An approach to the carbon backbone of bielschowskysin, part 2: Non-photochemical strategy

Article abstract of DOI:10.1002/ejoc.201300870

The stereocontrolled synthesis of complex and highly substituted polycyclic synthetic precursor 2 of the diterpene bielschowskysin is presented. Key steps include a regio- and stereoselective hydroalumination as well as an optimized Cr/Ni-mediated carbon-carbon bond formation between two complex fragments to establish the northern hemisphere of the natural product. An approach to the northern section of the complex diterpenoid bielschowskysin is described. Formation of the dihydrofuran ring moiety was achieved through stereoselective epoxidation, followed by alkyne opening and stereoselective formation of a vinyl halide suitable for chromium-mediated coupling. A final oxidation step furnished the hemiacetal. Copyright

Full text of DOI:10.1002/ejoc.201300870

FULL PAPER
DOI: 10.1002/ejoc.201300870
An Approach to the Carbon Backbone of Bielschowskysin, Part 2:
Non-Photochemical Strategy
Jean-Baptiste Farcet,[a] Martin Himmelbauer,[a] and Johann Mulzer*[a]
Keywords: Total synthesis / Natural products / Terpenoids / Chromium / Hydroalumination
The stereocontrolled synthesis of complex and highly substi-
tuted polycyclic synthetic precursor 2 of the diterpene biel-
schowskysin is presented. Key steps include a regio- and
stereoselective hydroalumination as well as an optimized Cr/
Ni-mediated carbon–carbon bond formation between two
complex fragments to establish the northern hemisphere of
the natural product.
rect substitution pattern in the southern region, whereas 2
has a fully developed northern hemisphere and waits for a
southern-section C–C-connection.
Introduction
The diterpene bielschowskysin, isolated in 2003 from the
gorgonian octocoral Pseudopterogorgia kallos,[1] is probably
the most complex natural product from the furanocem-
branoid group.[2] Over the past few years, the attractive mo-
lecular architecture has created a challenge for many syn-
thetic groups,[3–9] including ours.[10,11] In the preceding pa-
per[12] we described a photochemical route to tetracycle 1
(Figure 1), which contains the full carbon skeleton of biel-
schowskysin, albeit with a wrong ring size. In this article, a
non-photochemical alternative to similarly advanced inter-
mediate 2 is presented. The functionalization is basically
different in both compounds: 1 was prepared by a ring clo-
sure in the northern section of the molecule and has a cor-
Results and Discussion
We recently published a stereoselective and optimized
scalable synthesis of the tricyclic alcohol 4 from known
alcohol 3.[10,11] For further elaboration, we reasoned that
after formation of oxirane 5, an epoxide opening with acet-
ylide and subsequent formation of a vinyl halide would set
the stage for chromium-mediated coupling with aldehyde 6
(Scheme 1).
Figure 1. Bielschowskysin and the furanocembranoid skeleton, as
well as two advanced synthetic intermediates 1 and 2.
Scheme 1. Previous work and retrosynthetic considerations.
[a] University of Vienna, Institute of Organic Chemistry,
Währinger Straße 38, 1090 Vienna, Austria
E-mail: johann.mulzer@univie.ac.at
Hence, 4 was epoxidized with a dr of 6:1 from the convex
side of the tricycle. Triethyl silyl (TES) protection furnished
precursor 7, which failed to deliver allylic alcohol 8a with
Alcaraz protocol[13] (trimethylsulfonium iodide and nBuLi)
http://mulzer.univie.ac.at/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300870.
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J.-B. Farcet, M. Himmelbauer, J. Mulzer
FULL PAPER
or homopropargylic alcohols 8b–c with acetylides. Similar obtained in moderate yield, though with excellent regio-
epoxide inertness towards nucleophiles has been observed and stereoselectivity. However, to our disappointment,
in our previous approach.[12]
Swern oxidation did not furnish dialdehyde 16. Instead, en-
Finally, allylic alcohol 10 was readily formed from ketone one 17 was obtained as the single product (Scheme 4), pre-
9,[10,11] but the undesired configuration of the tertiary sumably through base-induced Grob-type fragmentation[16]
alcohol could not be inverted through a Mislow–Evans re- of the activated alcohol intermediate followed by oxidation
arrangement protocol (Scheme 2).[14]
of the allylic alcohol. This reaction could be extended to
several other substrates and may be an interesting access to
highly functionalized cyclopentanes.
Scheme 2. Investigations to open epoxide 7 and to invert the stereo-
chemistry of tertiary alcohol 10.
Reasoning that the presence of the lactone strongly inter-
feres with epoxide opening at the terminal position, we re-
turned to intermediate 12,[10,11] which was converted into
epoxide 5 as a single diastereoisomer (Scheme 3). Now, the
addition of commercially available lithium acetylide ethyl-
enediamine complex provided pure homopropargylic
alcohol 13 in excellent yield (Scheme 3).
Scheme 4. Grob-type rearrangement under Swern conditions and
formation of 18.
To avoid fragmentation, tertiary alcohol 13 was pro-
tected with TMSOTf and 2,6-lutidine. Unfortunately, yet
not unexpectedly, this afforded 18 as the sole product
(Scheme 4).[17] Hence, we decided to carry on without pro-
Scheme 3. Epoxide opening and formation of 13.
In parallel, diastereoisomerically and enantiomerically
pure aldehyde 6 was prepared in 11 steps from d-(+)-gluc-
ose.[12] A number of procedures for coupling of fragments
6 and 13 were tested. Because Takai conditions[15] failed,
[CrCl2, NiCl2, H2O, PPh3, dimethylformamide (DMF)] we
converted the alkyne into a suitably metalated vinyl deriva-
tive (Scheme 4). In fact, trimethyltin derivative 15 could be Scheme 5. Synthesis of vinyl iodide 21.
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An Approach to the Carbon Backbone of Bielschowskysin, Part 2
By using standard conditions (Table 1, Entry 2) alcohol
22 was formed in 50% isolated yield together with 31% of
side product 23. Varying the reaction temperature (Table 1,
Entries 1–3) mainly altered the diastereoisomeric ratio.
Similarly, changing the source of chromium and generating
CrCl2 in situ (Table 1, Entry 4) did not reduce the amount
of side product 23. Changing the solvent from DMSO to
dimethylacetamide (DMA) significantly increased the dia-
stereoselectivity, but not the yield (Table 1, Entry 6). Slow
addition of 21 or performing the reaction in an ultra sound
bath (Table 1, Entries 9 and 10) or the use of Pd(OAc)2 as
co-catalyst (Table 1, Entry 11) gave unsatisfactory results.
However, the use of Ni(acac)2 (Table 1, Entry 12) instead of
NiCl2, or administering the Ni-reagent in excess (Table 1,
Entries 13 and 14) both helped to promote C–C-connection
versus proton transfer, so that 22 was formed in 54–64%
yield.
Scheme 6. Coupling of vinyl iodide 21 and aldehyde 6.
tection and to use the tertiary alcohol as an anchor for the
formation of the envisaged vinyl halide. According to an
established protocol[18] [cat. tBuOK, dimethyl sulfoxide
(DMSO)], homopropargylic alcohol 13 was isomerized to
crystalline propargylic alcohol 19 (Scheme 5), whose struc-
ture was confirmed by single crystal diffraction.[19] Hydro-
alumination of 19 led to intermediate 20, which was
quenched with iodine to give (Z)-vinyl iodide 21 with excel-
lent regio- and stereocontrol (Scheme 5).[20]
Initially, coupling experiments of vinyl iodide 21 and al-
dehyde 6 were attempted through iodine-lithium exchange.
With equimolar amounts of both partners, dehalogenated
starting material 23 was formed as the single product of the
reaction. Obviously, the vinyl lithium species once formed is
immediately quenched by proton transfer from the tertiary
alcohol. Indeed, when alcohol 21 was first deprotonated
with lithium bis(trimethylsilyl)amide (LiHMDS) followed
by iodine-lithium exchange with tBuLi/LiCl, coupling prod-
uct 22 was isolated in 10% yield along with 80% of 23
(Scheme 6). As vinyl lithium was found to be too basic for
our purposes, we turned to the Nozaki–Hiyama–Kishi
(NHK) reaction[21,22] as an option for adding vinyl iodides
to aldehydes. We carefully screened conditions to optimize
the coupling of fragments 21 and 6 (Scheme 6, Table 1).
Scheme 7. Formation of hemiacetal 2.
Table 1. Optimization of the NHK coupling reaction.
Entry
Conditions[a]
%Yield[b]
of 22 (dr)
%Yield[b]
of 23
1
2
3
4
5
6
7
8
CrCl2 + NiCl2 (0.1) in DMSO, 10 °C
CrCl2 + NiCl2 (0.1) in DMSO, r.t.
CrCl2 + NiCl2 (0.1) in DMSO, 40 °C
CrCl3/LiAlH4 + NiCl2 (0.1) in DMSO, r.t.
CrCl2 + NiCl2 (0.1) in DMF, r.t.
49 (1.7:1)
50 (3.6:1)
30 (4.5:1)
52 (3.4:1)
30 (3.8:1)
16 (8.0:1)
0 (n.d.)
52 (2.1:1)
17 (3.7:1)
24 (2.8:1)
15 (n.d.)
57 (3.8:1)
54 (3.0:1)
64 (2.4:1)
33
31
30
36
54
74
64
28
76
38
69
29
39
25
CrCl2 + NiCl2 (0.1) in DMA, r.t.
CrCl2 + NiCl2 (0.1) in DME/DMSO (10:1), 60 °C
CrCl2 + NiCl2 (0.1) in DMSO/HMPA (2:1), r.t.
CrCl2 + NiCl2 (0.1) in DMSO, r.t.[c]
CrCl2 + NiCl2 (0.1) in DMSO, r.t.[d]
CrCl2 + Pd(OAc)2 (0.1) in DMSO, r.t.
CrCl2 + Ni(acac)2 (0.1) in DMSO, r.t.
CrCl2 + Ni(acac)2 (3) in DMSO, r.t.
CrCl2 + NiCl2 (3) in DMSO, r.t.
9
10
11
12
13
14
[a] Standard conditions: 0.05 m, 50 mg of 21, 2 equiv. of 6, 7 equiv. of [Cr] + co-catalyst. [b] Isolated yield. [c] Addition of 21 by syringe
pump over 1 h. [d] In ultrasound bath; n.d.: not determined.
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Scheme 8. Hypothetical end game.
(31 mg, 0.09 mmol) in CH2Cl2 (1.8 mL) was added imidazole (Im;
15 mg, 0.23 mmol) followed by triethylsilyl chloride (TESCl; 20 μL,
0.12 mmol) at 0 °C. The mixture was stirred for 1 h at room temp.
Standard work up was followed by column chromatography of the
residue (SiO2, Hex/EtOAc, 30:1) furnishing 20 mg (48 % over 2
steps) of TES-protected 7 as a colorless oil in a dr of 6:1. Main
In all cases alcohol 22 was obtained as an inconsequen-
tial diastereoisomeric mixture, which was oxidized to fur-
nish hemiacetal 2 in a 5:1 anomeric ratio (Scheme 7).
A hypothetical end game is suggested in Scheme 8. Intro-
duction of a sulfone would be followed by acid promoted
removal of the acetonide, oxidation and formation of di-
carbonyl intermediate 24. This has already been performed
with a simpler analogue.[10,11] Base-induced cyclization and
reductive removal of the sulfone[23] would lead to 25, which
is about five steps away from the target.
1
diastereoisomer: H NMR (400 MHz, CDCl3): δ = 5.23 (dt, J1 =
5.5, J2 = 7.9 Hz, 1 H), 3.88 (d, J = 10.5 Hz, 1 H), 3.81 (d, J =
10.8 Hz, 1 H), 3.56 (dd, J1 = 7.2, J2 = 8.4 Hz, 1 H), 3.06 (dd, J1 =
2.0, J2 = 7.0 Hz, 1 H), 2.90 (d, J = 4.7 Hz, 1 H), 2.70 (d, J =
4.6 Hz, 1 H), 2.56 (ddd, J1 = 2.1, J2 = 7.9, J3 = 14.7 Hz, 1 H), 1.94
(dd, J1 = 5.5, J2 = 14.6 Hz, 1 H), 1.31 (s, 3 H), 0.96 (t, J = 8.0 Hz,
9 H), 0.84 (s, 9 H), 0.62 (q, J = 8.0 Hz, 6 H), 0.09 (s, 3 H), 0.08 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.1, 83.7, 83.0,
61.0, 59.2, 57.3, 50.4, 47.1, 42.7, 29.8, 25.7 (3 C), 23.1, 18.0, 6.8 (3
C), 4.5 (3 C), –2.3, –2.4 ppm. HRMS (EI): calcd. for C23H42O5Si2
Conclusions
A synthesis of an advanced precursor of bielschowskysin
has been presented in 21 steps and 7.4% overall yield start- Na [M + Na]+ 477.2468; found 477.2454. IR: ν = 2954, 2877, 1770,
˜
1461, 1254, 1142, 1103, 990, 834, 729 cm–1. [α]2D2 = –41.8 (c = 0.55;
ing from known alcohol 3. Formation of the properly sub-
stituted vinyl halide by regio- and stereoselective hydro-
CHCl3). Rf (Hex/EtOAc, 5:1) = 0.44.
alumination was followed by an optimized NHK coupling,
which furnished pentacycle 2 after oxidation. On evaluating
intermediates 1 and 2, we favor the route leading to 1. So
(1S,2S,4S,5R,6R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-ethenyl-2-
(methoxymethoxy)-4-methyl-7,7-bis{[(triethylsilyl)oxy]-
methyl}bicyclo[3.2.0]heptan-6-ol (10): At 0 °C vinyl MgBr (1 m in
this will be our preferred line, and 2 will remain as back up. Et2O, 564 μL, 0.56 mmol) was added to a solution of ketone 9
(200 mg, 0.28 mmol) dissolved in Et2O (2.8 mL). The reaction ves-
sel was stirred overnight at room temp. Standard work up was fol-
lowed by column chromatography of the residue (SiO2, Hex/
Experimental Section
EtOAc, 20:1 then 10:1) furnishing 207 mg (99%) of alcohol 10 as
a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 5.94 (dd, J1
=
General: Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br. s = broad singlet), coupling constant J, integration. Infrared
spectra were recorded as thin films of pure product with an ATR
unit. High-resolution mass spectra were measured as ESI-TOF
with a resolution of 10,000.
10.4, J2 = 17.0 Hz, 1 H), 5.17 (dd, J1 = 1.3, J2 = 17.0 Hz, 1 H),
5.04 (dd, J1 = 1.4, J2 = 10.8 Hz, 1 H), 4.64 (d, J = 6.4 Hz, 1 H),
4.60–4.52 (m, 1 H), 4.48 (d, J = 10 Hz, 1 H), 4.47 (d, J = 6.2 Hz,
1 H), 3.79 (d, J = 10.2 Hz, 1 H), 3.70 (d, J = 9.1 Hz, 1 H), 3.37–
3.31 (m, 5 H), 2.64 (t, J = 8 Hz, 1 H), 2.58 (dd, J1 = 1.5, J2
=
8.0 Hz, 1 H), 2.52 (t, J = 11.8 Hz, 1 H), 1.98 (ddd, J1 = 1.7, J2 =
7.0, J3 = 12.0 Hz, 1 H), 1.48 (s, 3 H), 1.00–0.90 (m, 18 H), 0.83 (s,
9 H), 0.64–0.54 (m, 12 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 142.9, 112.4, 95.4, 82.4, 78.9, 75.3,
64.5, 60.9, 55.3, 52.1, 51.4, 47.3, 40.8, 25.9 (3 C), 24.3, 18.1, 7.0 (3
C), 6.9 (3 C), 4.6 (6 C), –2.0, –2.2 ppm. HRMS (EI): calcd. for
Standard Workup Procedure: The reaction was then diluted with
Et2O (10 mL/0.1 mmol) and NH4Cl (7 mL/0.1 mmol), the phases
were separated and the aqueous phase was extracted with Et2O
(2ϫ 5 mL/0.1 mmol). The combined organic phases were washed
with water (5 mL/0.1 mmol), brine (5 mL/0.1 mmol), dried with
MgSO4 and concentrated under reduced pressure.
C32H66O6Si3Na [M + Na]+ 653.4065; found 653.4068. IR: ν =
˜
(1S,1aR,3aS,5S,5aR)-5-{[tert-Butyl(dimethyl)silyl]oxy}-5-methyl-
1a-{[(triethylsilyl)oxy]methyl}hexahydro-2H-spiro[3-oxacyclobuta-
[cd]pentalene-1,2Ј-oxiran]-2-one (7): A solution of dimethyldioxir-
ane (DMDO; 0.07 m in acetone, 0.55 mmol) was added to primary
2954, 2878, 1461, 1253, 1100, 1046, 1004, 834, 806, 742 cm–1
.
[α]2D2 = –59.2 (c = 1.0; CHCl3). Rf (Hex/EtOAc, 10:1) = 0.69.
tert-Butyl{[(1ЈR,2ЈS,4ЈS,5ЈS,7ЈS)-4Ј-(methoxymethoxy)-2,2,2Ј-tri-
alcohol 4 (30 mg, 0.09 mmol). The resulting mixture was stirred at methyldispiro[1,3-dioxane-5,6Ј-bicyclo[3.2.0]heptane-7Ј,2ЈЈ-oxiran]-
room temp. for 5 d and was evaporated to yield 31 mg (quantita-
tive) of the epoxide intermediate. To a solution of free alcohol
2Ј-yl]oxy}dimethylsilane (5): To a solution of 12 (277 mg,
0.46 mmol) in tetrahydrofuran (THF; 3 mL) in a Teflon® vial was
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An Approach to the Carbon Backbone of Bielschowskysin, Part 2
slowly added a 70% HF solution in pyridine (269 μL, 9.22 mmol)
acetylide ethylenediamine complex (1.02 g, 11.1 mmol) in one por-
at 0 °C. The mixture was stirred for 30 min at this temperature until tion at room temp. Next, the mixture was warmed to 50 °C and
analysis by TLC indicated clean conversion. Standard work up was
followed by column chromatography of the residue (SiO2, Hex/
stirred for 1 h. Standard work up yielded 630 mg (quantitative) of
crude and pure tertiary alcohol 13 as a light brown viscous oil. H
1
EtOAc, 2:1) furnishing 170 mg (99%) of the diol intermediate as a NMR (400 MHz, CDCl3): δ = 4.60 (d, J = 6.3 Hz, 1 H), 4.54 (d,
1
viscous colorless oil. H NMR (400 MHz, CDCl3): δ = 4.88 (d, J
= 1.9 Hz, 1 H), 4.83 (d, J = 2.5 Hz, 1 H), 4.71 (d, J = 6.6 Hz, 1 4.24 (dd, J1 = 2.7, J2 = 11.6 Hz, 1 H), 3.98 (dd, J1 = 2.8, J2
H), 4.69 (d, J = 6.6 Hz, 1 H), 4.64–4.55 (m, 1 H), 4.05 (d, J = 11.1 Hz, 1 H), 3.68 (d, J = 11.6 Hz, 1 H), 3.34 (s, 3 H), 3.14 (dd,
J = 6.4 Hz, 1 H),4.45–4.37 (m, 1 H), 4.30 (d, J = 13.1 Hz, 1 H),
=
11.9 Hz, 1 H), 3.80 (dd, J1 = 3.1, J2 = 11.1 Hz, 1 H), 3.77–3.63 (m,
3 H), 3.37 (s, 3 H), 3.20 (br. d, J = 7.0 Hz, 1 H), 3.07–2.98 (m, 2
J1 = 2.7, J2 = 17.2 Hz, 1 H), 2.88 (br. s, 1 H), 2.81 (dd, J1 = 2.7,
J2 = 17.5 Hz, 1 H), 2.52 (dd, J1 = 1.7, J2 = 8.6 Hz, 1 H), 2.32 (t, J
H), 2.12 (ddd, J1 = 1.4, J2 = 6.4, J3 = 13.4 Hz, 1 H), 1.86 (t, J = = 8.2 Hz, 1 H), 2.12 (ddd, J1 = 1.9, J2 = 6.7, J3 = 12.3 Hz, 1 H),
12.0 Hz, 1 H), 1.37 (s, 3 H), 0.84 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.0, 108.8, 97.1, 81.6,
80.8, 71.7, 65.7, 55.9, 55.1, 52.2, 45.6, 43.9, 25.8 (3 C), 24.0, 18.1,
–2.2, –2.3 ppm. HRMS (ESI): calcd. for C19H36O5SiNa [M +
2.13 (t, J = 2.5 Hz, 1 H), 1.66 (dd, J1 = 11.1, J2 = 12.6 Hz, 1 H),
1.56 (s, 3 H), 1.44 (s, 3 H), 1.36 (s, 3 H), 0.81 (s, 9 H), 0.08 (s, 3
H), 0.08 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 98.1,
96.7, 81.6, 81.4, 80.1, 75.8, 72.4, 66.5, 63.4, 58.5, 55.5, 47.9, 43.3,
39.9, 28.8, 25.8 (3 C), 25.7, 24.6, 19.1, 18.1, –2.1, –2.9 ppm. HRMS
(ESI): calcd. for C24H42O6SiNa [M + Na]+ 477.2648; found
Na]+ 395.2230; found 395.2219. IR: ν = 3435, 2929, 1462, 1372,
˜
1253, 1151, 1106, 1034, 835, 772 cm–1. [α]2D0 = –64.4 (c = 1.0;
CHCl3). Rf (Hex/EtOAc, 2:1) = 0.12.
477.2643. IR: ν = 3464, 2928, 2855, 1200, 1151, 1107, 1073, 1042,
˜
834, 773 cm–1. [α]2D0 = –31.3 (c = 1.0; CHCl3). Rf (Hex/EtOAc, 4:1)
To a solution of the diol (1.15 g, 3.09 mmol) in CH2Cl2 (61 mL)
was added purified meta-chloroperoxybenzoic acid (mCPBA;
1.60 g, 9.26 mmol) at room temp. After 5 h the mixture was diluted
with CH2Cl2 (100 mL) and satd. aq. Na2S2O3 (20 mL) were added.
The organic phase was washed with aq. KOH (1 m, 2ϫ 30 mL) and
brine (30 mL) and dried with MgSO4, filtered, and concentrated to
yield 1.20 g (quantitative) of the epoxide intermediate as a colorless
viscous oil. H NMR (400 MHz, CDCl3): δ = 6.71 (d, J = 6.5 Hz,
1 H), 6.69 (d, J = 6.5 Hz, 1 H),4.64–4.56 (m, 1 H), 3.94–3.87 (m,
2 H), 3.80–3.68 (m, 2 H), 3.53 (dd, J1 = 10.0, J2 = 12.2 Hz, 1 H),
= 0.20.
(1S,2S,4S,5R,6S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-{(2Z)-3-[di-
methyl(phenyl)silyl]-2-(trimethylstannanyl)prop-2-en-1-yl}-7,7-bis-
(hydroxymethyl)-2-(methoxymethoxy)-4-methylbicyclo[3.2.0]heptan-
6-ol (15): To a solution of acetonide 13 (120 mg, 0.25 mmol) in
MeOH (2.6 mL) was added camphorsulfonic acid (CSA; 6.1 mg,
0.03 mmol) at 0 °C. After 1 h, TLC analysis showed an almost
completed reaction. Standard work up was followed by column
chromatography of the residue (SiO2, EtOAc/Hex, 2:1 to 1:1) fur-
nishing the diol intermediate 102 mg (93%) as an amorphous white
solid. 1H NMR (400 MHz, CDCl3): δ = 4.66 (s, 1 H), 4.66 (s, 1 H),
1
3.38 (s, 3 H), 3.04 (d, J = 4.1 Hz, 1 H), 2.87 (dd, J1 = 2.2, J2
=
7.9 Hz, 1 H), 2.77 (d, J = 8.2 Hz, 1 H), 2.74 (d, J = 4.1 Hz, 1 H),
2.68 (dd, J1 = 3.0, J2 = 9.8 Hz, 1 H), 2.22 (ddd, J1 = 2.1, J2 = 6.3,
J3 = 12.4 Hz, 1 H), 1.92 (dd, J1 = 11.3, J2 = 12.0 Hz, 1 H), 1.31
(s, 3 H), 0.83 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 97.1, 80.7, 80.1, 68.0, 63.7, 62.1, 55.9, 54.6,
48.4, 47.6, 46.8, 40.6, 25.8 (3 C), 24.4, 18.1, –2.2, –2.4 ppm. HRMS
4.55–4.47 (m, 1 H), 4.06–3.86 (m, 4 H), 3.75 (dd, J1 = 4.6, J2
=
9.9 Hz, 1 H), 3.51 (br. s, 1 H), 3.36 (s, 3 H), 2.84 (br. s, 1 H), 2.75–
2.55 (m, 4 H), 2.21 (ddd, J1 = 1.8, J2 = 6.7, J3 = 12.6 Hz, 1 H),
2.16 (t, J = 2.6 Hz, 1 H), 1.78 (dd, J1 = 11.5, J2 = 12.3 Hz, 1 H),
1.45 (s, 3 H), 0.82 (s, 9 H), 0.09 (s, 3 H), 0.09 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 97.1, 81.2, 80.6, 80.5, 76.2, 73.2,
66.5, 60.7, 59.3, 55.9, 50.6, 47.4, 39.7, 25.8 (3 C), 25.5, 24.8, 18.1,
–2.2, –2.3 ppm. HRMS (ESI): calcd. for C21H38O6SiNa [M +
(EI): calcd. for C H O Si [M+] 388.2276; found 388.2263. IR: ν
˜
19 36
6
= 3470, 2928, 2855, 1254, 1152, 1103, 1036, 979, 832, 773 cm–1.
[α]2D0 = –19.7 (c = 1.0; CHCl3). Rf (Hex/EtOAc, 2:1) = 0.14.
Na]+ 437.2335; found 437.2322. IR: ν = 3413, 2952, 2856, 1254,
˜
1157, 1104, 1037, 976, 836, 774 cm–1. [α]2D5 = +4.0 (c = 0.7; CHCl3).
Rf (Hex/EtOAc, 2:1) = 0.19.
At 0 °C, pyridinium p-toluenesulfonate (PPTS; 71 mg, 0.28 mmol)
was added to a solution of the diol (2.20 g, 5.66 mmol) and 2,2-
dimethoxypropane (6.96 mL, 56.6 mmol) in acetone (57 mL). After
10 min at 0 °C the reaction was warmed to room temp. and stirring
was continued for 30 min. Standard work up gave acetonide 5
To a solution of the alkyne diol (27 mg, 0.07 mmol) in THF
(0.2 mL) was added trimethylstannyldimethylphenylsilane (29 μL,
0.07 mmol) followed by Pd(PPh3)4 (4 mg, 0.01 mmol). This mixture
was stirred at 70 °C for 45 min. The crude reaction mixture was
concentrated and directly applied onto a column for purification
by chromatography (SiO2, Hex/EtOAc, 5:1 to 2:1) to afford 23 mg
(50%) of desired diol 15 as a single regio- and stereoisomer. 1H
NMR (400 MHz, CDCl3): δ = 7.54–7.50 (m, 2 H), 7.36–7.31 (m, 3
H), 6.77 (s, 1 H), 4.67 (s, 2 H), 4.57–4.48 (m, 1 H), 4.02–3.8 (m, 5
H), 3.64 (dd, J1 = 3.9, J2 = 17.0 Hz, 1 H), 3.37 (s, 3 H), 2.97 (dd,
J1 = 1.6, J2 = 14.1 Hz, 1 H), 2.71 (d, J = 14.3 Hz, 1 H), 2.69 (t, J
= 8.6 Hz, 1 H), 2.59 (t, J = 5.4 Hz, 1 H), 2.48 (dd, J1 = 1.7, J2 =
8.8 Hz, 1 H), 2.20 (ddd, J1 = 1.6, J2 = 6.3, J3 = 12.3 Hz, 1 H), 1.89
(dd, J1 = 11.3, J2 = 11.6 Hz, 1 H), 1.49 (s, 3 H), 0.83 (s, 9 H), 0.38
(s, 3 H), 0.37 (s, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H), 0.01 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 166.8, 146.4, 139.1, 134.3 (2 C),
129.2, 128.0 (2 C), 97.0, 81.6, 80.7, 79.8, 66.9, 62.5, 61.6, 55.9, 52.7,
49.3, 47.5, 39.6, 25.9, 25.8 (3 C), 18.1, –0.6, –0.7, –2.1, –2.3, –4.9
(3 C) ppm. HRMS (ESI): calcd. for C32H58O6Si2SnNa [M + Na]+
1
2.18 g (90%) as a colorless oil. H NMR (400 MHz, CDCl3): δ =
4.67 (d, J = 6.4 Hz, 1 H), 4.59 (d, J = 6.3 Hz, 1 H), 4.57–4.49 (m,
1 H), 4.34 (d, J = 12.1 Hz, 1 H), 4.00 (dd, J1 = 2.0, J2 = 11.7 Hz,
1 H), 3.86 (dd, J1 = 2.0, J2 = 11.3 Hz, 1 H), 3.83 (d, J = 11.9 Hz,
1 H), 3.36 (s, 3 H), 3.14 (d, J = 5.2 Hz, 1 H), 3.01 (d, J = 5.2 Hz,
1 H), 2.77 (dd, J1 = 2.1, J2 = 8.2 Hz, 1 H), 2.49 (t, J = 8.0 Hz, 1
H), 2.16 (ddd, J1 = 2.1, J2 = 6.0, J3 = 12.6 Hz, 1 H), 1.81 (d, J =
12.0 Hz, 1 H), 1.40 (s, 3 H), 1.32 (s, 3 H), 1.29 (s, 3 H), 0.81 (s, 9
H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 97.4, 96.6, 80.7, 79.4, 66.5, 65.2, 63.7, 55.5, 54.8, 47.5, 47.3,
41.3, 40.7, 27.2, 25.8 (3 C), 24.4, 20.4, 18.0, –2.2, –2.3 ppm. HRMS
(ESI): calcd. for C22H40O6SiNa [M + Na]+ 451.2492; found
451.2500. IR: ν = 2933, 2856, 1467, 1371, 1256, 1152, 1080, 1045,
˜
834, 774 cm–1. [α]2D5 = –59.7 (c = 0.3; CHCl3). Rf (Hex/EtOAc, 2:1)
= 0.36.
(1R,2S,4S,5S,7S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-(methoxy-
methoxy)-2,2Ј,2Ј-trimethyl-7-(prop-2-yn-1-yl)spiro[bicyclo[3.2.0]-
heptane-6,5Ј-[1,3]dioxan]-7-ol (13): To a solution of crude epoxide
5 (595 mg, 1.39 mmol) in DMSO (13.9 mL) was added lithium
737.2692; found 737.2693. IR: ν = 3390, 2953, 2856, 1253, 1157,
˜
1110, 1036, 836, 731, 702 cm–1. [α]2D3 = –15.0 (c = 0.6; CHCl3). Rf
(Hex/EtOAc, 3:1) = 0.23.
Eur. J. Org. Chem. 2013, 8245–8252
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8249

J.-B. Farcet, M. Himmelbauer, J. Mulzer
2-[(1S,2S,3S,5S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-2-{(3Z)-4-[di- 2.45 (dd, J1 = 2.0, J2 = 8.2 Hz, 1 H), 2.28 (dd, J1 = 11.1, J2
FULL PAPER
=
methyl(phenyl)silyl]-3-(trimethylstannanyl)but-3-enoyl}-5-(meth-
12.4 Hz, 1 H), 2.22 (t, J = 8.6 Hz, 1 H), 1.98 (ddd, J1 = 1.8, J2 =
6.8, J3 = 12.5 Hz, 1 H), 1.93 (s, 3 H), 1.61 (s, 3 H), 1.46 (s, 3 H),
oxymethoxy)-3-methylcyclopentyl]prop-2-enal (17): To a solution of
oxalyl chloride (9 μL, 0.11 mmol) in CH2Cl2 (0.6 mL) at –78 °C 1.37 (s, 3 H), 0.81 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. 13C
was added DMSO (14 μL, 0.20 mmol). The solution was stirred
20 min at –78 °C then alcohol 15 (12 mg, 0.02 mmol) in CH2Cl2
(0.5 mL) was slowly added to the reaction mixture. The solution
was stirred at –78 °C for 1 h. Et3N (46 μL, 0.33 mmol) was intro-
duced and stirring was continued at –78 °C for 1 h, then the reac-
tion was warmed to –40 °C within 2 h. Standard work up was fol-
lowed by column chromatography of the residue (SiO2, Hex/
EtOAc, 3:1) furnishing 12 mg (quantitative) of aldehyde 17 as an
NMR (100 MHz, CDCl3): δ = 98.1, 96.7, 86.1, 81.8, 80.3, 79.0,
72.6, 66.5, 64.8, 58.0, 55.6, 46.1, 44.0, 39.3, 29.1, 26.0 (3 C), 22.6,
19.1, 18.2, 4.1, –2.0, –2.1 ppm. HRMS (ESI): calcd. for C24H42O6S-
iNa [M + Na]+ 477.2648; found 477.2637. IR: ν = 3448, 2928, 2855,
˜
1372, 1257, 1151, 1078, 1044, 835, 773 cm–1, m.p. 124–125 °C.
[α]2D2 = –45.9 (c = 1.2; CHCl3). Rf (Hex/EtOAc, 4:1) = 0.13. X-ray:
see ref.[17]
(1R,2S,4S,5S,7R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-7-[(1Z)-2-
iodoprop-1-en-1-yl]-4-(methoxymethoxy)-2,2Ј,2Ј-trimethylspiro[bi-
cyclo[3.2.0]heptane-6,5Ј-[1,3]dioxan]-7-ol (21): A solution of alkyne
19 (2.15 g, 4.73 mmol) dissolved in THF (20 mL) was added to a
suspension of MeONa (1.12 g, 20.8 mmol) in LiAlH4 (0.15 m in
THF, 69.3 mL, 10.4 mmol) at –20 °C. The mixture was slowly
warmed to room temp. and stirred for 36 h. The solution was co-
oled to 0 °C and EtOAc (924 μL, 9.46 mmol) was added. After
10 min the solution was further cooled to –21 °C and treated with
a solution of I2 (3.59 g, 14.2 mmol) in THF (12 mL). The reaction
was stirred at this temperature for 30 min and warmed to 0 °C
within 1 h. Standard work up was followed by column chromatog-
raphy of the residue (SiO2, Hex/EtOAc, 10:1) furnishing 1.78 g
(65 %) of vinyl iodide 21 as a viscous colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 6.49 (s, 1 H), 4.59 (d, J = 6.5 Hz, 1 H),
4.56 (d, J = 6.6 Hz, 1 H), 4.46–4.38 (m, 1 H), 4.23 (dd, J1 = 2.9,
J2 = 11.1 Hz, 1 H), 4.20 (d, J = 13.0 Hz, 1 H), 4.07 (dd, J1 = 2.8,
J2 = 13.1 Hz, 1 H), 3.71 (d, J = 11.5 Hz, 1 H), 3.35 (s, 3 H), 2.83
1
amorphous white solid. H NMR (400 MHz, CDCl3): δ = 9.37 (s,
1 H), 7.51–7.47 (m, 2 H), 7.35–7.32 (m, 3 H), 6.47 (t, J = 0.8 Hz,
1 H), 6.41 (t, J = 0.9 Hz, 1 H), 6.06 (d, J = 0.9 Hz, 1 H), 4.51 (d,
J = 6.4 Hz, 1 H), 4.46–4.40 (m, 2 H), 3.97 (dt, J1 = 0.7, J2 = 8.3 Hz,
1 H), 3.46 (dd, J1 = 1.1, J2 = 16.2 Hz, 1 H), 3.29 (s, 3 H), 3.30 (dd,
J1 = 1.3, J2 = 16.3 Hz, 1 H), 3.24 (dd, J1 = 0.9, J2 = 8.3 Hz, 1 H),
2.28 (ddd, J1 = 1.1, J2 = 7.1, J3 = 13.5 Hz, 1 H), 2.19 (dd, J1
=
6.9, J2 = 13.2 Hz, 1 H), 1.33 (s, 3 H), 0.89 (s, 9 H), 0.36 (s, 3 H),
0.36 (s, 3 H), 0.13 (s, 3 H), 0.13 (s, 3 H), 0.06 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 209.4, 194.9, 160.5, 146.8, 145.8,
139.9, 134.1 (2 C), 129.1, 127.9 (2 C), 96.3, 82.2, 78.0, 66.7, 64.0,
55.6, 48.8, 40.8, 29.8, 25.9 (3 C), 25.2, 18.1, 0.8, 0.8, –2.1, –2.1,
–6.0 (3 C) ppm. HRMS (ESI): calcd. for C32H54O5Si2SnNa [M +
Na]+ 717.2429; found 717.2433. IR: ν = 2927, 2853, 2358, 1695,
˜
1252, 1150, 1111, 1043, 835, 773 cm–1. [α]2D0 = –23.1 (c = 0.33;
CHCl3). Rf (Hex/EtOAc, 10:1) = 0.36.
(1S,1aR,2S,3aS,7aR,7bS)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-
methyl-1-(prop-2-yn-1-yl)-7a-{[(trimethylsilyl)oxy]methyl}-
octahydro-4,6-dioxacyclobuta[cd]azulen-1-ol (18): To a solution of
acetonide 13 (192 mg, 0.42 mmol) in CH2Cl2 was sequentially
added 2,6-lutidine (221 μL, 1.90 mmol) and TMSOTf (229 μL,
mmol) at 0 °C. After 1 h standard work up was followed by column
chromatography of the residue (SiO2, Hex/EtOAc, 10:1) to yield
(br. s, 1 H), 2.66 (d, J = 0.9 Hz, 3 H), 2.62 (dd, J1 = 1.8, J2
=
8.6 Hz, 1 H), 2.32 (t, J = 8.3 Hz, 1 H), 2.10 (ddd, J1 = 1.8, J2 =
6.9, J3 = 12.9 Hz, 1 H), 1.65 (dd, J1 = 10.6, J2 = 12.8 Hz, 1 H),
1.46 (s, 3 H), 1.45 (s, 3 H), 1.33 (s, 3 H), 0.81 (s, 9 H), 0.08 (s, 3
H), 0.08 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 124.5,
98.2, 96.8, 96.7, 81.6, 80.3, 76.2, 67.0, 63.7, 59.3, 55.6, 47.9, 45.3,
39.8, 37.3, 29.2, 25.8 (3 C), 23.8, 19.0, 18.1, –2.1, –2.3 ppm. HRMS
(ESI): calcd. for C24H43O6SiINa [M + Na]+ 605.1771; found
1
100 mg (52%) of ether 18 as a colorless oil. H NMR (400 MHz,
CDCl3): δ = 4.91 (d, J = 5.3 Hz, 1 H), 4.75 (d, J = 5.5 Hz, 1 H),
4.63 (q, J = 8.3 Hz, 1 H), 4.49 (d, J = 12.8 Hz, 1 H), 3.98 (d, J =
12.8 Hz, 1 H), 3.96 (dd, J1 = 2.0, J2 = 11.0 Hz, 1 H), 3.42 (t, J =
11.5 Hz, 1 H), 3.31 (dd, J1 = 2.6, J2 = 16.4 Hz, 1 H), 2.72 (dd, J1
= 1.9, J2 = 11.5 Hz, 1 H), 2.62 (dd, J1 = 1.6, J2 = 9.2 Hz, 1 H),
2.58 (dd, J1 = 2.7, J2 = 16.3 Hz, 1 H), 2.38 (t, J = 8.9 Hz, 1 H),
605.1751. IR: ν = 2929, 2856, 1255, 1200, 1152, 1098, 1072, 1045,
˜
835, 774 cm–1. [α]2D2 = –25.1 (c = 0.45; CHCl3). Rf (Hex/EtOAc, 3:1)
= 0.37.
(1R,2S,4S,5S,7S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-7-[(1Z)-3-
{(2S,3R,4R,5R)-3-ethenyl-5-methoxy-4-[(triethylsilyl)oxy]tetra-
hydrofuran-2-yl}-3-hydroxy-2-methylprop-1-en-1-yl]-4-(methoxy-
methoxy)-2,2Ј,2Ј-trimethylspiro[bicyclo[3.2.0]heptane-6,5Ј-[1,3]di-
oxan]-7-ol (22a/22b): A mixture of vinyl iodide 21 (50 mg,
85.8 μmol) and aldehyde 6 (49 mg, 172 μmol) was dried by azeo-
trope distillation in benzene. The dried starting materials were dis-
solved in degassed DMSO (1.8 mL) and CrCl2 (74 mg, 601 μmol)
and NiCl2 (33 mg, 257 μmol) were sequentially added at room
temp. The resulting mixture was stirred at room temp. for 20 h.
Standard work up was followed by column chromatography of the
residue (SiO2, Hex/EtOAc, 8:1) giving 12 mg (19%) of 22b as the
minor diastereoisomer, 10 mg (25%) of 23, and 29 mg (45%) of
22a as the major diastereoisomer.
2.20 (dd, J1 = 8.9, J2 = 13.4 Hz, 1 H), 2.08 (ddd, J1 = 1.5, J2
=
7.5, J3 = 13.3 Hz, 1 H), 2.04 (t, J = 2.4 Hz, 1 H), 1.48 (s, 3 H),
0.81 (s, 9 H), 0.25 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 93.5, 83.7, 81.5, 81.3, 80.3, 71.5,
68.0, 66.2, 59.3, 54.3, 46.4, 41.9, 25.7 (3 C), 25.5, 25.1, 18.0, 2.1 (3
C), –2.1, –2.2 ppm. HRMS (ESI): calcd. for C23H42O5Si2Na [M +
Na]+ 477.2468; found 477.2473. IR: ν = 2953, 2928, 2854, 1253,
˜
1168, 1102, 1073, 1014, 838, 773 cm–1. [α]2D0 = –7.0 (c = 0.5; CHCl3).
Rf (Hex/EtOAc, 4:1) = 0.57.
(1R,2S,4S,5S,7R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-(methoxy-
methoxy)-2,2Ј,2Ј-trimethyl-7-(prop-1-yn-1-yl)spiro[bicyclo[3.2.0]-
heptane-6,5Ј-[1,3]dioxan]-7-ol (19): To a solution of terminal alkyne
13 (200 mg, 0.44 mmol) in DMSO (4.4 mL) was added tBuOK
(25 mg, 0.22 mmol) in one portion. The mixture was stirred at
room temp. for 5 h. Standard work up was followed by column
chromatography of the residue to yield 128 mg (64% from 12) of
internal alkyne 19 as a crystalline light yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 4.58 (d, J = 6.3 Hz, 1 H), 6.54 (d, J =
6.3 Hz, 1 H), 4.47–4.39 (m, 1 H), 4.31 (dd, J1 = 2.4, J2 = 12.4 Hz,
1 H), 4.14 (dd, J1 = 2.4, J2 = 11.5 Hz, 1 H), 4.11 (d, J = 12.7 Hz,
1 H), 3.79 (d, J = 11.9 Hz, 1 H), 3.34 (s, 3 H), 3.18 (br. s, 1 H),
Major Diastereoisomer 22a: (2D NMR analysis: see Supporting In-
1
formation) H NMR (400 MHz, CDCl3): δ = 5.94 (ddd, J1 = 9.0,
J2 = 10.0, J3 = 17.3 Hz, 1 H), 5.91 (br. s, 1 H), 5.28 (dd, J1 = 1.7,
J2 = 17.4 Hz, 1 H), 5.20–5.15 (m, 2 H), 4.65 (s, 1 H), 4.65 (d, J =
6.3 Hz, 1 H), 4.56 (d, J = 6.5 Hz, 1 H), 4.54–4.50 (m, 1 H), 4.25
(d, J = 7.8 Hz, 1 H), 4.21 (s, 1 H), 4.20 (dd, J1 = 1.7, J2 = 15.6 Hz,
1 H), 4.10 (d, J = 12.5 Hz, 1 H), 4.07 (d, J = 4.4 Hz, 1 H), 4.06 (s,
1 H), 3.68 (d, J = 11.4 Hz, 1 H), 3.43 (s, 3 H), 3.35 (s, 3 H), 2.91
8250
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8245–8252

An Approach to the Carbon Backbone of Bielschowskysin, Part 2
(dt, J1 = 4.3, J2 = 9.1 Hz, 1 H), 2.62 (dd, J1 = 1.9, J2 = 8.7 Hz, 1 ketone (Hex/EtOAc, 5:1 Rf = 0.20). After 24 h in the fridge (4 °C)
H), 2.38 (d, J = 8.4 Hz, 1 H), 2.29 (d, J = 2.5 Hz, 1 H), 2.06 (ddd,
J1 = 2.2, J2 = 7.0, J3 = 13.0 Hz, 1 H), 1.84 (d, J = 1.1 Hz, 3 H),
1.77 (dd, J1 = 11.1, J2 = 13.2 Hz, 1 H), 1.43 (s, 3 H), 1.41 (s, 3 H),
1.32 (s, 3 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.81 (s, 9 H), 0.59 (q, J =
8.0 Hz, 6 H), 0.06 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 137.9, 135.3, 128.1, 118.6, 110.8, 97.8, 96.6, 83.3, 81.8,
80.3, 80.2, 76.7, 74.0, 67.0, 63.6, 60.3, 56.5, 55.5, 50.2, 48.0, 45.7,
39.7, 26.7, 25.9 (3 C), 23.3, 21.2, 20.3, 18.1, 6.9 (3 C), 4.9 (3 C),
–2.1, –2.2 ppm. HRMS (ESI): calcd. for C38H70O10Si2Na [M +
the residue no longer contained the former product. Purification
by column chromatography (SiO2, Hex/EtOAc, 5:1) delivered 5 mg
(47 %) of half acetal 2 as a 5:1 anomeric mixture. 1H NMR
(400 MHz, CDCl3): δ = 5.85 (ddd, J1 = 9.2, J2 = 10.3, J3 = 19.6 Hz,
1 H), 5.83 (br. s, 1 H), 5.12–5.04 (m, 2 H), 4.74 (s, 1 H), 4.65 (d, J
= 6.4 Hz, 1 H), 4.60 (s, 1 H), 4.57 (d, J = 6.5 Hz, 1 H), 4.49–4.43
(m, 1 H), 4.31 (d, J = 12.8 Hz, 1 H), 4.26 (dd, J1 = 1.8, J2
=
11.6 Hz, 1 H), 4.21 (d, J = 9.0 Hz, 1 H), 4.03 (d, J = 4.61 Hz, 1
H), 3.88 (J1 = 1.6, J2 = 12.5 Hz, 1 H), 3.67 (d, J = 11.5 Hz, 1 H),
3.40 (s, 3 H), 3.35 (s, 3 H), 2.89 (dt, J1 = 4.4, J2 = 9.1 Hz, 1 H),
2.76 (dd, J1 = 1.9, J2 = 8.5 Hz, 1 H), 2.31 (d, J = 8.1 Hz, 1 H),
2.11 (ddd, J1 = 2.2, J2 = 6.5, J3 = 12.5 Hz, 1 H), 1.80 (d, J =
1.2 Hz, 3 H), 1.72 (t, J = 12.0 Hz, 1 H), 1.41 (s, 3 H), 1.34 (s, 3 H),
1.31 (s, 3 H), 0.95 (t, J = 7.4 Hz, 9 H), 0.82 (s, 9 H), 0.60 (q, J =
7.9 Hz, 6 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 140.5, 135.9, 124.6, 117.6, 108.9, 108.6, 98.0, 96.8,
90.0, 85.3, 80.5, 80.5, 80.3, 66.0, 63.2, 58.4, 55.5, 54.3, 47.8, 47.5,
45.5, 39.3, 25.9, 25.9 (3 C), 24.8, 20.6, 18.1, 13.0, 6.9 (3 C), 4.9 (3
C), –2.3, –2.6 ppm. HRMS (ESI): calcd. for C38H68O10Si2Na [M +
Na]+ 765.4405; found 765.4427. IR: ν = 3452, 2953, 2358, 1372,
˜
1256, 1199, 1077, 1044, 1002, 835 cm–1. [α]2D0 = –31.2 (c = 0.25;
CHCl3). Rf (Hex/EtOAc, 5:1) = 0.16.
Minor Diastereoisomer 22b: 1H NMR (400 MHz, CDCl3): δ = 6.11
(d, J = 11.4 Hz, 1 H), 5.93 (br. s, 1 H), 5.79 (ddd, J1 = 9.2, J2 =
10.1, J3 = 17.4 Hz, 1 H), 5.37 (s, 1 H), 5.28 (dd, J1 = 1.9, J2
=
17.3 Hz, 1 H), 5.19 (dd, J1 = 2.1, J2 = 10.3 Hz, 1 H), 4.67 (s, 1 H),
4.60 (d, J = 6.6 Hz, 1 H), 4.56 (d, J = 6.4 Hz, 1 H), 4.49–4.43 (m,
1 H), 4.23–4.17 (m, 2 H), 4.15 (d, J = 13.1 Hz, 1 H), 4.09 (d, J =
10.7 Hz, 1 H), 4.06 (d, J = 4.2 Hz, 1 H), 3.84 (d, J = 11.4 Hz, 1
H), 3.65 (d, J = 11.4 Hz, 1 H), 3.46 (s, 3 H), 3.35 (s, 3 H), 3.07 (dt,
J1 = 3.9, J2 = 9.6 Hz, 1 H), 2.51 (dd, J1 = 2.1, J2 = 8.6 Hz, 1 H),
2.25 (dd, J1 = 8.6, J2 = 9.4 Hz, 1 H), 2.06 (ddd, J1 = 2.0, J2 = 6.7,
J3 = 12.7 Hz, 1 H), 1.83 (d, J = 1.0 Hz, 3 H), 1.71 (dd, J1 = 10.9,
J2 = 12.4 Hz, 1 H), 1.44 (s, 3 H), 1.43 (s, 3 H), 1.33 (s, 3 H), 0.93
(t, J = 8.0 Hz, 9 H), 0.80 (s, 9 H), 0.59 (q, J = 8.0 Hz, 6 H), 0.06
(s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
137.8, 133.3, 126.5, 119.9, 111.0, 97.9, 96.8, 83.3, 81.8, 80.7, 79.3,
76.0, 71.3, 67.2, 64.0, 59.1, 56.9, 55.6, 47.8, 47.4, 45.9, 39.4, 26.3,
25.8 (3 C), 25.8, 23.8, 19.2, 18.1, 6.8 (3 C), 4.8 (3 C), –2.1,
–2.3 ppm. HRMS (ESI): calcd. for C38H70O10Si2Na [M + Na]+
Na]+ 763.4249; found 763.4247. IR: ν = 3469, 2927, 1409, 1256,
˜
1205, 1111, 1046, 1001, 834, 773 cm–1. [α]2D2 = +22.4 (c = 0.25;
CHCl3). Rf (Hex/EtOAc, 5:1) = 0.11.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H NMR and 13C NMR spectra of all products as
well as COSY, HMBC, HSQC and NOESY spectra of 22a.
Acknowledgments
Financial support from the University of Vienna (doctoral pro-
gram, Initiativkolleg Functional Molecules IK I041-N) and from
the Austrian Science Fund (FWF) (Project P22180) is gratefully
acknowledged. The authors thank H. P. Kählig, L. Brecker and S.
Felsinger for NMR assistance, M. Drescher for experimental work,
and A. Roller and V. Arion (all University of Vienna) for X-ray
analysis.
765.4405; found 765.4396. IR: ν = 3464, 2973, 2339, 1381, 1261,
˜
1190, 1065, 1041, 1023, 834 cm–1. [α]2D2 = –30.0 (c = 0.5; CHCl3).
Rf (Hex/EtOAc, 5:1) = 0.30.
(1R,2S,4S,5S,7S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-(methoxy-
methoxy)-2,2Ј,2Ј-trimethyl-7-[(1E)-prop-1-en-1-yl]spiro[bicyclo-
[3.2.0]heptane-6,5Ј-[1,3]dioxan]-7-ol (23): 1H NMR (400 MHz,
CDCl3): δ = 6.11 (dq, J1 = 1.4, J2 = 15.3 Hz, 1 H), 5.87 (dq, J1 =
6.6, J2 = 15.0 Hz, 1 H), 4.60 (d, J = 6.4 Hz, 1 H), 4.56 (d, J =
6.3 Hz, 1 H), 4.50–4.42 (m, 1 H), 4.24 (dt, J1 = 1.1, J2 = 11.5 Hz,
1 H), 4.12–4.10 (m, 2 H), 3.73 (d, J = 11.3 Hz, 1 H), 3.35 (s, 3 H),
2.76 (s, 1 H), 2.50 (dd, J1 = 2.0, J2 = 8.5 Hz, 1 H), 2.29 (t, J =
8.6 Hz, 1 H), 2.10 (ddd, J1 = 1.9, J2 = 6.9, J3 = 12.8 Hz, 1 H),
1.83–1.75 (m, 4 H), 1.42 (s, 3 H), 1.35 (s, 3 H), 1.25 (s, 3 H), 0.81
(s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 131.5, 124.4, 98.0, 96.7, 81.8, 80.6, 67.6, 64.1, 59.1,
55.6, 48.0, 44.9, 39.3, 29.8, 28.9, 25.8 (3 C), 23.9, 18.9, 18.2, 18.1,
–2.1, –2.2 ppm. HRMS (ESI): calcd. for C24H44O6SiNa [M +
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Eur. J. Org. Chem. 2013, 8245–8252