Synthesis of stereoisomers of artemisia and chrysanthemum bis(acetylenic) enol ether spiroacetals

Article abstract of DOI:10.1021/jo301810d

An 11-step synthesis is described of two diastereomeric candidates for a bis(acetylenic) enol ether spiroacetal isolated from Chrysanthemum boreale. Key steps in the synthetic route include spiroacetal lactone alkylidenation and subseqent modified Cadiota-Chodkiewicz cross-coupling to install the bis(acetylenic) enol ether functionality. From NMR comparisons, neither of the candidates, whose structures were confirmed by single-crystal X-ray diffraction, correspond to the natural product, and a proposal for the correct structure is put forward.

Full text of DOI:10.1021/jo301810d

Article
pubs.acs.org/joc
Synthesis of Stereoisomers of Artemisia and Chrysanthemum
Bis(acetylenic) Enol Ether Spiroacetals
Boshen Wu, George C. Feast,† Amber L. Thompson,† and Jeremy Robertson*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: An 11-step synthesis is described of two diastereomeric candidates
for a bis(acetylenic) enol ether spiroacetal isolated from Chrysanthemum boreale.
Key steps in the synthetic route include spiroacetal lactone alkylidenation and
subseqent modified Cadiot−Chodkiewicz cross-coupling to install the bis-
(acetylenic) enol ether functionality. From NMR comparisons, neither of the
candidates, whose structures were confirmed by single-crystal X-ray diffraction,
correspond to the natural product, and a proposal for the correct structure is put
forward.
Our interest in this general area stemmed from a report of
the isolation from Chrysanthemum boreale of diacetoxy variant
Z-cis-4 (Figure 2), referred to in this paper as CB-II.9 The Z-
INTRODUCTION
■
Plants of the genera Artemisia and Chrysanthemum (Asteraceae)
produce, among other secondary metabolites, structurally
intriguing bis(acetylenic) enol ether spiroacetals including
“homo-tonghaosu” (1),1 lactiflodiyne A (2),2 and AL-1 (3)3
(Figure 1). These three examples encapsulate the structural
Figure 1. Representative Artemisia and Chrysanthemum bis(acetylenic)
enol ether spiroacetals.
variations in the spiro[4.5] series; viz. mono-oxygenation in the
tetrahydropyranyl ring and either alkene, epoxide, chlorohydrin,
or (acylated) diol functionality in the hydrofuran ring. From a
stereochemical perspective, variations are found in the
geometry of the enol ether double bond, the relative
stereochemistry of the spiro-center with respect to functionality
in the five-membered ring and the axial/equatorial disposition
of substituents in the tetrahydropyranyl ring. Some of these
stereochemical aspects were addressed in Bohlmann’s seminal
work in this area,4,5 with notable subsequent contributions by
Marco and Hofer6 and Ye.2 To date, apart from homo-
tonghaosu, which has been synthesized a number of times, total
syntheses of natural products in this class have been achieved
only by Mukai’s research group.7,8
Figure 2. Originally proposed structures for CB-II and -III from
Chrysanthemum boreale and diacetate stereoisomers discussed in this
paper.12
stereochemistry reported for the enol ether double bond and
the cis-disposition of the acetoxy substituents in the hydrofuran
ring are particularly unusual because the only other Z-
configured enol ethers in this class (except for “CB-III” (5)
reported in the same paper) are homo-tonghaosu and its
acetoxy and isovaleryloxy derivatives in the tetrahydropyranyl
Received: August 24, 2012
Published: October 31, 2012
© 2012 American Chemical Society
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Scheme 1
ring;10 that is, natural products containing an alkene in the
hydrofuran ring and which are prone to E-/Z- isomerization. In
addition, all of the other reported hydrofuran-oxygenated
examples have a trans-relative disposition of the substituents,
formally derived by SN2-mode opening at the allylic center of
epoxides of the AL-1 type. In light of these interesting
stereochemical aspects, and because the configuration of the
spiro-center in CB-II had not been assigned, we completed a
total synthesis of a candidate diastereomer Z-cis-4a based on
DDQ-mediated oxidative activation and spirocyclization of 2-
(4-hydroxybutyl)furan derivative 7 (Scheme 1).11
acidic conditions led directly to spirocyclization and lactoniza-
tion producing a pair of spiro-diastereomers 14 that were
silylated (→ 15) in readiness for introduction of the acetylenic
side-chain.
The stereochemical relationship between the tetrahydropyr-
anyl oxygen and adjacent silyloxy substituent in these isomers
was established by NOE experiments; see the Supporting
Information. On the assumption that the spirocyclization
proceeds under thermodynamic control, hydrogen bonding
between the tetrahydropyranyl oxygen and the adjacent
hydroxyl may be sufficient to account for the favored formation
of diastereomer 14s.
From that work it became apparent that the structure
reported for CB-II required revision as, among other differences
The conversion of the carbonyl group in [m,n]-spiroacetal
lactones (m,n = 4 or 5) into an exocyclic alkene has not been
described except in two papers reporting direct methylenation
with Petasis reagent, Cp2TiMe2.18 However, such trans-
formations applied to simple lactones are reasonably well-
known, and after failing to achieve a direct Wittig olefination
with hexa-2,4-diyn-1-ylidenetriphenylphosphorane, we em-
barked upon a strategy comprising organometallic addition
followed by dehydration of the so-formed lactol to deliver the
enol ether. Application of conditions reported for propargyl
addition to a glucurono-γ-lactone derivative,19 in which the
propargyl source is 3-lithio-1-trimethylsilylpropyne,20 was
successful so long as the reaction temperature and time were
kept to a minimum. Thus, adding TMEDA to increase the rate
of addition, and quenching the reaction at −78 °C within 5−10
min, led to clean product formation (45% isolated) with full
recovery of unreacted lactone (55%) which was then recycled.
Significantly longer reaction times led to unraveling of the
spiroacetal and hydride transfer to deliver monocyclic lactol 17
(with unassigned stereochemistry) as outlined in Scheme 3.
Dehydration of the diastereomeric mixture of lactols was easily
achieved via the mesylate and the two spiro-epimers 16s and
16a were obtained efficiently. These isomers were separated
and key NOE correlations allowed assignment of both the
relative stereochemistry at the spiro-center and the Z-
stereochemistry of the enol ether double bond in each
compound (for details, see the Supporting Information).
Interestingly, the major isomer at this stage possessed an
anti-relationship between the tetrahydropyranyl oxygen and
adjacent silyloxy group, presumably reflecting the ability of the
intermediate lactol to attain a more stable anti-,anti-disposition
of oxygen functionality by reversible ring-opening.
1
between the H NMR data, the H-6/H-7 vicinal coupling
constant (numbering, Figure 2) of our synthetic compound Z-
cis-4a (3J ∼ 4.5 Hz) did not match the reported value (3J = 7.5
Hz). Examination of molecular models showed that,
irrespective of the relative spiro-center configuration, the
dihedral angle between these coupling protons could not vary
beyond about 40°. Combined with an expectation that the
acetoxy substituents would favor an approximate gauche rather
than eclipsed relationship, it is unlikely that a cis-diacetate of
this type could give rise to a significantly larger coupling
constant than that observed for diacetate Z-cis-4a.13
This paper describes syntheses of the two spiro-diaster-
eomers of CB-II in the trans-diacetate series (Z-trans-4s and Z-
trans-4a, Figure 2), shows that neither is a correct match for
CB-II, and proposes a structure for both CB-II and, by
implication, CB-III.
RESULTS AND DISCUSSION
Initially, we expended considerable effort in attempting to
convert cis-diol intermediates such as 8−10 (Figure 3) to the
■
Figure 3. cis-Diol substrates investigated as potential precursors to
trans-diols.
trans-diol/diacetate motif,14 all to no avail, and we switched to a
route in which the correct diol stereochemistry was established
prior to spirocyclization. For this, furan derivative 1115
(Scheme 2) was oxidized efficiently according to Salomon’s
procedure, and the first-formed Z-ketoacid was isomerized as
described16 to the E-isomer 12. We were unable to effect
asymmetric dihydroxylation of this electron-deficient alkene
and only Sharpless’ conditions with citric acid17 were effective
in generating the racemic diol 13. Silyl deprotection under
Each isomer was then subjected to a four-step sequence to
complete syntheses of the CB-II candidate isomers Z-trans-4s
and Z-trans-4a (Scheme 4). Selective deprotection21 of the
alkynylsilane set the scene for modified22 Cadiot−Chodkiewicz
cross coupling with 1-iodopropyne,23 paralleling the end stages
of Mukai’s route to AL-2 and related molecules.7 Final
deprotection and double acetylation completed the sequences
without epimerization at the spiro-center.
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Scheme 2
trans-4s, the CH(OAc)−CH(OAc) dihedral angle is 164° in a
conformation that accommodates an antiperiplanar arrange-
ment of the (C-6)−OAc and hydrofuranyl-O−(C-5) bonds, as
well as a potential [(C-6)−H]σ−[tetrahydropyranyl-O−(C-
5)]σ* interaction. On the other hand, in Z-trans-4a, the overall
conformation is the same as that in Z-trans-4s but the
hydrofuranyl H and AcO substituents are swapped resulting
in a corresponding dihedral angle of 91°; here, the (C-6)−OAc
bond is antiperiplanar with respect to both the (C-7)−OAc and
tetrahydropyranyl-O−(C-5) bonds, and a [(C-6)−H]σ−
[hydrofuranyl-O−(C-5)]σ* interaction is possible. In these
two compounds and diacetate Z-cis-4a, for which crystal data
are available, the H-6/H-7 coupling constant obtained in
solution (CDCl3 or CCl4) and that calculated using the
dihedral angle (ϕ), measured in the solid state, fits the Karplus
equation J(ϕ) = 7.0 cos2ϕ − 0.10 cosϕ + 1.0.
Scheme 3
NMR Data Comparison with CB-II. Table 1 lists 1H NMR
data (coupling constants rounded to the nearest 0.5 Hz) for
CB-II,9 our three synthetic diacetates (Z-trans-4s, Z-trans-4a,
and Z-cis-4a11), and E-trans-4s (Figure 2) isolated6 by Marco
from Chrysanthemum lavandulifolium and synthesized7 by
Mukai.
Scheme 4
With these data viewed together certain trends emerge. (1)
For the Z-compounds, the H-1 resonances are distinctly split
into a td for the axial proton and a dd or d for the equatorial
proton, whereas in Marco’s compound E-trans-4s and CB-II
both H-1 protons appear together at ∼3.7−3.8 ppm; (2) the H-
6/H-7 coupling constant is not, in itself, diagnostic of the
relative stereochemistry in the hydrofuran ring; however, it is
notable that CB-II and both Z- and E-trans-4s all show J = 7.5
Hz; (3) of the two CH(OAc) protons, the chemical shift of H-7
is the more sensitive to stereochemistry, being notably shifted
upfield in Z-trans-4a in which it is 1,3-anti-disposed to the
tetrahydropyranyl oxygen (it is correspondingly syn in Z-trans-
4s, Z-cis-4a and E-trans-4s); (4) the chemical shift of the
olefinic proton H-9 in the Z- isomers, in which this proton is
trans-disposed to the hydrofuran oxygen, is shifted upfield by
between ∼0.2−0.5 ppm compared with that in CB-II and E-
trans-4s; (5) the resonances for H-6, H-7, and H-9 show a
consistent solvent dependence, appearing ∼0.02−0.13 ppm
upfield in CCl4 relative to the shifts in CDCl3.
Crystals suitable for single-crystal X-ray diffraction experi-
ments24 were grown of both isomers, thereby confirming the
stereochemistry predicted on the basis of the NOE studies in
intermediates 16s and 16a. The crystal structures explain an
unexpected feature of the NMR data for these diacetates; viz.
the critical H-6/H-7 coupling constant in isomer Z-trans-4s is
7.5 Hz, but in isomer Z-trans-4a this is reduced to 1.0 Hz. In Z-
On balance, these NMR trends suggest a close match
between the data for CB-II and Marco’s compound E-trans-4s,
although the different solvents used (CCl4 and CDCl3) make a
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1
Table 1. Comparison H NMR Data (in CCl4 unless Stated Otherwise)
proton
H-1
CB-II9
Z-trans-4s
Z-trans-4a
Z-cis-4a11
E-trans-4s6
a
3.73 (2H, t, J = 5.0 Hz)
3.80 (br d, J = 11.0 Hz)
3.77 (br d, J = 11.5 Hz)
3.76 (br d, J = 10.5 Hz)
3.82 (2H, m)
a
,
b
3.98 (td, J = 11.0, 3.0 Hz) 3.99 (td, J = 11.5, 3.5 Hz) 3.97 (td, J = 10.4, 4.0 Hz) 3.83 (2H, m)
a
a
a
3.83 (dd, J = 12.0, 4.5 Hz) 3.78 (dd, J = 11.5, 4.5 Hz) 3.67−3.79 (m)
a
a
a
3.96 (td, J = 12.0, 3.0 Hz) 3.98 (td, J = 11.5, 3.5 Hz) 3.83−3.97(m)
a
a
a
H-(2−4)
1.50−1.90 (6H, m)
4.99 (d, J = 7.5 Hz)
1.60−1.89 (6H, m)
1.50−1.86 (6H, m)
1.53−1.87 (6H, m)
1.52−2.00 (6H, m)
1.50−1.82 (6H, m)
1.55−2.05 (6H, m)
1.50−1.60 (2H, m)
1.60−1.80 (4H, m)
1.60−1.80 (6H, m)
a
a
a
,b
a
H-6
H-7
H-9
H-14
OAc
5.00 (d, J = 7.5 Hz)
5.13 (d, J = 7.5 Hz)
4.99 (s)
5.08 (d, J = 5.0 Hz)
5.20 (d, J = 5.0 Hz)
5.16 (d, J = 7.5 Hz)
a
a
a
a,b
5.11 (d, J = 1.5 Hz)
5.14−5.17 (2H, m)
a
6.07 (dd, J = 7.5, 2.0 Hz) 5.85 (d, J = 7.5 Hz)
5.98 (dd, J = 7.5, 2.0 Hz)
5.40 (s)
5.93 (dd, J = 5.0, 2.0 Hz
6.25 (dd, J = 7.5, 2.0 Hz)
a
a
a
a
a
,b
5.52 (t, J = 1.5 Hz)
6.01 (dd, J = 5.0, 2.0 Hz) 6.25 (dd, J = 8.0, 1.0 Hz)
a
5.03 (dq, J = 2.0, 1.0 Hz) 4.61 (s)
4.79 (s)
4.52 (s)
5.14 (dq, J = 2.0, 1.0 Hz)
a
a
a,b
4.70 (dq, J = 2.0, 1.0 Hz)
4.88 (∼quin, J = 1.25 Hz) 4.59−4.63 (m)
see H-6
a
1.97 (3H, d, J = 1.0 Hz)
2.02 (3H, s)
2.03 (3H, s)
1.97 (3H, s)
1.96 (3H, d, J = 1.0 Hz)
a
a
a
a,
b
2.00 (3H, d, J = 1.0 Hz)
2.00 (3H, d, J = 1.0 Hz)
2.00 (3H, d, J = 1.0 Hz)
1.96 (3H, s)
a
a
a
2.08 (3H, s)
2.10 (3H, s)
2.08 (3H, s)
2.12 (3H, s)
2.10 (3H, s)
2.12 (3H, s)
2.04 (3H, s)
2.09 (3H, s)
2.15 (6H, s)
2.15 (3H, s)
2.16 (3H, s)
,
,
b
b
a
a
a
2.10 (3H, s)
2.11 (3H, s)
2.07 (3H, s)
a
a
a
2.15 (3H, s)
2.12 (3H, s)
2.10 (3H, s)
a
b
In CDCl3. From ref 7.
firm conclusion impossible.25 If CB-II is, in fact, E-trans-4s then
the glycol 6 “CB-IV” (Figure 2) obtained9 by hydrolysis of CB-
II (and CB-III) should be reassigned to E-trans-6s, which was
reported recently from Ajania przewalskii (Asteraceae).26 In
fact, the reported NMR data differ (Table 2), and on this basis
corresponding E-enol ethers, but this remains an attractive
possibility.28
EXPERIMENTAL SECTION
■
General Methods. Infrared spectra were recorded using neat
samples on an FT-IR spectrometer as thin films on NaCl plates or
directly on a diamond ATR module; peaks are reported in
wavenumbers (cm−1) and their intensities as broad (br), strong (s),
medium (m), and weak (w) as appropriate. Proton (1H) and carbon
(13C) NMR spectra were recorded at the frequencies stated and in the
specified solvents. Chemical shifts (δ) are reported in parts per million
downfield of tetramethylsilane with respect to standard reference
peaks. Assignments in NMR listings are made on the basis of chemical
shift and coupling constant data in combination with COSY, HMQC,
HSQC, HMBC, NOE, and NOESY data as necessary. Coupling
constants (J) are quoted to the nearest 0.5 Hz. High resolution mass
spectra (HRMS) were obtained using electrospray ionization (ESI)
and a time-of-flight (TOF) analyzer.
1
Table 2. Selected H NMR Data (in CDCl3)
proton
CB-IV9
E-trans-6s26
H-6
H-7
H-9
H-14
3.80 (d, J = 6.5 Hz)
3.95 (br s)
4.59 (br s)
5.17 (br s)
1.96 (3H, s)
4.84 (dd, J = 6.5, 2.0 Hz)
5.08 (dq, J = 2.0, 1.0 Hz)
1.96 (3H, d, J = 1.0 Hz)
and in view of the originally proposed structure for CB-IV, Zhu
reasonably concluded that these glycols are different.26
However, we have found that glycols in this class show
5-[4-(tert-Butyldimethylsilyloxy)butyl]-5-hydroxyfuran-
2(5H)-one (S1).16 To a stirred solution of [4-tert-butyldimethylsilyl-
oxy)butyl]furan 11 (2.00 g, 7.86 mmol) in tert-butyl alcohol and water
(5:1, 40 mL) were added NaH2PO4·H2O (1.74 g, 12.6 mmol) and
NaClO2 (2.27 g, 25.1 mmol). The resulting mixture was stirred at rt
for 4 h and then diluted with water (150 mL) and extracted with
chloroform (3 × 200 mL). The combined organic layers were washed
with brine (200 mL), dried (MgSO4), and concentrated. Flash
chromatography (petroleum ether/ether/acetic acid, 80:20:1) fur-
nished the title compound S1 as a pale yellow oil (2.22 g, 98%): Rf
0.37 (petroleum ether/ethyl acetate, 80:20); IR (neat) 3385br, 2955s,
2931s, 2859s, 1770s, 1256m, 1102s, 835s, 776m; 1H NMR (400 MHz,
CDCl3) 0.04 (6H, s, Si(CH3)2), 0.88 (9H, s, C(CH3)3), 1.42−1.71
(4H, m, H-2′, H-3′), 1.90−2.06 (2H, m, H-1′), 3.62 (2H, t, J = 6.0 Hz,
H-4′), 4.20−4.30 (1H, br, OH), 6.09 (1H, d, J = 5.5 Hz, H-3), 7.21
(1H, d, J = 5.5 Hz, H-4); 13C NMR (100 MHz, CDCl3) −5.3
(Si(CH3)2), 18.3 (C(CH3)3), 20.2 (C-2′), 25.9 (C(CH3)3), 31.8 (C-
3′), 36.9 (C-1′), 62.9 (C-4′), 108.0 (C-5), 123.1 (C-3), 154.2 (C-4),
1
concentration-dependent H NMR shifts, particularly for the
H-6, H-7 and H-9 resonances, and these data, therefore, offer
no illumination of the situation.25
CONCLUSION
■
This paper has described the synthesis of two further candidate
structures for CB-II, a bis(acetylenic) spiroacetal isolated from
Chrysanthemum boreale. These syntheses are short, at 11 steps
from 11, and efficient (23% for Z-trans-4s, 26% for Z-trans-4a
overall). Neither of these candidates provides a match for the
data published for CB-II, and unambiguous confirmation of the
identity of CB-II must await resynthesis27 of Marco’s
compound E-trans-4s and, if necessary, the remaining
diastereomers. So far, we have been unable to isomerize Z-
trans-4s and Z-trans-4a or precursors 16s and 16a to the
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170.3 (C-2); HRMS (ESI+) calcd for C14H26NaO4Si+ (M + Na+)
309.1493, found 309.1498.
0.42 (petroleum ether/ether, 95:5); IR (neat) 3418br, 2956s, 2789s,
1802s, 1651w, 1458m, 1239m, 1171s, 1103s; H NMR (500 MHz,
1
(E)-8-[(tert-Butyldimethylsilyl)oxy]-4-oxooct-2-enoic Acid
(12).16 To a stirred solution of butenolide S1 (4.50 g, 15.7 mmol)
in a mixture of THF, water, and acetone (5:4:1, 3 mL) was added
pyridine (12.6 μL, 0.157 mmol) at rt. The resulting mixture was stirred
at rt for 2 h, and then the solvent was removed. Flash chromatography
(petroleum ether/ether/acetic acid, 80:20:1) furnished the title
compound 12 as a colorless oil (4.27 g, 95%): Rf 0.27 (petroleum
ether/ether/acetic acid, 80:20:1); IR (neat) 3197br, 2955s, 2931s,
2858s, 1699s, 1256s, 1103s, 837s, 777m; 1H NMR (500 MHz, CDCl3)
0.05 (6H, s, Si(CH3)2), 0.89 (9H, s, C(CH3)3), 1.52−1.58 (2H, m, H-
7), 1.71 (2H, app. quin, J = 7.5 Hz, H-6), 2.69 (2H, t, J = 7.5 Hz, H-5),
3.63 (2H, t, J = 6.0 Hz, H-8), 6.67 (1H, d, J = 16.0 Hz, H-3), 7.13 (1H,
d, J = 16.0 Hz, H-2); 13C NMR (125 MHz, CDCl3) −5.3 (Si(CH3)2),
18.3 (C(CH3)3), 20.2 (C-6), 25.9 (C(CH3)3), 32.0 (C-7), 41.4 (C-5),
62.7 (C-8), 129.6 (C-2), 141.0 (C-3), 170.0 (C-1), 199.4 (C-4);
HRMS (ESI+) calcd for C14H27O4Si+ (M + H+) 287.1673, found
287.1676.
CDCl3) 0.65−0.77 (12H, m, 2 × Si(CH2CH3)3), 0.96−1.04 (18H, m,
2 × Si(CH2CH3)3), 1.57−1.93 (6H, m, H-8, H-9, H-10), 3.85−3.92
(3H, m, H-4, H-7), 4.56 (1H, d, J = 8.5 Hz, H-3); 13C NMR (125
MHz, CDCl3) 4.9 and 5.0 (2 × Si(CH2CH3)3), 6.7 (2 ×
Si(CH2CH3)3), 18.7 (C-9), 24.3 (C-8), 30.8 (C-10), 63.4 (C-7),
73.7 (C-3), 80.2 (C-4), 102.9 (C-5), 173.1 (C-2); HRMS (ESI+) calcd
+
for C20H40NaO5Si2 (M + Na+) 439.2306, found 439.2303. Data for
15a: Rf 0.60 (petroleum ether/ether, 95:5); IR (neat) 3406br, 2955s,
1
2878s, 1798s, 1459m, 1416m, 1238m, 1166s; H NMR (500 MHz,
CDCl3) 0.63−0.76 (12H, m, 2 × Si(CH2CH3)3), 0.96−1.02 (18H, m,
2 × Si(CH2CH3)3), 1.51−2.00 (6H, m, H-8, H-9, H-10), 3.82 (1H, dd,
J = 11.5, 4.5 Hz, H-7eq), 3.98 (1H, td, J = 11.5, 3.0 Hz, H-7ax), 4.04
(1H, d, J = 8.5 Hz, H-4), 4.23 (1H, d, J = 8.5 Hz, H-3); 13C NMR
(125 MHz, CDCl3) 4.7 and 4.8 (2 × Si(CH2CH3)3), 6.6 (2 ×
Si(CH2CH3)3), 18.0 (C-9), 24.5 (C-8), 28.7 (C-10), 64.1 (C-7), 75.3
(C-3), 81.6 (C-4), 105.7 (C-5), 171.5 (C-2); HRMS (ESI+) calcd for
+
C20H40NaO5Si2 (M + Na+) 439.2306, found 439.2305.
(2R*,3R*)-8-[(tert-Butyldimethylsilyl)oxy]-2,3-dihydroxy-4-
oxooctanoic Acid (13). To a stirred solution of acid 12 (670 mg,
2.34 mmol) and citric acid (338 mg, 1.76 mmol) in a mixture of tert-
butyl alcohol and water (1:1, 5 mL) was added K2OsO4·2H2O (43 mg,
0.117 mmol) followed by NMO solution (50% aq solution, 580 μL,
2.81 mmol). The resulting mixture was stirred for 100 min and then
concentrated. Flash chromatography (methanol/dichloromethane/
acetic acid, 10:90:3) furnished the title compound 13 as a pale brown
oil (673 mg, 90%) which was used without purification: Rf 0.29
(petroleum ether/ether/acetic acid, 80:20:1); IR (neat) 3420br, 2954s,
(3R*,4R*)-3,4-Bis[(triethylsilyl)oxy]-2-[3-(trimethylsilyl)prop-
2-yn-1-yl]-1,6-dioxaspiro[4.5]decan-2-ol (S2). To a stirred
solution of 1-(trimethylsilyl)propyne (41 μL, 0.277 mmol) and
TMEDA (42 μL, 0.280 mmol) in anhydrous, degassed THF (1.1 mL)
at −78 °C was added BuLi (1.6 M in hexanes, 173 μL, 0.277 mmol).
After the solution was stirred for 1 h, a solution of lactone 15s (96 mg,
0.230 mmol) in anhydrous, degassed THF (5.8 mL) was added. The
mixture was stirred at −78 °C for 10 min, and then acetic acid (0.3
mL) was added to quench the reaction. Ether (15 mL) and water (15
mL) were added, and the layers were separated. The aqueous layer was
extracted with ether (3 × 15 mL), and the combined organic layers
were dried (MgSO4) then concentrated. Flash chromatography
(petroleum ether/ether, 80:20) furnished the title compound S2 as a
mixture of four diastereomers (dr not determined) and as a colorless
oil (54 mg, 44%, 98% brsm): Rf 0.58 (petroleum ether/ether, 70:30);
IR (neat) 3418br, 2957s, 2915s, 2879m, 2181w, 1461m, 1249m,
1
2931s, 2887m, 2859m, 1720s, 1255s, 1101s, 837s, 813s; H NMR
(500 MHz, CDCl3) 0.05 (6H, s, Si(CH3)2), 0.89 (9H, s, C(CH3)3),
1.50−1.59 (2H, m, H-6), 1.66−1.76 (2H, m, H-7), 2.55−2.73 (2H, m,
H-5), 3.60−3.67 (2H, m, H-8), 4.53−4.64 (1H, app. s, H-2), 4.64−
4.74 (1H, app. s, H-3); 13C NMR (125 MHz, CDCl3) −5.4
(Si(CH3)2), 18.3 (C(CH3)3), 19.9 (C-7), 25.9 (C(CH3)3), 31.9 (C-
6), 37.7 (C-5), 62.8 (C-8), 71.4 (br, C-3), 77.3 (br, C-2), 175.4 (br, C-
1), 208.1 (br, C-4); HRMS (ESI+) calcd for C14H28NaO6Si+ (M +
Na+) 343.1547, found 343.1540.
1
1124s, 1091s, 978m, 844m; H NMR (500 MHz, CDCl3) 0.14−0.17
(9H, m, Si(CH3)3), 0.64−0.74 (12H, m, 2 × Si(CH2CH3)3), 0.96−
1.03 (18H, m, 2 × Si(CH2CH3)3), 1.46−1.95 (6H, m, H-8, H-9, H-
10), 2.62−2.82 (2H, m, H-1′), 3.60−4.31 (5H, m, H-3, H-4, H-7,
OH); 13C NMR (125 MHz, CDCl3) −0.08, 0.02, and 0.04
(Si(CH3)3), 4.92, 4.95, 5.00, and 5.15 (2 × Si(CH2CH3)3), 6.75,
6.80, 6.82, and 6.90 (2 × Si(CH2CH3)3), 18.9, 19.2, and 19.3 (C-9),
24.9 (2 peaks), 25.1 and 25.2 (C-8), 28.3 and 31.0 (C-1′), 29.6 (2
peaks) and 29.7 (C-10), 61.9, 62.0 (2 peaks) and 62.2 (C-7), 78.4,
78.7, 82.7, and 83.0 (C-3), 82.5 (2 peaks, C-4), 86.0, 86.2, and 86.4
(C-3′), 99.9, 100.4, 102.1, 102.4, 102.6, 102.7 (2 peaks), 102.9, 104.2,
104.3, 105.5, and 105.7 (C-2, C-5, C-2′); HRMS (ESI+) calcd for
(3R*,4R*,5S*)-3,4-Dihydroxy-1,6-dioxaspiro[4.5]decan-2-
one (14s) and (3R*,4R*,5R*)-3,4-Dihydroxy-1,6-dioxaspiro-
[4.5]decan-2-one (14a). To a stirred solution of crude dihydroxy
acid 13 (200 mg, 0.624 mmol) in a mixture of THF (6 mL) and water
(11.5 μL, 0.638 mmol) was added p-toluenesulfonic acid monohydrate
(60 mg, 0.315 mmol) at rt; some precipitation occurred. The resulting
suspension was stirred at rt for 3 h and then concentrated. Flash
chromatography (dichloromethane/ethyl acetate/acetic acid, 66:33:1)
furnished the title compound 14 as a mixture of two diastereomers 14s
and 14a (6:1, respectively) and as a white solid (94 mg, 83%): Rf 0.44
(methanol/dichloromethane/acetic acid, 10:90:3); IR (neat) 3406br,
2951m, 1784s, 1644w, 1234m, 1148m, 1097s, 935m, 883m; 1H NMR
(500 MHz, d6-acetone) 1.58−2.03 (6H, m, H-8, H-9, H-10), 3.81−
3.85 (3H, m, H-4, H-7), 4.43 (1H, dd, J = 9.0, 5.0 Hz, H-3), 4.48 (1H,
d, J = 9.0 Hz, (C-4)OH), 5.12 (1H, d, J = 5.0 Hz, (C-3)OH); 13C
NMR (125 MHz, d6-acetone) data for 14s 19.5 (C-9), 25.1 (C-8),
31.0 (C-10), 63.8 (C-7), 73.2 (C-3), 79.9 (C-4), 103.4 (C-5), 174.1
(C-2); data for 14a 18.9 (C-9), 25.4 (C-8), 29.1 (C-10), 64.5 (C-7),
74.7 (C-3), 81.1 (C-4), 106.7 (C-5), 172.8 (C-2); HRMS (ESI+) calcd
+
C26H52NaO5Si3 (M + Na+) 551.3015, found 551.3016.
(3R*,4R*,5S*,Z)-3,4-Bis[(triethylsilyl)oxy]-2-[3-(trimethyl-
silyl)prop-2-yn-1-ylidene]-1,6-dioxaspiro[4.5]decane (16s) and
(3R*,4R*,5R*,Z)-3,4-Bis[(triethylsilyl)oxy]-2-[3-(trimethylsilyl)-
prop-2-yn-1-ylidene]-1,6-dioxaspiro[4.5]decane (16a). To a
stirred solution of lactol S2 (a mixture of four diastereomers, 91 mg,
0.172 mmol) in dichloromethane (5 mL) at 0 °C was added
triethylamine (192 μL, 1.38 mmol) and then methanesulfonyl chloride
(53.4 μL, 0.688 mmol). The resulting mixture was stirred at rt for 100
min, and then ether (5 mL) and NaHCO3 solution (satd aq, 5 mL)
were added. The aqueous layer was extracted with ether (3 × 5 mL),
and the combined organic layers were dried (MgSO4) and
concentrated. Flash chromatography (petroleum ether/ether, 95:5)
furnished the title compounds (16s, 14 mg, 16%) and (16a, 56 mg,
64%) both as colorless oils. Data for 16s: Rf 0.62 (petroleum ether/
ether, 95:5); IR (neat) 3406br, 2956s, 2879s, 2136m, 1666m, 1458m,
+
for C8H12NaO5 (M + Na+) 211.0577, found 211.0577.
(3R*,4R*,5S*)-3,4-Bis[(triethylsilyl)oxy]-1,6-dioxaspiro[4.5]-
decan-2-one (15s) and (3R*,4R*,5R*)-3,4-Bis[(triethylsilyl)oxy]-
1,6-dioxaspiro[4.5]decan-2-one (15a). To a stirred solution of diol
14 (a mixture of diastereomers 14s and 14a, 51 mg, 0.271 mmol) in
anhydrous DMF (0.3 mL) at 0 °C was added imidazole (111 mg, 1.63
mmol) followed by chlorotriethylsilane (137 μL, 0.814 mmol). The
resulting mixture was warmed to rt and stirred for 3 h, and then water
(5 mL) and ether (5 mL) were added. The aqueous layer was
extracted with ether (3 × 5 mL), and the combined organic layers
were dried (MgSO4) and concentrated. Flash chromatography
(petroleum ether/ether, 97:3) furnished the title compounds (15s, 96
mg, 85%) and (15a, 18 mg, 16%) as colorless oils. Data for 15s: Rf
1
1416m, 1247m, 1155m, 1128m, 972m, 848m, 743m; H NMR (500
MHz, CDCl3) 0.20 (9H, s, Si(CH3)3), 0.63−0.73 (12H, m, 2 ×
Si(CH2CH3)3), 0.95−1.03 (18H, m, 2 × Si(CH2CH3)3), 1.55−2.02
(6H, m, H-8, H-9, H-10), 3.72 (1H, d, J = 8.0 Hz, H-4), 3.81 (1H, dd,
J = 11.5, 4.0 Hz, H-7eq), 3.95 (1H, td, J = 11.5, 3.5 Hz, H-7ax), 4.64
(1H, d, J = 2.0 Hz, H-1′), 4.73 (1H, dd, J = 8.0, 2.0 Hz, H-3); 13C
NMR (125 MHz, CDCl3) 0.16 (Si(CH3)3), 5.1 and 5.2 (2 ×
10627
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The Journal of Organic Chemistry
Article
Si(CH2CH3)3), 6.8 and 6.9 (2 × Si(CH2CH3)3), 19.0 (C-9), 24.7 (C-
8), 31.2 (C-10), 62.7 (C-7), 76.1 (C-3), 79.0 (C-1′), 81.3 (C-4), 97.4
(C-3′), 100.2 (C-2′), 103.3 (C-5), 166.5 (C-2); HRMS (ESI+) calcd
the combined organic layers were dried (MgSO4) and then
concentrated carefully. The volatile iodoalkyne (90 mg, 32%), an oil,
was used in the coupling step (with 18s) without purification. For
coupling with 18a, the iodoalkyne was obtained in 31% yield (346 mg)
from 1-(trimethylsilyl)propyne (1.0 mL, 6.75 mmol), N-iodosuccini-
mide (1.96 g, 8.71 mmol), and AgNO3 (1.36 g, 8.00 mmol) in acetone
(48 mL). Data as reported.
+
for C26H50NaO4Si3 (M + Na+) 533.2909, found 533.2910. Data for
16a: Rf 0.79 (petroleum ether/ether, 95:5); IR (neat) 3385br, 2957s,
2879m, 2135w, 1665w, 1457m, 1247w, 1155m, 1116s, 1077m; 1H
NMR (500 MHz, CDCl3) 0.20 (9H, s, Si(CH3)3), 0.61−0.69 (12H, m,
2 × Si(CH2CH3)3), 0.94−1.00 (18H, m, 2 × Si(CH2CH3)3), 1.50−
1.97 (6H, m, H-8, H-9, H-10), 3.77 (1H, dd, J = 11.5, 4.5 Hz, H-7eq),
3.86 (1H, d, J = 7.5 Hz, H-4), 4.03 (1H, td, J = 11.5, 3.0 Hz, H-7ax),
4.38 (1H, dd, J = 7.5, 1.5 Hz, H-3), 4.61 (1H, d, J = 1.5 Hz, H-1′); 13C
NMR (125 MHz, CDCl3) 0.17 (Si(CH3)3), 4.9 and 5.0 (2 ×
Si(CH2CH3)3), 6.7 and 6.8 (2 × Si(CH2CH3)3), 18.3 (C-9), 24.9 (C-
8), 28.8 (C-10), 63.5 (C-7), 76.9 (C-3), 78.9 (C-1′), 82.3 (C-4), 97.2
(C-3′), 100.4 (C-2′), 107.1 (C-5), 166.2 (C-2); HRMS (ESI+) calcd
(3R*,4R*,5S*,Z)-3,4-Bis[(triethylsilyl)oxy]-2-(hexa-2,4-diyn-1-
ylidene)-1,6-dioxaspiro[4.5]decane (S4s). To a stirred solution of
alkyne 18s (22 mg, 50.1 μmol) and freshly prepared iodoalkyne S3
(90 mg, 0.542 mmol) in degassed pyrrolidine (2.5 mL) at rt was added
CuI (3.0 mg, 15.8 μmol). The solution became green immediately.
After being stirred for 1.5 h, the reaction mixture became yellow and
was diluted with water (10 mL). The mixture was extracted with ether
(3 × 15 mL), and the combined organic extracts were washed with
water (15 mL) and brine (15 mL), dried (MgSO4), and concentrated.
Flash chromatography (petroleum ether/ether, 97:3) furnished the
title compound S4s as a pale yellow oil (17 mg, 70%): Rf 0.50
(petroleum ether/ether, 95:5); IR (neat) 2955s, 2916s, 2878s, 2144w,
1661m, 1458m, 1238m, 1200m, 1155s, 1126s, 1112s, 970m, 946m; 1H
NMR (500 MHz, CDCl3) 0.63−0.73 (12H, m, 2 × Si(CH2CH3)3),
0.95−1.03 (18H, m, 2 × Si(CH2CH3)3), 1.51−1.85 (6H, m, H-8, H-9,
H-10), 1.99 (3H, d, J = 1.0 Hz, H-6′), 3.70 (1H, d, J = 8.0 Hz, H-4),
3.80 (1H, dd, J = 11.5, 4.5 Hz, H-7eq), 3.92 (1H, td, J = 11.5, 3.5 Hz,
H-7ax), 4.60 (1H, dq, J = 2.0, 1.0 Hz, H-1′), 4.73 (1H, dd, J = 8.0, 2.0
Hz, H-3); 13C NMR (125 MHz, CDCl3) 4.7 (C-6′), 5.1 and 5.3 (2 ×
Si(CH2CH3)3), 6.8 and 6.9 (2 × Si(CH2CH3)3), 18.9 (C-9), 24.5 (C-
8), 31.1 (C-10), 62.7 (C-7), 65.1 (C-4′), 69.9 (C-2′), 76.3 (C-3), 77.2
(C-3′), 77.9 (C-1′), 79.3 (C-5′), 81.2 (C-4), 103.7 (C-5), 168.2 (C-2);
+
for C26H50NaO4Si3 (M + Na+) 533.2909, found 533.2907.
(3R*,4R*,5S*,Z)-3,4-Bis[(triethylsilyl)oxy]-2-(prop-2-yn-1-yli-
dene)-1,6-dioxaspiro[4.5]decane (18s). To a stirred solution of
spiroacetal 16s (66 mg, 0.129 mmol) in absolute ethanol (2.2 mL) at 0
°C was added a solution of AgNO3 (88 mg, 0.518 mmol) in water (2.2
mL). A white suspension formed immediately. The mixture was stirred
for 1 h in the dark and was then diluted with dichloromethane (20
mL) and transferred into a rapidly stirred solution of KCN (202 mg,
3.10 mmol) in water (44 mL). After 2 min, the mixture was extracted
with dichloromethane (3 × 20 mL), and the combined organic extracts
were dried (MgSO4) and concentrated. Flash chromatography
(petroleum ether/ether, 97:3) furnished the title compound 18s as a
colorless oil (44 mg, 78%): Rf 0.76 (petroleum ether/ether, 95:5); IR
(neat) 3316m, 2956s, 2878s, 2104w, 1670m, 1459m, 1238m, 1201m,
1155m, 1127m, 1048m; 1H NMR (500 MHz, CDCl3) 0.63−0.74
(12H, m, 2 × Si(CH2CH3)3), 0.96−1.04 (18H, m, 2 × Si(CH2CH3)3),
1.54−2.06 (6H, m, H-8, H-9, H-10), 3.06 (1H, d, J = 1.5 Hz, H-3′),
3.72 (1H, d, J = 8.0 Hz, H-4), 3.81 (1H, dd, J = 11.5, 4.5 Hz, H-7eq),
3.94 (1H, td, J = 11.5, 3.0 Hz, H-7ax), 4.59 (1H, t, J = 1.5 Hz, H-1′),
4.74 (1H, dd, J = 8.0, 1.5 Hz, H-3); 13C NMR (125 MHz, CDCl3) 5.1
and 5.3 (2 × Si(CH2CH3)3), 6.8 and 6.9 (2 × Si(CH2CH3)3), 19.0 (C-
9), 24.6 (C-8), 31.1 (C-10), 62.7 (C-7), 76.1 (C-3), 77.8 (C-1′), 78.8
(C-2′), 80.2 (C-3′), 81.2 (C-4), 103.5 (C-5), 166.6 (C-2); HRMS
+
HRMS (ESI+) calcd for C26H44NaO4Si2 (M + Na+) 499.2670, found
499.2660.
(3R*,4R*,5R*,Z)-3,4-Bis[(triethylsilyl)oxy]-2-(hexa-2,4-diyn-
1-ylidene)-1,6-dioxaspiro[4.5]decane (S4a). To a stirred solution
of alkyne 18s (88 mg, 0.201 mmol) and freshly prepared iodoalkyne
S3 (346 mg, 2.08 mmol) in degassed pyrrolidine (10.1 mL) at rt was
added CuI (11.5 mg, 60.4 μmol). The solution turned green
immediately. After being stirred for 1.5 h, the reaction mixture
became yellow and was diluted with water (50 mL). The mixture was
extracted with ether (3 × 50 mL), and the combined organic extracts
were washed with water (50 mL), brine (50 mL), then dried (MgSO4)
and concentrated. Flash chromatography (petroleum ether/ether,
97:3) furnished the title compound S4a as a pale yellow oil (68 mg,
71%): Rf 0.61 (petroleum ether/ether, 95:5); IR (neat) 2956s, 2917s,
2878s, 2144w, 1660m, 1458m, 1240m, 1155s, 1114s, 973m, 946m; 1H
NMR (500 MHz, CDCl3) 0.62−0.69 (12H, m, 2 × Si(CH2CH3)3),
0.95−1.00 (18H, m, 2 × Si(CH2CH3)3), 1.51−1.95 (6H, m, H-8, H-9,
H-10), 1.99 (3H, d, J = 1.0 Hz, H-6′), 3.76 (1H, dd, J = 11.5, 4.5 Hz,
H-7eq), 3.85 (1H, d, J = 7.0 Hz, H-4), 4.04 (1H, td, J = 11.5, 3.0 Hz, H-
7ax), 4.38 (1H, dd, J = 7.0, 2.0 Hz, H-3), 4.57 (1H, dq, J = 2.0, 1.0 Hz,
H-1′); 13C NMR (125 MHz, CDCl3) 4.7 (C-6′), 4.8 and 5.0 (2 ×
Si(CH2CH3)3), 6.7 and 6.8 (2 × Si(CH2CH3)3), 18.2 (C-9), 24.8 (C-
8), 28.7 (C-10), 63.5 (C-7), 65.2 (C-4′), 70.0 (C-2′), 77.1 (C-3′), 77.2
(C-3), 77.8 (C-1′), 79.1 (C-5′), 82.1 (C-4), 107.7 (C-5), 167.9 (C-2);
HRMS (ESI+): calcd for C26H44NaO4Si2+ (M + Na+) 499.2670, found
499.2662.
+
(ESI+) calcd for C23H42NaO4Si2 (M + Na+) 461.2514, found
461.2511.
(3R*,4R*,5R*,Z)-3,4-Bis[(triethylsilyl)oxy]-2-(prop-2-yn-1-yli-
dene)-1,6-dioxaspiro[4.5]decane (18a). To a stirred solution of
spiroacetal 16a (264 mg, 0.517 mmol) in absolute ethanol (8.8 mL) at
0 °C was added a solution of AgNO3 (352 mg, 2.07 mmol) in water
(8.8 mL). A white suspension formed immediately. The mixture was
stirred for 1 h in the dark and was then diluted with dichloromethane
(100 mL) and transferred into a rapidly stirred solution of KCN (808
mg, 12.4 mmol) in water (176 mL). After 2 min, the mixture was
extracted with dichloromethane (3 × 100 mL), and the combined
organic extracts were dried (MgSO4) and concentrated. Flash
chromatography (petroleum ether/ether, 97:3) furnished the title
compound 18a as a colorless oil (175 mg, 77%): Rf 0.87 (petroleum
ether/ether, 95:5); IR (neat) 3316w, 2955s, 2878s, 2103w, 1668m,
1458m, 1114s; 1H NMR (500 MHz, CDCl3) 0.63−0.70 (12H, m, 2 ×
Si(CH2CH3)3), 0.94−1.02 (18H, m, 2 × Si(CH2CH3)3), 1.54−1.98
(6H, m, H-8, H-9, H-10), 3.05 (1H, d, J = 2.5 Hz, H-3′), 3.77 (1H, dd,
J = 11.5, 4.5 Hz, H-7eq), 3.86 (1H, d, J = 7.0 Hz, H-4), 4.04 (1H, td, J
= 11.5, 3.0 Hz, H-7ax), 4.39 (1H, dd, J = 7.0, 1.5 Hz, H-3), 4.55−4.56
(1H, m, H-1′); 13C NMR (125 MHz, CDCl3) 4.9 and 5.0 (2 ×
Si(CH2CH3)3), 6.7 and 6.8 (2 × Si(CH2CH3)3), 18.3 (C-9), 24.8 (C-
8), 28.8 (C-10), 63.4 (C-7), 76.8 (C-3), 77.7 (C-1′), 78.9 (C-2′), 80.1
(C-3′), 82.2 (C-4), 107.4 (C-5), 166.4 (C-2); HRMS (ESI+) calcd for
(3R*,4R*,5S*,Z)-2-(Hexa-2,4-diyn-1-ylidene)-1,6-dioxaspiro-
[4.5]decane-3,4-diol (Z-trans-6s). To a stirred solution of bis(silyl
ether) S4s (10 mg, 21.0 μmol) in THF (0.4 mL) at 0 °C was added
TBAF solution (1.0 M in THF, 52.5 μL, 52.5 μmol). The resulting
mixture was warmed to rt and stirred for 1 h. Water (5 mL) and ether
(5 mL) were added to the reaction mixture, and the layers were
separated. The aqueous layer was extracted with ether (3 × 5 mL), and
the combined organic layers were dried (MgSO4) and concentrated.
Preparative TLC (dichloromethane/methanol, 95:5) furnished the title
compound Z-trans-6s as a colorless oil (5.0 mg, 96%): Rf 0.37
(dichloromethane/methanol, 95:5); IR (neat) 3398br, 2926s, 2162w,
+
C23H42NaO4Si2 (M + Na+) 461.2514, found 461.2505.
1-Iodopropyne (S3).23 To a stirred solution of 1-(trimethylsilyl)-
propyne (250 μL, 1.69 mmol) in freshly distilled acetone (12 mL) at rt
was added N-iodosuccinimide (490 mg, 2.18 mmol) and AgNO3 (340
mg, 2.00 mmol). After the solution was stirred for 1 h in the dark, the
white precipitate was filtered, and the filtrate was diluted with water
(40 mL) and petroleum ether (40 mL). The layers were separated; the
aqueous layer was extracted with petroleum ether (3 × 40 mL), and
1
2182w, 2143w, 1738s, 1662s, 1367s, 1259m, 1131s, 1109s; H NMR
(500 MHz, CDCl3) 1.54−2.05 (6H, m, H-8, H-9, H-10), 2.00 (3H, d,
J = 1.0 Hz, H-6′), 2.25−2.73 (2H, br s, 2 × OH), 3.63 (1H, d, J = 7.5
Hz, H-4), 3.81 (1H, app. d, J = 11.0 Hz, H-7eq), 3.98 (1H, td, J = 11.0,
10628
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The Journal of Organic Chemistry
Article
1
3.5 Hz, H-7ax), 4.63 (1H, d, J = 7.5 Hz, H-3), 4.77 (1H, app. s, H-1′);
13C NMR (125 MHz, CDCl3) 4.7 (C-6′), 18.5 (C-9), 24.5 (C-8), 30.5
(C-10), 63.2 (C-7), 64.9 (C-4′), 69.1 (C-2′), 76.5 (C-3), 77.8 (C-3′),
79.2 (C-1′), 79.7 (C-5′), 80.8 (C-4), 103.5 (C-5), 168.7 (C-2); HRMS
(1H, t, J = 1.5 Hz, H-7); H NMR (500 MHz, CCl4) (numbered
according to Figure 2 and Table 1) 1.53−1.87 (6H, m, H-2, H-3, H-4),
2.03 (3H, s, H-14), 2.10 and 2.12 (2 × 3H, 2 × s, 2 × COCH3), 3.77
(1H, br d, J = 11.5 Hz, H-1eq), 3.99 (1H, td, J = 11.5, 3.5 Hz, H-1ax),
4.79 (1H, s, H-9), 4.99 (1H, s, H-6), 5.40 (1H, s, H-7); 13C NMR
(125 MHz, CDCl3) 4.7 (C-6′), 18.7 (C-9), 20.6 and 20.9 (2 ×
COCH3), 24.5 (C-8), 29.7 (C-10), 62.9 (C-7), 64.8 (C-4′), 68.7 (C-
2′), 75.5 (C-3), 78.6 (C-4), 78.8 (C-3′), 80.3 (C-5′), 83.7 (C-1′),
109.1 (C-5), 164.3 (C-2), 169.2 and 170.0 (2 × COCH3); HRMS
+
(ESI+) calcd for C14H16NaO4 (M + Na+) 271.0941, found 271.0942.
(3R*,4R*,5R*,Z)-2-(Hexa-2,4-diyn-1-ylidene)-1,6-dioxaspiro-
[4.5]decane-3,4-diol (Z-trans-6a). To a stirred solution of bis(silyl
ether) S4a (60 mg, 0.126 mmol) in THF (2.5 mL) at 0 °C was added
TBAF solution (1.0 M in THF, 0.3 mL, 0.30 mmol). The resulting
mixture was warmed to rt and stirred for 1 h. Water (10 mL) and ether
(15 mL) were added to the reaction mixture, and the layers were
separated. The aqueous layer was extracted with ether (3 × 15 mL),
and the combined organic layers were dried (MgSO4) then
concentrated. Flash chromatography (dichloromethane/methanol,
95:5) furnished the title compound Z-trans-6a as a colorless oil (31
mg, 99%): Rf 0.34 (dichloromethane/methanol, 95:5); IR (neat)
3398br, 2950s, 2192m, 2142m, 1739s, 1656s, 1367s, 1217s, 1136s,
1093s, 747s; 1H NMR (500 MHz, CDCl3) 1.62−2.04 (6H, m, H-8, H-
9, H-10), 2.00 (3H, d, J = 1.0 Hz, H-6′), 2.86 (1H, d, J = 11.5 Hz, (C-
3)OH), 3.73−3.78 (2H, m, H-7eq), (C-4)OH), 3.93 (1H, dd, J = 5.5,
1.5 Hz, H-4), 4.01 (1H, td, J = 11.0, 4.0 Hz, H-7ax), 4.24 (1H, ddd, J =
11.5, 1.5, 1.0 Hz, H-3), 4.91 (1H, dq = quin, J = 1.0 Hz, H-1′); 13C
NMR (125 MHz, CDCl3) 4.7 (C-6′), 18.5 (C-9), 24.6 (C-8), 27.4 (C-
10), 62.9 (C-7), 64.9 (C-4′), 69.2 (C-2′), 77.6 (C-3), 78.2 (C-3′), 79.4
(C-4), 80.1 (C-5′), 82.8 (C-1′), 110.1 (C-5), 168.7 (C-2); HRMS
+
(ESI+) calcd for C18H20NaO6 (M + Na+) 355.1152, found 355.1143.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra of all new compounds; selected
NOE(SY) data; ORTEP representations of compounds Z-
trans-4s and Z-trans-4a; X-ray data for Z-trans-4s and Z-trans-4a
in CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jeremy.robertson@chem.ox.ac.uk.
Author Contributions
+
(ESI+) calcd for C14H16NaO4 (M + Na+) 271.0941, found 271.0941.
†G.C.F and A.L.T. obtained the X-ray diffraction data.
(3R*,4R*,5S*,Z)-3,4-Diacetoxy-2-(hexa-2,4-diyn-1-ylidene)-
1,6-dioxaspiro[4.5]decane (Z-trans-4s). To a stirred solution of
diol Z-trans-6s (5.0 mg, 20.1 μmol) in pyridine (1 mL) at rt was added
acetic anhydride (19 μL, 0.201 mmol). The reaction mixture was
stirred for 14 h at rt, diluted with ether (10 mL), and washed with
CuSO4 solution (satd aq, 3 × 5 mL). The combined aqueous extracts
were extracted with ether (3 × 10 mL), and the combined organic
extracts were dried (MgSO4) and then concentrated. Preparative TLC
(petroleum ether/ethyl acetate, 80:20) furnished the title compound Z-
trans-4s as a pale yellow solid (5.0 mg, 72%): Rf 0.37 (petroleum
ether/ethyl acetate, 80:20); IR (neat) 2954m, 2917s, 2849s, 2145w,
1748s, 1665m, 1371m, 1239s, 1115m, 1074m, 1047m; 1H NMR (500
MHz, CDCl3) (numbered according to Figure 2 and Table 1) 1.50−
1.86 (6H, m, H-2, H-3, H-4), 2.00 (3H, d, J = 1.0 Hz, H-14), 2.10 and
2.15 (2 × 3H, 2 × s, 2 × COCH3), 3.83 (1H, dd, J = 12.0, 4.5 Hz, H-
1eq), 3.96 (1H, td, J = 12.0, 3.0 Hz, H-1ax), 4.70 (1H, dq, J = 2.0, 1.0
Hz, H-9), 5.13 (1H, d, J = 7.5 Hz, H-6), 5.98 (1H, dd, J = 7.5, 2.0 Hz,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the China Oxford Scholarship Fund, the Overseas
Research Students Award Scheme, and Jesus College, Oxford,
for funding. We are very grateful to the following from the
University of Oxford: Phillip Unsworth for preliminary studies
and Drs. Tim Claridge and Barbara Odell for supporting NMR
spectroscopy.
REFERENCES
■
(1) This compound has been isolated from a variety of sources over
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1
H-7); H NMR (500 MHz, CCl4) (numbered according to Figure 2
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5.00 (1H, d, J = 7.5 Hz, H-6), 5.85 (1H, d, J = 7.5 Hz, H-7); 13C NMR
(125 MHz, CDCl3) 4.7 (C-6′), 18.7 (C-9), 20.8 (2 peaks) (2 ×
COCH3), 24.2 (C-8), 30.7 (C-10), 63.2 (C-7), 64.8 (C-4′), 68.3 (C-
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were extracted with ether (3 × 50 mL), and the combined organic
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0.42 (petroleum ether/ethyl acetate, 80:20); IR (neat) 3016m, 2970m,
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̈
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10630
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