried
(MgSO4) and concentrated. The resulting residue was dissolved in
THF (26 mL) and an equimolar (1:1) solution of TBAF/AcOH (8.3
mL, 7.92 mmol, 0.95 M) was added. The reaction mixture was stirred
for 14 h at rt before being concentrated in vacuo. The resulting oil was
purified via flash chromatography on silica gel (4:1 hexanes/EtOAc, v/
v) to afford alcohol (R)-11c (673.2 mg, 70% over two steps) as a
colorless oil; Rf 0.30 (2:1 hexanes/EtOAc, v/v); [α]2D3 −26.1 (c 1.04,
hexanes/EtOAc, v/v); [α]2D3 −26.3 (c 1.05, CHCl3); H NMR (400
1
MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H),
6.43−6.37 (m, 1H), 5.62 (dd, J = 6.8, 6.8 Hz, 1H), 5.11 (s, 1H), 5.02−
5.00 (m, 1H), 4.49 (dd, J = 8.4, 8.4 Hz, 1H), 3.80 (ddd, J = 8.8, 8.8, 3.6
Hz, 1H), 2.32 (s, 3H), 2.21−2.12 (m, 1H), 1.91 (ddd, J = 14.0, 6.4, 3.6
Hz, 1H), 1.86 (d, J = 0.8 Hz, 3H), 1.78 (s, 3H), 1.38 (s, 3H), 1.34 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 199.4, 163.8, 150.7, 141.7,
141.3, 137.0, 136.0, 130.8 (2C), 123.6 (2C), 115.1, 109.9, 77.9, 77.8,
76.7, 35.1, 27.3, 26.9, 25.8, 17.9, 12.3; IR (neat) 2985, 2933, 1724,
1676, 1528, 1273, 1101 cm−1; HRMS (ESI) m/z for C22H27NaNO7
[M + Na]+ calcd 440.1680, obsd 440.1682.
(R)-1-{(4S,5S)-5-[(E)-3-{[(Allyloxy)carbonyl]oxy}-2-methylbuta-
1,3-dien-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}-3-methylbut-3-en-2-
yl 4-Nitrobenzoate [(R)-13c]. Enone (R)-12c (164.4 mg, 0.394 mmol)
in DME (2.0 mL) was added dropwise to a −78 °C solution of
KHMDS (94.3 mg, 0.473 mmol) in DME (5.0 mL), and the mixture
was stirred for 15 min prior to the introduction of neat allyl
chloroformate (0.21 mL, 1.97 mmol). The reaction mixture was then
warmed to −50 °C and stirred for 1 h before the addition of saturated
aqueous NH4Cl (5 mL). The mixture was extracted with EtOAc (3 ×
10 mL) and the combined organic extracts were dried over MgSO4
and concentrated. Purification via flash chromatography on silica gel
(8:1 hexanes/EtOAc, v/v) gave enol carbonate (R)-13c (76.5 mg,
39%) as a colorless oil; Rf 0.45 (4:1 hexanes/EtOAc, v/v); [α]2D3 −37.0
1
(c 1.08, CHCl3); H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.8 Hz,
2H), 8.20 (d, J = 8.8 Hz, 2H), 5.95 (dddd, J = 16.0, 10.8, 5.6, 5.6 Hz,
1H), 5.70 (d, J = 8.8 Hz, 1H), 5.63 (dd, J = 7.2, 7.2 Hz, 1H), 5.43−
5.36 (m, 1H), 5.33−5.27 (m, 1H), 5.15 (d, J = 2.4 Hz, 1H), 5.13 (s,
1H), 5.05 (d, J = 2.4 Hz, 1H), 5.03−5.00 (m, 1H), 4.68−4.62 (m,
2H), 4.42 (dd, J = 8.8, 8.8 Hz, 1H), 3.72 (ddd, J = 8.4, 8.4, 2.8 Hz,
1H), 2.09 (ddd, J = 14.0, 9.2, 7.6 Hz, 1H), 1.96−1.92 (m, 1H), 1.92
(d, J = 0.8 Hz, 3H), 1.79 (s, 3H), 1.37 (s, 3H), 1.32 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 163.9, 153.8, 153.0, 150.6, 141.8, 136.2, 133.8,
131.3, 130.9 (2C), 124.2, 123.6 (2C), 119.4, 115.0, 109.4, 103.9, 78.0,
77.6, 77.0, 69.1, 34.8, 27.4, 27.0, 17.9, 14.1; IR (neat) 2985, 2933,
1763, 1726, 1527, 1350, 1273, 1224, 1116 cm−1; HRMS (ESI) m/z for
C26H31NaNO9 [M + Na]+ calcd 524.1891, obsd 524.1892.
tert-Butyl-{[(4S,5S)-5-{2-[(tert-butyldimethylsilyl)oxy]-3-methyl-
but-3-en-1-yl}-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}diphenyl-
silane (10d). Imidazole (154.5 mg, 2.27 mmol) and a catalytic amount
of DMAP were added to a solution of alcohols (R)-8 and (S)-9 (343.1
mg, 0.755 mmol, prepared from aldehyde 7) in DMF (1 mL) at rt.
The mixture was stirred until it was homogeneous, and TBSCl (170.3
1
CHCl3); H NMR (400 MHz, CDCl3) δ 8.29−8.25 (m, 2H), 8.22−
8.17 (m, 2H), 5.67 (dd, J = 7.2, 7.2 Hz, 1H), 5.13 (s, 1H), 5.03−5.00
(m, 1H), 3.95 (ddd, J = 8.4, 8.4, 3.6 Hz, 1H), 3.82−3.74 (m, 2H),
3.66−3.59 (m, 1H), 2.16−2.09 (m, 2H), 2.01 (ddd, J = 14.0, 6.8, 3.6
Hz, 1H), 1.81 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H); 13C NMR (100
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mg, 1.13 mmol) was added in one portion. The reaction mixture was
stirred at rt for 14 h before it was partitioned between a solution of
NH4Cl (10 mL) and Et2O (10 mL). The layers were separated and the
aqueous layer was extracted with Et2O (3 × 10 mL). The organic
extracts were combined, dried over Na2SO4, and concentrated. The
residue was purified via flash chromatography on silica gel (8:1
hexanes/EtOAc, v/v) to furnish silyl ethers 10d (425.8 mg, 99%) as a
colorless oil; Rf 0.61 (7:1 hexanes/EtOAc, v/v); 1H NMR (400 MHz,
CDCl3) δ 7.75−7.66 (m, 8H), 7.47−7.35 (m, 12H), 4.97−4.94 (m,
1H), 4.93−4.90 (m, 1H), 4.86−4.82 (m, 1H), 4.78−4.75 (m, 1H),
4.38−4.31 (m, 2H), 4.26−4.19 (m, 1H), 3.95−3.88 (m, 1H), 3.83−
3.62 (m, 6H), 1.94 (ddd, J = 13.6, 10.8, 2.0 Hz, 1H), 1.85−1.75 (m,
3H), 1.71 (s, 3H), 1.68 (s, 3H), 1.42 (s, 6H), 1.37 (s, 3H), 1.35 (s,
3H), 1.07 (s, 9H), 1.06 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.09 (s,
3H), 0.07 (s, 3H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
148.6, 146.7, 135.82 (2C), 135.79 (2C), 135.77 (4C), 133.5, 133.4
(2C), 133.3, 129.9, 129.81 (2C), 129.79, 127.83 (6C), 127.8 (2C),
112.2, 110.6, 108.7, 108.6, 81.5, 81.1, 75.6, 75.5, 74.7, 73.5, 64.4, 64.0,
41.0, 39.9, 27.71, 27.66, 27.0 (2C), 26.95 (3C), 26.93 (3C), 26.03
(3C), 25.97 (3C), 19.4, 19.3, 18.4, 18.3, 17.2, 16.7, −4.57, −4.64,
−4.9, −5.0; IR (neat) 2957, 2929, 2893, 2857, 1473, 1428, 1378, 1251,
1113 cm−1; HRMS (ESI) m/z for C33H52O4NaSi2 [M + Na]+ calcd
591.3296, obsd 591.3282.
[(4S,5S)-5-{2-[(tert-Butyldimethylsilyl)oxy]-3-methylbut-3-en-1-
yl}-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (11d). Silyl ether mix-
ture 10d (421.6 mg, 0.741 mmol) was taken up in a solution of 10%
NaOH in MeOH (7.5 mL). The mixture was warmed at 65 °C for 2.5
h and then cooled to rt before a solution of NH4Cl (10 mL) was
added. The mixture was extracted with EtOAc (3 × 15 mL) and the
organic extracts were combined, dried over Na2SO4, and concentrated
under reduced pressure. Purification via flash chromatography (8:1
hexanes/EtOAc, v/v) afforded a mixture of primary alcohols 11d
(224.9 mg, 92%) as a colorless oil; Rf 0.34 (4:1 hexanes/EtOAc, v/v);
1H NMR (400 MHz, CDCl3) δ 4.94−4.92 (m, 1H), 4.92−4.90 (m,
1H), 4.84−4.81 (m, 1H), 4.77−4.74 (m, 1H), 4.30−4.24 (m, 2H),
4.06−3.98 (m, 1H), 3.82−3.71 (m, 5H), 3.70−3.64 (m, 1H), 3.63−
3.54 (m, 2H), 2.19 (br s, 2H), 1.92−1.81 (m, 1H), 1.77−1.69 (m,
1H), 1.68 (s, 3H), 1.66 (s, 3H), 1.61−1.52 (m, 1H), 1.40 (s, 3H), 1.39
(s, 3H), 1.37 (s, 3H), 1.35 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.053 (s,
3H), 0.050 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 148.2, 146.3, 112.2, 110.8, 108.8, 108.7, 81.8, 81.7, 74.4,
74.2, 73.6, 73.4, 62.1, 62.0, 40.4, 39.5, 27.6, 27.5, 27.11, 27.07, 25.9
(6C), 18.3 (2C), 17.3, 17.0, −4.6, −4.7, −5.0, −5.1; IR (neat) 3469,
2954, 2929, 2889, 2857, 1472, 1463, 1380, 1251, 1165 cm−1; HRMS
(ESI) m/z for C17H34NaO4Si [M + Na]+ calcd 353.2119, obsd
353.2128.
(E)-4-[(4S,5S)-5-{2-[(tert-Butyldimethylsilyl)oxy]-3-methylbut-3-
en-1-yl}-2,2-dimethyl-1,3-dioxolan-4-yl]-3-methylbut-3-en-2-one
(12d). A solution of DMSO (1.76 mL, 24.8 mmol) in CH2Cl2 (19.8
mL) was cooled to −78 °C before addition of oxalyl chloride (1.05
mL, 12.4 mmol) dropwise. The reaction mixture was stirred for 30 min
at −78 °C, after which a solution of alcohols 11d (2.05 g, 6.20 mmol)
in CH2Cl2 (5 mL) was added dropwise and the mixture was stirred for
1 h. Triethylamine (6.91 mL, 49.6 mmol) was then added, the cold
bath was removed, and the reaction mixture was warmed to rt and
stirred for an additional 15 min. A saturated solution of NH4Cl (20
mL) was then added to the reaction mixture and the layers were
separated. The aqueous portion was extracted with EtOAc (3 × 50
mL). The combined extracts were dried over MgSO4, filtered, and
concentrated in vacuo to afford an aldehyde that was used directly in
the next step. A suspension of NaH (297.7 mg, 7.44 mmol, 60% in oil)
in THF (3.8 mL) was cooled to 0 °C, and a solution of diethyl 3-
oxobutan-2-ylphosphonate (1.61 g, 7.75 mmol) in THF (7.1 mL) was
added dropwise. The cloudy reaction mixture was stirred at 0 °C and
became transparent (time required for complete consumption of base
varied with different batches). Stirring continued at 0 °C for an
additional 50 min before addition of a solution of the freshly prepared
aldehyde in THF (7.1 mL) dropwise. The cold bath was removed, and
the reaction mixture was warmed to rt and stirred for 36 h. The
mixture was partitioned between a saturated solution of NH4Cl (30
mL) and EtOAc (30 mL). The layers were separated and the aqueous
layer was extracted with EtOAc (3 × 30 mL). The organic extracts
were combined and dried (MgSO4), and solvent was removed under
reduced pressure. The resulting residue was purified via flash
chromatography on silica gel (20:1 hexanes/EtOAc, v/v) to afford
enones 12d (1.70 g, 72% over 2 steps) as a pale yellow oil; Rf 0.39 (7:1
hexanes/EtOAc, v/v); 1H NMR (400 MHz, CDCl3) δ 6.44−6.41 (m,
1H), 6.41−6.39 (m, 1H), 4.94−4.91 (m, 1H), 4.89−4.86 (m, 1H),
4.83−4.79 (m, 1H), 4.78−4.75 (m, 1H), 4.47 (t, J = 8.4 Hz, 1H), 4.41
(t, J = 8.4 Hz, 1H), 4.29−4.20 (m, 2H), 3.98−3.91 (m, 1H), 3.70
(ddd, J = 8.4, 8.4, 3.6 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 1.86 (d, J =
1.6 Hz, 3H), 1.83 (d, J = 1.2 Hz, 3H), 1.70−1.65 (m, 5H), 1.63 (s,
3H), 1.59 (dd, J = 7.2, 5.2 Hz, 2H), 1.45 (s, 3H), 1.44 (s, 6H), 1.40 (s,
3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H), 0.00 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 199.62, 199.56, 148.0, 146.5,
141.0, 140.9, 138.1, 137.1, 112.3, 111.0, 109.6, 109.5, 78.0, 77.92,
77.87, 77.4, 74.4, 73.3, 39.3, 38.5, 27.6, 27.5, 27.1, 27.0, 25.9 (6C),
25.79, 25.76, 18.34, 18.31, 17.3, 16.5, 12.3, 12.2, −4.5, −4.6, −5.0,
−5.1; IR (neat) 2955, 2928, 2897, 2858, 1680, 1473, 1379, 1252, 1076
cm−1; HRMS (ESI) for C21H38NaO4Si [M + Na]+ calcd 405.2432,
obsd 405.2433.
Allyl {(E)-4-[(4S,5S)-5-{2-[(tert-Butyldimethylsilyl)oxy]-3-methyl-
but-3-en-1-yl}-2,2-dimethyl-1,3-dioxolan-4-yl]-3-methylbuta-1,3-
dien-2-yl} Carbonate (13d). Potassium bis(trimethylsilyl)amide (71.0
mg, 0.365 mmol), obtained from a inert atmosphere glovebox, was
taken up in DME (7 mL) and cooled to −78 °C, followed by the
dropwise addition of enones 12d (68.1 mg, 0.178 mmol) in DME (2
mL). The reaction mixture was warmed to −50 °C for 1 h and the
solution became orange during that time period. The reaction mixture
was again cooled to −78 °C, and neat allyl chloroformate (37.8 mL,
0.356 mmol) was added. The mixture was warmed to rt and stirred for
1 h before addition of a saturated solution of NH4Cl (6 mL). The
mixture was extracted with EtOAc (3 × 15 mL), dried over MgSO4,
and concentrated under reduced pressure. The residue was purified via
flash chromatography on silica gel (15:1 hexanes/EtOAc, v/v) to yield
enol carbonates 13d (73.5 mg, 88%) as a colorless oil; Rf 0.57 (4:1
hexanes/EtOAc, v/v); 1H NMR (400 MHz, CDCl3) δ 6.01−5.87 (m,
2H), 5.75−5.66 (m, 2H), 5.41−5.38 (m, 1H), 5.37−5.34 (m, 1H),
5.31−5.28 (m, 1H), 5.28−5.25 (m, 1H), 5.14−5.10 (m, 2H), 5.04−
4.99 (m, 2H), 4.93−4.89 (m, 1H), 4.87−4.84 (m, 1H), 4.80−4.77 (m,
1H), 4.76−4.73 (m, 1H), 4.69−4.62 (m, 4H), 4.37 (t, J = 8.4 Hz, 1H),
4.32 (t, J = 8.4 Hz, 1H), 4.27−4.20 (m, 2H), 3.84 (ddd, J = 8.8, 8.8,
2.4 Hz, 1H), 3.55 (ddd, J = 8.8, 8.8, 3.2 Hz, 1H), 1.90 (d, J = 1.2 Hz,
3H), 1.88 (d, J = 1.2 Hz, 3H), 1.79−1.71 (m, 1H), 1.67 (s, 3H), 1.65−
1.58 (m, 5H), 1.58−1.53 (m, 1H), 1.41 (s, 3H), 1.40 (s, 3H), 1.38 (s,
3H), 1.34 (s, 3H), 0.87 (s, 9H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s,
3H), 0.00 (s, 3H), −0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
154.0 (2C), 152.97, 152.96, 148.2, 146.5, 133.3, 133.1, 131.4 (2C),
125.0, 124.8, 119.29, 119.26, 112.3, 110.8, 108.9, 108.8, 103.4 (2C),
78.1, 77.8, 77.7, 77.4, 74.7, 73.3, 68.98, 68.97, 39.2, 38.2, 27.6, 27.4,
27.1, 27.0, 25.92 (3C), 25.90 (3C), 18.29, 18.26, 17.3, 16.2, 14.1, 14.0,
−4.6, −4.7, −5.0, −5.1; IR (neat) 2955, 2930, 2889, 2857, 1764, 1458,
1370, 1224 cm−1; HRMS (ESI) for C25H42NaO6Si [M + Na]+ calcd
489.2643, obsd 489.2596.
Allyl {(3aS,5S,5aR,9aS,9bS)-5-[(methoxycarbonyl)oxy]-2,2,5a,9-
Tetramethyl-3a,4,5,5a,6,7,9a,9b-octahydronaphtho[1,2-d][1,3]-
dioxol-8-yl} Dicarbonate (14). Dicarbonate (S)-13a (56.6 mg, 0.138
mmol) and BHT (3.0 mg, 0.014 mmol) were dissolved in 1,2-
dichlorobenzene (13.8 mL) and warmed at 180 °C for 3 days. The
solvent was removed via low-pressure vacuum distillation. Purification
of the residue via flash chromatography on silica gel (30:1 to 10:1
hexanes/EtOAc, v/v) afforded 14 (19.9 mg, 35%) as a pale yellow oil;
Rf 0.31 (4:1 hexanes/EtOAc, v/v); [α]2D3 −10.9 (c 0.93, CHCl3); H
1
NMR (400 MHz, CDCl3) δ 5.96 (dddd, J = 16.4, 10.4, 6.0, 6.0 Hz,
1H), 5.42−5.35 (m, 1H), 5.32−5.27 (m, 1H), 4.76 (dd, J = 2.8, 2.8
Hz, 1H), 4.68−4.63 (m, 2H), 3.79 (s, 3H), 3.70 (ddd, J = 13.2, 8.8, 4.8
Hz, 1H), 3.53 (dd, J = 11.6, 8.8 Hz, 1H), 2.73−2.66 (m, 1H), 2.44−
2.32 (m, 1H), 2.29 (ddd, J = 14.0, 4.4, 2.8 Hz, 1H), 2.24−2.15 (m,
1H), 2.11 (ddd, J = 13.6, 13.6, 3.2 Hz, 1H), 1.95−1.86 (m, 1H), 1.72
(s, 3H), 1.47−1.42 (m, 1H), 1.42 (s, 3H), 1.41 (s, 3H), 1.10 (s, 3H);
3904
dx.doi.org/10.1021/jo400029u | J. Org. Chem. 2013, 78, 3895−3907

The Journal of Organic Chemistry
Article
13C NMR (100 MHz, CDCl3) δ 155.6, 153.6, 142.1, 132.0, 122.3,
[1,3]dioxol-8-yl} Carbonate (19) and Allyl {(3aS,5S,5aR,9aS,9bS)-5-
[(tert-Butyldimethylsilyl)oxy]-2,2,5a,9-tetramethyl-
3a,4,5,5a,6,7,9a,9b-octahydronaphtho[1,2-d][1,3]dioxol-8-yl} Car-
bonate (20). Silyl ethers 13d (76.4 mg, 164 μmol) and BHT (3.6
mg, 16.3 μmol) were dissolved in 1,2-dichlorobenzene (16.5 mL) and
heated at 225−250 °C in a sealed tube for 3 days. The solvent was
removed by vacuum distillation and the residue was purified via flash
chromatography on silica gel (100:0 to 20:1 hexanes/EtOAc, v/v) to
yield 19 (20.9 mg, 27.4%) as a off-white, waxy solid and 20 (11.5 mg,
15.0%) as a colorless oil, as well as a mixture containing both isomers
(15.6 mg, 20.4%; 19:20 = 1:2).
118.4, 109.4, 80.7, 78.4, 77.9, 68.5, 54.3, 43.8, 39.8, 31.6, 30.3, 27.2,
27.1, 24.5, 17.5, 14.5; IR (neat) 2984, 2956, 2929, 1751, 1273 cm−1;
HRMS (ESI) m/z for C21H30NaO8 [M + Na]+ calcd 433.1833, obsd
433.1837.
Allyl {(3aS,5R,5aR,9aS,9bS)-5-[(methoxycarbonyl)oxy]-2,2,5a,9-
Tetramethyl-3a,4,5,5a,6,7,9a,9b-octahydronaphtho[1,2-d][1,3]-
dioxol-8-yl} Dicarbonate (15). Dicarbonate (R)-13a (43.1 mg, 0.105
mmol) and BHT (2.3 mg, 0.011 mmol) were dissolved in 1,2-
dichlorobenzene (10.5 mL) and warmed at 180 °C for 2 days. The
solvent was removed via low-pressure vacuum distillation. The residue
was purified via flash chromatography on silica gel (30:1 to 10:1
hexanes/EtOAc, v/v), which afforded 15 (22.2 mg, 49%) as a waxy
solid; Rf 0.35 (4:1 hexanes/EtOAc, v/v); [α]2D3 −25.9 (c 1.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 5.95 (dddd, J = 16.4, 10.8, 5.6, 5.6 Hz,
1H), 5.42−5.35 (m, 1H), 5.32−5.26 (m, 1H), 4.68−4.63 (m, 2H),
4.53 (dd, J = 11.2, 4.4 Hz, 1H), 3.79 (s, 3H), 3.51 (dd, J = 11.2, 8.8
Hz, 1H), 3.43−3.35 (m, 1H), 2.43 (ddd, J = 11.2, 4.0, 4.0 Hz, 1H),
2.36−2.25 (m, 2H), 2.23−2.14 (m, 1H), 1.96 (app q, J = 11.6 Hz,
1H), 1.81 (dd, J = 13.2, 6.8 Hz, 1H), 1.71 (s, 3H), 1.51 (ddd, J = 12.0,
12.0, 7.2 Hz, 1H), 1.41 (s, 6H), 1.08 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 155.5, 153.2, 142.3, 131.5, 121.2, 119.2, 110.3, 81.2, 78.4,
77.6, 68.9, 55.1, 45.6, 39.6, 33.3, 30.0, 27.1, 27.0, 23.9, 14.1, 12.9; IR
(thin film) 2985, 2929, 1752, 1442, 1385, 1370, 1267, 1186, 1164,
1087, 1039, 1010, 978 cm−1; HRMS (ESI) m/z for C21H30NaO8 [M +
Na]+ calcd 433.1833, obsd 433.1825.
Spectral Data for 19. Rf 0.83 (15:1 hexanes/EtOAc, v/v, eluted five
1
times); [α]2D3 −39.5 (c 1.04, CHCl3); H NMR (400 MHz, CDCl3) δ
5.96 (dddd, J = 16.4, 10.8, 5.6, 5.6 Hz, 1H), 5.42−5.35 (m, 1H), 5.31−
5.26 (m, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.50 (dd, J = 11.2, 8.4 Hz, 1H),
3.44 (dd, J = 10.8, 4.4 Hz, 1H), 3.32 (ddd, J = 12.8, 8.8, 4.0 Hz, 1H),
2.37−2.25 (m, 1H), 2.25−2.12 (m, 3H), 1.95 (dd, J = 12.8, 6.8 Hz,
1H), 1.87 (app q, J = 12.0 Hz, 1H), 1.70 (s, 3H), 1.40 (s, 3H), 1.39 (s,
3H), 1.37−1.31 (m, 1H), 0.97 (s, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.3, 142.4, 131.6, 121.6,
119.1, 109.7, 79.0, 78.0, 76.5, 68.8, 45.6, 41.1, 34.0, 33.8, 27.2, 27.1,
25.9 (3C), 24.3, 18.2, 14.1, 12.3, −3.9, −4.8; IR (thin film) 2953, 2929,
2858, 1752, 1239, 1151, 1104, 1074 cm−1; HRMS (ESI) m/z for
C25H42NaO6Si [M + Na]+ calcd 489.2643, obsd 489.2644.
Spectral Data for 20. Rf 0.70 (15:1 hexanes/EtOAc, v/v, eluted five
times); [α]2D3 −9.90 (c 0.53, CHCl3); H NMR (400 MHz, CDCl3)
1
δ5.96 (dddd, J = 16.4, 10.8, 6.0, 6.0 Hz, 1H), 5.42−5.35 (m, 1H),
5.31−5.27 (m, 1H), 4.68−4.64 (m, 2H), 3.83 (ddd, J = 11.6, 8.8, 5.6
Hz, 1H), 3.63 (dd, J = 2.4, 2.4 Hz, 1H), 3.50 (dd, J = 11.6, 8.8 Hz,
1H), 2.70−2.64 (br m, 1H), 2.36−2.26 (m, 1H), 2.21−2.12 (m, 1H),
2.09−2.02 (m, 2H), 2.01−1.95 (m, 1H), 1.72 (d, J = 1.2 Hz, 3H), 1.41
(s, 3H), 1.40 (s, 3H), 1.28−1.18 (m, 1H), 0.98 (s, 3H), 0.90 (s, 9H),
0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.4,
141.7, 131.7, 122.7, 119.1, 108.9, 78.5, 77.6, 75.9, 68.8, 42.7, 40.9, 32.7,
32.6, 27.2 (2C), 26.0 (3C), 24.6, 18.2, 17.8, 14.4, −4.4, −4.7; IR (neat)
2953, 2929, 2858, 1751, 1239, 1067, 833 cm−1; HRMS (ESI) m/z for
C25H42NaO6Si [M + Na]+ calcd 489.2643, obsd 489.2650.
(3aS,5R,5aR,9aS,9bS)-8-{[(Allyloxy)carbonyl]oxy}-2,2,5a,9-tetra-
methyl-3a,4,5,5a,6,7,9a,9b-octahydronaphtho[1,2-d][1,3]dioxol-5-
yl Benzoate (17). Enol carbonate (R)-13b (74.7 mg, 0.164 mmol) and
BHT (3.6 mg, 0.0164 mmol) were dissolved in 1,2-dichlorobenzene
(16.4 mL) and warmed at 180 °C for 24 h. The solvent was removed
via low-pressure vacuum distillation. Purification of the residue via
flash chromatography on silica gel (8:1 hexanes/EtOAc, v/v) afforded
17 (38.8 mg, 52%) as a white, waxy solid; Rf 0.52 (4:1 hexanes/EtOAc,
v/v); [α]2D3 −55.7 (c 1.07, CHCl3); H NMR (500 MHz, CDCl3) δ
1
8.05−8.02 (m, 2H), 7.60−7.56 (m, 1H), 7.48−7.44 (m, 2H), 5.76
(dddd, J = 14.4, 8.4, 4.4, 4.4 Hz, 1H), 5.39 (dq, J = 14.0, 1.2 Hz, 1H),
5.29 (dq, J = 8.4, 0.8 Hz, 1H), 4.97 (dd, J = 8.8, 3.6 Hz, 1H), 4.68−
4.64 (m, 2H), 3.59 (dd, J = 9.2, 6.8 Hz, 1H), 3.52−3.46 (m, 1H), 2.49
(ddd, J = 9.2, 3.2, 3.2 Hz, 1H), 2.44−2.39 (m, 1H), 1.74 (d, J = 0.8 Hz,
3H), 1.55 (ddd, J = 10.0, 10.0, 6.0 Hz, 1H), 1.43 (s, 3H), 1.428 (s,
3H), 1.23 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.9, 153.2,
142.3, 133.3, 131.5, 130.2, 129.8 (2C), 128.6 (2C), 121.3, 119.1, 110.2,
78.6, 77.8, 77.4, 68.9, 45.8, 39.9, 33.6, 30.1, 27.1, 27.0, 24.0, 14.1, 13.3;
IR (thin film) 2985, 2933, 2893, 1751, 1718, 1450, 1381, 1369, 1271,
1244, 1111 cm−1; HRMS (ESI) m/z for C26H32NaO7 [M + Na]+ calcd
479.2040, obsd 479.2047.
(3aS,5R,5aR,9aS,9bS)-8-{[(Allyloxy)carbonyl]oxy}-2,2,5a,9-tetra-
methyl-3a,4,5,5a,6,7,9a,9b-octahydronaphtho[1,2-d][1,3]dioxol-5-
yl 4-Nitrobenzoate (18). Enol carbonate (R)-13c (75.9 mg, 0.151
mmol) and BHT (3.3 mg, 0.0151 mmol) were dissolved in 1,2-
dichlorobenzene (15 mL) and warmed at 180 °C for 24 h. The solvent
was removed via low-pressure vacuum distillation. Purification of the
residue via flash chromatography on silica gel (8:1 hexanes/EtOAc, v/
v) afforded 18 (45.0 mg, 59%) as a white foam; Rf 0.41 (4:1 hexanes/
EtOAc, v/v); [α]2D3 −54.7 (c 0.87, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 8.30 (d, J = 7.2 Hz, 2H), 8.20 (d, J = 6.8 Hz, 2H), 5.96
(dddd, J = 14.0, 8.4, 4.4, 4.4 Hz, 1H), 5.42−5.35 (m, 1H), 5.31−5.27
(m, 1H), 5.00 (dd, J = 9.2, 3.6 Hz, 1H), 4.68−4.65 (m, 2H), 3.59 (dd,
J = 8.8, 6.8 Hz, 1H), 3.49 (ddd, J = 10.0, 6.8, 3.2 Hz, 1H), 2.50 (ddd, J
= 8.8, 3.2, 3.2 Hz, 1H), 2.45−2.40 (m, 1H), 2.37−2.28 (m, 1H), 2.22−
2.15 (m, 1H), 2.05 (app q, J = 8.8 Hz, 1H), 1.76−1.71 (m, 4H), 1.60−
1.55 (m, 1H), 1.434 (s, 3H), 1.43 (s, 3H), 1.24 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 164.1, 153.2, 150.9, 142.2, 135.5, 131.5, 130.9
(2C), 123.8 (2C), 121.2, 119.2, 110.4, 78.6, 78.4, 77.7, 68.9, 45.8, 39.9,
33.6, 30.1, 27.1, 27.0, 24.0, 14.1, 13.4; IR (thin film) 2985, 2933, 1751,
1724, 1529, 1382, 1273, 1242, 1163, 1115 cm−1; HRMS (ESI) m/z for
C26H31NaNO9 [M + Na]+ calcd 524.1891, obsd 524.1888.
{[(2S,3S)-2,3-Bis(benzyloxy)-5-methoxypent-4-en-1-yl]oxy}(tert-
butyl)diphenylsilane (22). Oxalyl chloride (3.13 mL, 37.0 mmol) was
added dropwise to a solution of DMSO (5.25 mL, 74.0 mmol) in
CH2Cl2 (60 mL) at −78 °C, and the reaction mixture was stirred for
15 min. Alcohol 2124 (10.0 g, 18.5 mmol) in CH2Cl2 (14.8 mL) was
added dropwise and the mixture was stirred for 1 h at −78 °C,
followed by the addition of triethylamine (20.6 mL, 148 mmol). The
reaction mixture was warmed to rt and stirred for 15 min before
saturated aqueous NH4Cl (100 mL) was added. The resultant mixture
was extracted with Et2O (3 × 100 mL), and the combined organic
extracts were washed with brine (100 mL), dried over MgSO4, and
concentrated with no further purification. Potassium bis-
(trimethylsilyl)amide (61.0 mL, 55.5 mmol, 0.91 M solution in
THF) was added to a −78 °C slurry of methoxymethyltriphenyl-
phosphonium chloride (25.4 g, 74.0 mmol) in THF (250 mL). The
deep red slurry was stirred for 1 h at −78 °C before a solution of
previously prepared crude aldehyde (9.96 g, 18.5 mmol) in THF (115
mL) was added dropwise. The reaction mixture was warmed to rt,
stirred for 14 h, and then partitioned between Et2O (200 mL) and
H2O (200 mL). The separated aqueous layer was extracted with Et2O
(3 × 200 mL), and the combined organic extracts were washed with
brine (200 mL), dried over MgSO4, and concentrated. Purification via
flash chromatography on silica gel (20:1 hexanes/EtOAc, v/v) gave a
diastereomeric mixture of enol ethers 22 (8.21 g, 78% over two steps)
as a pale yellow oil; Rf 0.61 (4:1 hexanes/EtOAc, v/v) 1H NMR (400
MHz, CDCl3, major diastereomer) δ 7.75−7.69 (m, 4H), 7.48−7.27
(m, 16H), 6.50 (d, J = 12.8 Hz, 1H), 4.80−4.62 (m, 4H), 4.41 (d, J =
12.0 Hz, 1H), 4.00−3.90 (m, 2H), 3.90−3.82 (m, 1H), 3.67−3.58 (m,
1H), 3.51 (s, 3H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3, mixture
of diastereomers) δ 151.2, 149.7, 139.3, 139.28, 139.1, 138.9, 135.8,
135.7, 133.9, 133.8, 133.7, 133.6, 129.7, 129.6, 128.33, 128.3, 128.2,
128.17, 128.13, 128.1, 127.9, 127.86, 127.8, 127.77, 127.7, 127.5,
127.4, 127.35, 127.2, 104.2, 99.8, 83.1, 82.8, 77.3, 73.7, 73.6, 72.2, 70.5,
Allyl {(3aS,5R,5aR,9aS,9bS)-5-[(tert-Butyldimethylsilyl)oxy]-
2,2,5a,9-tetramethyl-3a,4,5,5a,6,7,9a,9b-octahydronaphtho[1,2-d]-
3905
dx.doi.org/10.1021/jo400029u | J. Org. Chem. 2013, 78, 3895−3907

The Journal of Organic Chemistry
Article
69.6, 64.4, 64.0, 60.5, 59.8, 55.9, 27.0, 26.9, 19.3; IR (neat) 3068, 2930,
2857, 1654, 1458, 1428, 1112, 1067 cm−1; HRMS (ESI) m/z for
C36H42NaO4Si [M + Na]+ calcd 589.2745, obsd 589.2730.
127.48, 112.0, 111.3, 81.0, 80.9, 76.0, 75.9, 74.5, 74.1, 73.1, 73.0, 72.5,
72.4, 64.2, 63.8, 37.8, 36.7, 27.04 (3C), 27.02 (3C), 26.1 (3C), 26.0
(3C), 19.4, 19.3, 18.34, 18.3, 16.9, 16.6, −4.3, −4.6, −4.8, −4.9; IR
(neat) 2954, 2928, 2886, 1251, 1112 cm−1; HRMS (ESI) m/z for
C44H60NaO4Si2 [M + Na]+ calcd 731.3922, obsd 731.3892.
(3S,4S)-3,4-Bis(benzyloxy)-5-[(tert-butyldiphenylsilyl)oxy]-
pentanal (23). Mercuric acetate (6.54 g, 20.51 mmol) was added in
one portion to enol ethers 22 (7.75 g, 13.76 mmol) in a THF/H2O
mixture (275 mL, 10:1) and stirred for 3 h at rt. Tetrabutylammonium
iodide (22.7 g, 61.52 mmol) was added to the reaction mixture and it
was stirred for an additional 2 h prior to the addition of saturated
aqueous NH4Cl (100 mL). The mixture was then extracted with
EtOAc (3 × 150 mL), and the combined extracts were dried and
concentrated. Purification via flash chromatography afforded 23 (7.23
g, 96%) as a viscous, yellow oil; Rf 0.50 (4:1 hexanes/EtOAc, v/v);
[α]2D3 +5.9 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.67−9.65
(m, 1H), 7.71−7.66 (m, 4H), 7.47−7.20 (m, 16H), 4.66 (d, J = 12.0
Hz, 1H), 4.55 (s, 2H), 4.48 (d, J = 11.6 Hz, 1H), 4.23−4.17 (m, 1H),
3.93 (dd, J = 10.8, 4.8 Hz, 1H), 3.83 (dd, J = 11.2, 6.0 Hz, 1H), 3.65−
3.60 (m, 1H), 2.74−2.67 (m, 1H), 2.62−2.54 (m, 1H), 1.08 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 201.2, 138.3, 138.1, 135.8 (4C),
(2S,3S)-2,3-Bis(benzyloxy)-5-[(tert-butyldimethylsilyl)oxy]-6-
methylhept-6-en-1-ol (26). Ammonium fluoride (183.0 mg, 4.94
mmol) was added to a solution of 25 (500 mg, 0.705 mmol) in
methanol (14 mL). The reaction mixture was warmed at 40 °C for 2.5
days before being cooled to 0 °C and quenched by the addition of
saturated aqueous NaHCO3 (10 mL). The mixture was extracted with
EtOAc (3 × 25 mL), and the pooled extracts were dried and
concentrated. Purification via flash chromatography on silica gel (8:1
hexanes/EtOAc, v/v) provided alcohol 26 (286.4 mg, 86%) as a
diastereomeric mixture in the form of a colorless oil; Rf 0.15 (8:1
hexanes/EtOAc, v/v); 1H NMR (400 MHz, CDCl3) δ 7.37−7.28 (m,
20H), 4.91−4.89 (br m, 1H), 4.79−4.76 (br m, 2H), 4.72−4.68 (m,
2H), 4.67−4.55 (m, 6H), 4.50 (d, J = 11.6 Hz, 1H), 4.28 (dd, J = 8.8,
3.2 Hz, 1H), 4.20 (app t, J = 6.0 Hz, 1H), 3.91 (ddd, J = 9.2, 4.4, 2.4
Hz, 1H), 3.87−3.77 (m, 2H), 3.75−3.71 (m, 1H), 3.70−3.61 (m, 4H),
2.17 (br s, 1H), 2.13 (br s, 1H), 1.99−1.88 (m, 2H), 1.80−1.71 (m,
2H), 1.69 (s, 3H), 1.67 (s, 3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.05 (s,
3H), 0.02 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 148.1, 147.3, 138.5 (2C), 138.31, 138.3, 128.64 (2C), 128.6
(2C), 128.58 (2C), 128.5 (2C), 128.1 (2C), 128.06 (2C), 128.0 (2C),
127.97 (2C), 127.9 (2C), 127.8 (2C), 112.0, 111.4, 79.0, 78.9, 76.4,
76.2, 74.2, 74.1, 72.7, 72.6, 72.5, 72.3, 62.0 (2C), 37.4, 36.3, 26.1 (3C),
26.0 (3C), 18.32, 18.3, 17.0, 16.7, −4.3, −4.6, −4.9, −4.91; IR (neat)
3439, 2956, 2929, 2889, 2858, 1459, 1250, 1073 cm−1; HRMS (ESI)
for C28H42NaO4Si [M + Na]+ calcd 493.2745, obsd 493.2758.
(5S,6S,E)-5,6-Bis(benzyloxy)-8-[(tert-butyldimethylsilyl)oxy]-3,9-
dimethyldeca-3,9-dien-2-one (27). Alcohol mixture 26 (263.4 mg,
0.559 mmol) was dissolved in CH2Cl2 (5.6 mL) and cooled to 0 °C.
Sodium bicarbonate (705.2 mg, 8.39 mmol) and Dess−Martin
periodinane (356.0 mg, 0.839 mmol) were added sequentially and
the cold bath was removed. The reaction mixture was stirred at rt for 2
h and then saturated solutions of NaHCO3 (10 mL) and NaS2O3 (10
mL) were added. The mixture was stirred vigorously for 30 min, and
the layers were separated. The aqueous layer was extracted with
CH2Cl2 (3 × 30 mL), the combined organic extracts were dried, and
the solvent was evaporated. The corresponding aldehyde was taken to
the next step with no further purification. A solution of 3-oxobutan-2-
ylphosphonate (256.3 mg, 1.23 mmol) in THF (1.9 mL) was added to
a cooled (0 °C) slurry of sodium hydride (44.8 mg, 1.12 mmol, 60% in
oil) in THF (2.2 mL). After 1 h, a solution of aldehyde in THF (1.9
mL) was added via cannula, and the reaction mixture was warmed to rt
and stirred for 14 h prior to the addition of saturated aqueous NH4Cl
(5 mL). The mixture was partitioned between water and EtOAc, and
the layers were separated. The aqueous layer was extracted with EtOAc
(3 × 20 mL), and the combined extracts were dried and concentrated.
Purification via flash chromatography (9:1 hexanes/EtOAc) afforded
27 (111.6 mg, 38%) as a mixture of isomers in the form of a colorless
oil. Enone 28 was obtained in 14% yield and spectral data are shown
below. The relative configuration was determined after the Diels−
Alder cycloaddition and COSY/NOESY analyses.
133.4, 133.38, 129.93, 129.91, 128.5 (4C), 128.2 (2C), 128.1 (2C),
127.92 (2C), 127.9 (2C), 127.88 (2C), 80.3, 74.0, 73.0, 72.97, 63.1,
45.2, 27.0 (3C), 19.3; IR (neat) 2930, 2856, 1724, 1589, 1458, 1112
cm−1; HRMS (ESI) m/z for C36H44NaO5Si [M + CH3OH + Na]+
calcd 607.2850, obsd 607.2851.
(5S,6S)-5,6-Bis(benzyloxy)-7-[(tert-butyldiphenylsilyl)oxy]-2-
methylhept-1-en-3-ol (24). Freshly prepared isopropenylmagnesium
bromide (42.4 mL, 21.2 mmol, 0.5 M solution in THF) was added to
aldehyde 23 (5.84 g, 10.6 mmol) in THF (50 mL) at 0 °C. The
reaction mixture was stirred for 1 h at 0 °C before being warmed to rt
and quenched by the addition of a saturated solution of NH4Cl (100
mL). The mixture was extracted with EtOAc (3 × 100 mL), and the
combined extracts were dried (MgSO4) and concentrated under
reduced pressure. Purification via flash chromatography on silica gel
(10:1 hexanes/EtOAc, v/v) afforded 24 (3.80 g, 60%) as a
diastereomeric mixture of alcohols in the form of a pale yellow oil.
Spectral Data for More Polar Isomer. Rf 0.39 (4:1 hexanes/EtOAc,
1
v/v); H NMR (400 MHz, CDCl3) δ 7.73−7.67 (m, 4H), 7.46−7.22
(m, 16H), 4.91 (s, 1H), 4.81−4.74 (m, 2H), 4.63 (d, J = 2.8 Hz, 1H),
4.60 (d, J = 3.6 Hz, 1H), 4.45 (d, J = 11.2 Hz, 1H), 4.16−4.11 (br m,
1H), 3.96 (dd, J = 11.2, 3.6 Hz, 1H), 3.89−3.80 (m, 2H), 3.75−3.71
(m, 1H), 3.02 (d, J = 1.2 Hz, 1H), 1.91 (ddd, J = 14.8, 4.0, 4.0 Hz,
1H), 1.68 (s, 3H), 1.65−1.60 (m, 1H), 1.09 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 147.1, 138.7, 138.0, 135.8 (4C), 133.51, 133.5, 129.9
(2C), 128.6 (2C), 128.5 (2C), 128.3 (2C), 128.0 (2C), 127.96, 127.9
(2C), 127.86 (2C), 127.8, 111.1, 80.7, 78.8, 74.9, 73.1, 72.9, 63.7, 35.9,
27.0 (3C), 19.4, 17.9; IR (neat) 3450, 3071, 2932, 2859, 1955, 1893,
1428, 1113 cm−1; HRMS (ESI) m/z for C38H46NaO4Si [M + Na]+
calcd 617.3058, obsd 617.3050.
(7S,8S)-7,8-Bis(benzyloxy)-2,2,3,3,12,12-hexamethyl-11,11-di-
phenyl-5-(prop-1-en-2-yl)-4,10-dioxa-3,11-disilatridecane (25). Imi-
dazole (1.03 g, 15.1 mmol) and a catalytic amount of DMAP were
added to a rt solution of alcohols 24 (3.00 g, 5.04 mmol) in DMF (8.4
mL). Upon complete solvation, TBSCl (1.14 g, 7.56 mmol) was added
in one portion and the reaction mixture was stirred at rt for 12 h.
Saturated aqueous NH4Cl (10 mL) was added, and the mixture was
extracted with EtOAc (3 × 25 mL). The combined organic extracts
were dried and the solvent was evaporated under reduced pressure.
Purification via flash chromatography on silica gel (8:1 hexanes/
EtOAc, v/v) afforded 25 (3.24 g, 91%) as a diastereomeric mixture in
Spectral Data for 28. Rf 0.30 (9:1 hexanes/EtOAc, v/v); [α]D23
+1.55 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34−7.27 (m,
10H), 6.55−6.51 (m, 1H), 4.87−4.85 (m, 1H), 4.77−4.74 (m, 1H),
4.71 (d, J = 11.6 Hz, 1H), 4.63−4.57 (m, 2H), 4.44 (d, J = 12.0 Hz,
1H), 4.32 (dd, J = 9.2, 5.2 Hz, 1H), 4.24 (dd, J = 8.0, 3.6 Hz, 1H), 3.75
(ddd, J = 8.4, 4.8, 3.6 Hz, 1H), 2.29 (s, 3H), 1.85 (ddd, J = 14.0, 8.4,
3.6 Hz, 1H), 1.71 (d, J = 0.8 Hz, 3H), 1.69−1.66 (m, 1H), 1.65 (s,
3H), 0.90 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 199.8, 147.9, 140.5, 140.2, 138.7, 138.1, 128.6 (2C), 128.5
(2C), 128.1 (2C), 128.0, 127.8 (2C), 127.7, 111.5, 78.4, 77.8, 73.8,
73.4, 71.5, 38.4, 26.0 (3C), 25.8, 18.3, 17.1, 12.1, −4.3, −4.9; IR (neat)
2950, 2930, 2855, 1677, 1458, 1251, 1072 cm−1; HRMS (ESI) m/z for
C32H46NaO4Si [M + Na]+ calcd 545.3058, obsd 545.3059.
1
the form of a colorless oil; Rf 0.56 (8:1 hexanes/EtOAc, v/v); H
NMR (400 MHz, CDCl3) δ 7.73−7.66 (m, 8H), 7.46−7.20 (m, 32H),
4.87−4.85 (m, 1H), 4.77−4.69 (m, 4H), 4.66−4.47 (m, 6H), 4.45−
4.39 (m, 1H), 4.24 (dd, J = 8.8, 3.2 Hz, 1H), 4.16 (dd, J = 7.6, 6.0 Hz,
1H), 3.96−3.79 (m, 5H), 3.78−3.63 (m, 2H), 3.57 (ddd, J = 8.4, 4.4,
4.4 Hz, 1H), 1.94−1.84 (m, 2H), 1.75−1.66 (m, 2H), 1.65 (s, 3H),
1.64 (s, 3H), 1.08 (s, 9H), 1.07 (s, 9H), 0.91 (s, 9H), 0.86 (s, 9H),
0.03 to −0.02 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 148.3, 147.3,
139.09, 139.07, 139.0 (2C), 135.81 (6C), 135.78 (2C), 133.7 (2C),
133.67 (2C), 129.8 (4C), 128.39 (2C), 128.37 (4C), 128.3 (2C),
128.0 (6C), 127.9 (2C), 127.8 (6C), 127.7 (2C), 127.6, 127.57, 127.5,
Allyl {(5S,6S,8S,E)-5,6-Bis(benzyloxy)-8-[(tert-butyldimethylsilyl)-
oxy]-3,9-dimethyldeca-1,3,9-trien-2-yl} Carbonate (29). A solution
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The Journal of Organic Chemistry
Article
of enone 28 (40.7 mg, 77.9 μmol) in DME (0.8 mL) was added
dropwise to a −78 °C solution of KHMDS (23.3 mg, 0.117 mmol) in
DME (0.33 mL). The reaction mixture was stirred for 15 min at −78
°C before allyl chloroformate (33 μL, 0.31 mmol) was added in one
portion, and stirring was continued for 1 h. Saturated aqueous NH4Cl
(3 mL) was added, and the mixture was extracted with EtOAc (3 × 10
mL). The combined extracts were dried over MgSO4 and the volatiles
were removed in vacuo. Purification via flash chromatography (20:1
hexanes/EtOAc, v/v) provided enol carbonate 29 (19.9 mg, 42%) as a
colorless oil; Rf 0.37 (8:1 hexanes/EtOAc, v/v); [α]2D3 +24.9 (c 0.995,
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■
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1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.34−7.27 (m, 10H), 5.93
(dddd, J = 16.0, 10.4, 5.6, 5.6 Hz, 1H), 5.83 (d, J = 9.6 Hz, 1H), 5.42−
5.34 (m, 1H), 5.30−5.25 (m, 1H), 5.10 (d, J = 2.0 Hz, 1H), 5.03 (d, J
= 2.4 Hz, 1H), 4.84 (br s, 1H), 4.79 (d, J = 11.6 Hz, 1H), 4.74−4.71
(m, 1H), 4.66−4.61 (m, 2H), 4.59−4.53 (m, 2H), 4.33 (d, J = 11.6
Hz, 1H), 4.28−4.21 (m, 2H), 3.68 (ddd, J = 8.4, 5.2, 3.2 Hz, 1H),
1.81−1.78 (m, 1H), 1.77 (s, 3H), 1.64 (s, 3H), 1.64−1.55 (m, 1H),
0.89 (s, 9H), 0.01 (s, 3H), −0.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 154.3, 153.3, 148.2, 139.2, 138.5, 132.2, 131.4, 128.4 (2C),
128.39 (2C), 128.1 (2C), 127.7 (2C), 127.67, 127.5, 127.0, 119.4,
111.3, 103.1, 78.9, 77.7, 73.9, 73.4, 70.5, 69.1, 38.7, 26.1 (3C), 18.3,
17.0, 14.2, −4.3, −4.9; IR (neat) 3068, 3029, 2951, 2928, 2857, 1870,
1845, 1762, 1225, 1072 cm−1; HRMS (ESI) m/z for C36H50NaO6Si
[M + Na]+ calcd 629.3269, obsd 629.3244.
Allyl {(4aR,5S,7S,8S,8aS)-7,8-Bis(benzyloxy)-5-[(tert-
butyldimethylsilyl)oxy]-1,4a-dimethyl-3,4,4a,5,6,7,8,8a-octahydro-
naphthalen-2-yl} Carbonate (30) and Allyl {(4aS,5S,7S,8S,8aS)-7,8-
Bis(benzyloxy)-5-[(tert-butyldimethylsilyl)oxy]-1,4a-dimethyl-
3,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl} Carbonate (31). Di-
benzyl ether 29 (19.6 mg, 32.3 μmol) and BHT (0.7 mg, 3.23 μmol)
were dissolved in 1,2-dichlorobenzene (6 mL), and the mixture was
heated at 250 °C in a sealed tube for 20 h. The solvent was removed
by low-pressure vacuum distillation, and the residue was purified via
flash chromatography on silica gel (20:1 hexanes/EtOAc, v/v) to
afford 30 (5.2 mg, 27%) as a colorless oil and a mixture containing
both 30 and 31 (4.9 mg, 25%; 30:31 = 1:1.7).
́
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(22) The clerodane numbering scheme will be used for both linear
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(23) Each transition state was named on the basis of the pseudoaxial
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Spectral Data for Major Isomer of 30 (trans). [α]2D3 −18.0 (c
0.255, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33−7.26 (m, 10H),
5.95 (dddd, J = 16.0, 10.4, 5.6, 5.6 Hz, 1H), 5.41−5.34 (m, 1H), 5.31−
5.25 (m, 1H), 5.18 (d, J = 11.2 Hz, 1H), 4.67−4.63 (m, 2H), 4.59 (d, J
= 11.2 Hz, 1H), 4.55 (d, J = 11.6 Hz, 1H), 4.54 (d, J = 11.2 Hz, 1H),
3.97 (ddd, J = 12.0, 8.4, 5.2 Hz, 1H), 3.58 (dd, J = 11.2, 8.4 Hz, 1H),
3.49 (dd, J = 2.4, 2.4 Hz, 1H), 2.74−2.67 (br m, 1H), 2.35−2.25 (m,
1H), 2.22−2.14 (m, 1H), 2.09−1.96 (m, 2H), 1.90 (ddd, J = 13.6,
12.0, 2.4 Hz, 1H), 1.79 (d, J = 1.2 Hz, 3H), 1.17 (dd, J = 13.2, 6.4 Hz,
1H), 0.95 (s, 3H), 0.90 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 153.4, 142.4, 139.4, 138.8, 131.7, 128.5 (2C),
128.4 (2C), 128.1 (2C), 127.7, 127.6 (2C), 127.3, 123.6, 119.0, 82.3,
80.9, 75.5, 73.2, 72.3, 68.7, 42.5, 39.9, 34.0, 32.1, 26.1 (3C), 24.5, 18.2,
17.5, 14.2, −4.3, −4.7; IR (neat) 3061, 3032, 2927, 2853, 1870, 1845,
1752, 1254, 1231, 1095 cm−1; HRMS (ESI) m/z for C36H50NaO6Si
[M + Na]+ calcd 629.3269, obsd 629.3269.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail sbutler@uttyler.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by The Ohio State University
(OSU). We thank the Ohio BioProduct Innovation Con-
sortium for support of the OSU mass spectrometric laboratory.
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