Synthesis of [n,5]-spiroketals by ring enlargement of donor-acceptor- substituted cyclopropane derivatives

Article abstract of DOI:10.1021/jo901902g

(Chemical Presented) Exocyclic enol ethers served as starting materials for the synthesis of [n,5]-spiroketals (n = 5, 6). A metal-mediated cyclopropanation using ethyl diazoacetate afforded spiroannelated cyclopropane derivatives bearing an ester group.

Full text of DOI:10.1021/jo901902g

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Synthesis of [n,5]-Spiroketals by Ring Enlargement of Donor-
Acceptor-Substituted Cyclopropane Derivatives
Christian Brand,† Gesche Rauch,† Michele Zanoni,† Birger Dittrich,‡ and
Daniel B. Werz*,†
†
€
Institut fu€r Organische und Biomolekulare Chemie der Georg-August-Universitat Gottingen, Tammannstr.
€
2, 37077 Go€ttingen, Germany, and ‡Institut fu€r Anorganische Chemie der Georg-August-Universita€t
€ €
Gottingen (X-ray Crystallography), Tammannstr. 4, 37077 Gottingen, Germany
dwerz@gwdg.de
Received September 2, 2009
Exocyclic enol ethers served as starting materials for the synthesis of [n,5]-spiroketals (n = 5, 6).
A metal-mediated cyclopropanation using ethyl diazoacetate afforded spiroannelated cyclopropane deriva-
tives bearing an ester group. A reduction of the corresponding ester by LiAlH4, followed by subsequent
oxidation using hypervalent iodine reagents, produced [n,5]-spiroketals in moderate to good yields. The key
step within this three-step sequence is the ring enlargement of the three-membered ring with an oxygen donor
and a carbonyl acceptor group into the five-membered enol ether system. Catalytic amounts of the Lewis acid
Yb(OTf)3 facilitate the ring enlargement and increase the yield of the corresponding spiroketal in many cases.
When Yb(OTf)3 was used, our experiments revealed an open transition state rather than a concerted
mechanism because the stereochemistry of the spirocenter was not conserved during the ring enlargement. As
a result, the thermodynamically more favored anomeric [n,5]-spiroketal was observed as the major product.
All the structures were established unambiguously by NOESY experiments.
Introduction
The classical route for the preparation of the spiroketal
motif is the Bronsted or Lewis acid mediated dehydrative
spirocyclization3 of the corresponding oxo diol 1 (Scheme 1).
This rather flexible method that can afford different ring
sizes is a thermodynamically driven process and commonly
results in a diaxial spiroketal arrangement 3. In such an
arrangement two anomeric effects are in operation leading to
a significant net energy stabilization.4 However, in the case of
acid-labile compounds (e.g., enol ethers) or in the case the
less thermodynamically stable isomer is required, this meth-
odology commonly fails.
The semirigid spiroketal moiety forms a characteristic
architectural feature in a plethora of simple as well as complex
natural products including insect pheromones and marine and
fungal toxins.1 A number of different ring arrangements are
observed in Nature; however the most abundant are [6,6]-,
[6,5]-, and [5,5]-spiroketals. The conformational and geo-
metric features of these frameworks have rendered spiroketals
as preferred targets in diversity-oriented synthesis.2
Accordingly, other spiroketal syntheses have attracted
considerable interest, and numerous elegant methods have
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DOI: 10.1021/jo901902g
r
Published on Web 10/28/2009
J. Org. Chem. 2009, 74, 8779–8786 8779
2009 American Chemical Society

Brand et al.
JOCArticle
SCHEME 1. Dehydrative Spirocyclization of Oxo Diol 1 as the
Classical Route to Spiroketals 2 (top) and the Most Favored
Conformation 3 of a [6,6]-Spiroketal (bottom)
SCHEME 2. Diels-Alder (a) and Stille Approach (b) for the
Synthesis of Spiroketals 6a/6b and 9, Respectively
been developed.5-7 The most popular approaches include
hetero-Diels-Alder reactions (e.g., in the synthesis of 6a/
6b),1f,8 acetylide anion additions to lactones,9 and the use of
organometallic reactions such as metathesis10 or Pd-catalyzed
cross-coupling reactions (e.g., for the preparation of 9).11 Two
examples are illustrated in Scheme 2.
Herein, we report a novel methodology for the construc-
tion of [n,5]-spiroketals of type 10 (n = 5, 6) based on the
unique properties of donor-acceptor-substituted three-mem-
bered rings.12 The general idea of the retrosynthesis is
depicted in Scheme 3. The key step involves the ring enlarge-
ment of a spiroannelated donor-acceptor-substituted cyclo-
propane derivative 11 that is easily accessible via the
cyclopropanation of exocyclic enol ethers of type 13. Ring
(5) For an overview: Ley, S. V.; Milroy, L.-G.; Myers, R. M. Science
of Synthesis; Thieme-Verlag: Stuttgart, 2007; Vol. 29, Product Class 9:
Spiroketals, pp 613-689.
openings and ring enlargements of cyclopropane derivatives
bearing an electron-withdrawing and an electron-donating
substituent have been intensively investigated12-16 and have
also been used in a variety of natural product syntheses.12a,17
However, to the best of our knowledge donor-acceptor-
substituted cyclopropanes have only rarely been used for
spiroketal synthesis.18
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Results and Discussion
As precursors for the formation of the spiroannelated
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8780 J. Org. Chem. Vol. 74, No. 22, 2009

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SCHEME 3. Retrosynthesis of [n,5]-Spiroketals 10 Using
Exocyclic Enol Ethers 13 as Starting Materials
SCHEME 4. Two Ways To Generate Exocyclic Enol Ethers 13:
(a) Petasis Olefination of Lactones 14, (b) Elimination of HI of
Corresponding Primary Iodides 15
unsubstituted six-membered exocyclic enol ethers tend to
rearrange to the endocyclic isomers, the five-membered
counterparts are more stable in their exocyclic form. Because
of this fact and a deeper interest in facile carbohydrate
modification in our group,19 mainly exocyclic glycals that
are easily available by several routes were used for our
methodological studies of the proposed sequence.20 Either
the corresponding fully protected lactones of type 14 were
reacted with Petasis reagent,21 or we eliminated HI from the
exocyclic iodomethyl group next to the oxygen center in 15
by the action of DBU (Scheme 4).20f A high degree of
substitution renders the six-membered cycles relatively
stable in their exocyclic glycal form.
alcohols 16a-16d in good to quantitative yield (for the
assignment of the respective stereoisomers, see Figure 1).
Exocyclic glycals of type 13 were treated with an excess of
ethyl diazoacetate under rhodium or copper catalysis to
afford the spiro-annelated cyclopropane derivatives of type
12 that were commonly obtained as a mixture of several
(up to four) different stereoisomers (Table 2).22 Figure 1
provides an assignment a-d for the different stereoisomers.
In our cases, the best results for the cyclopropanation
reaction were achieved by using elemental copper powder
in hot toluene; the use of copper(I) catalysts such as Cu(OTf)
generated in situ from Cu(OTf)2 and phenyl hydrazine or the
use of Rh2(OAc)4 at room temperature afforded lower
yields. The resulting cyclopropyl esters 12a-12d were re-
duced with LiAlH4 in THF furnishing the corresponding
FIGURE 1. Assignment of the different stereoisomers of the cyclo-
propyl esters 12a-12d and the corresponding alcohols 16a-16d,
respectively.
The generation of the donor-acceptor-substituted cyclo-
propane in 11 (by oxidation of the hydroxy methyl group of
16) has to be performed in such a way that the oxidizing
agent does not attack the newly generated enol ether system
of 10 that is also prone to oxidation. Previous experiments in
our group concerning the annelation of tetrahydrofuran
units by performing a similar sequence using IBX as an
oxidizing agent revealed an instantaneous ring enlargement
of the three-membered to the five-membered ring; cyclopro-
panes bearing an aldehyde functionality were not ob-
served.16 In contrast to these results, the investigations
with respect to spiroketal formation did not reveal such a
clear-cut preference for the ring enlargement to the five-
membered spiro compound when just IBX was used as an
oxidizing agent. Therefore spirocyclopropyl derivative 19b
was chosen as a model compound to investigate a variety of
different oxidation methods and conditions in order to
optimize the transformation of 19b to spiroketal 20
(Table 1). The Swern reaction afforded only traces of the
desired spiroketal, whereas slightly better results were ob-
tained when hypervalent iodine reagents such as
Dess-Martin periodinane (DMP) or IBX, respectively, were
employed. Hence, our attention focused toward the use of
IBX in combination with different Lewis acids. It turned out
that the choice of the Lewis acid is of utmost importance to
increase the yield of the desired transformation. Whereas
hard Lewis acids such as Ti(Oi-Pr)4 and SnCl4 lead only to
traces of product (Table 2, entries 5 and 6) and Lewis acids
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TABLE 1. Different Oxidations Methods/Conditions and Additives
for the Conversion of the Cyclopropane Derivative 19b into the [5,5]-
Spiroketal 20
two faces of the double bond is shielded by bulky substitu-
ents. However, in general we were not interested in control-
ling the facial selectivity.23 For an examination of the
suggested sequence different stereoisomers were welcome.
In some cases the product mixtures, either as ester or as
alcohol, could be easily separated by silica gel column
chromatography; in other cases a separation even by HPLC
proved to be almost impossible.
We had a high degree of optimism that the ring enlarge-
ment reaction to afford the spiroketal would lead, even with
mixtures of cyclopropyl derivatives, to one major product.
We assumed that the push-pull-substituted three-mem-
bered ring generated in situ rearranges into the five-mem-
bered ring via an open-chain intermediate rather than via a
concerted mechanism. The tendency to form such an open
chain should even be greater when coordinating compounds
are used such as Lewis acids. If the latter scenario were true,
one would observe a product distribution of the correspond-
ing spiroketals solely determined by the relative thermo-
dynamic stability of the products.
The ring enlargement reactions gave moderate to good
yields of the corresponding spiroketals. In several cases trace
amounts of the highly unstable donor-acceptor-substituted
cyclopropane derivatives bearing aldehyde moieties could be
found as side products. Entry 9 reveals that conjugation of
the oxygen donor to an aromatic cycle does not destroy its
ability to act as a donor in the push-pull system.
Entry
1
Conditions
Additivesa Yield [%]
5
(COCl)2 (1.1 equiv), DMSO (2.2 equiv),
NEt3 (4.0 equiv), -78 °C, CH2Cl2, 30 min
DMP (1.2 equiv), CH2Cl2, rt, 2 h
IBX (1.2 equiv), DMSO, rt, 12 h
IBX (1.2 equiv), DMSO, rt, 8 h
IBX (1.2 equiv), DMSO, rt, 8 h
IBX (1.2 equiv), DMSO, rt, 8 h
IBX (1.2 equiv), DMSO, rt, 8 h
IBX (1.2 equiv), DMSO, rt, 8 h
IBX (1.2 equiv), DMSO, rt, 8 h
IBX (1.2 equiv), DMSO, rt, 8 h
IBX (2.0 equiv), DMSO, rt, 8 h
IBX (1.2 equiv), DMSO, 60 °C, 8 h
2
3
4
5
6
7
8
9
22
15
26
b
Ti(Oi-Pr)4
SnCl4
-
-
c
BF3 OEt2
MgCl2
ZnCl2
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
15
18
44
55
53
24
3
10
11
12
a0.1 equiv of additive was used. bTraces of the product were observed.
cComplete decomposition.
such as BF3 OEt2 and MgCl2 have almost no influence on
3
the reaction outcome (Table 2, entries 7 and 8), soft Lewis
acids such as ZnCl2 and Yb(OTf)3 increase the yield to 44%
and 55%, respectively (Table 1, entries 9 and 10). A larger
excess of IBX did not result in better yield. Higher reaction
temperatures led to worse results than those when perform-
ing the reaction at room temperature (Table 2, entries 11 and
12). We assume that the action of a Lewis acid is necessary in
order to weaken the bond between the electron-donating and
the electron-withdrawing substituent in the three-membered
ring. However, after the ring enlargement the Lewis acid
must not be allowed to attack the newly generated enol ether
system. Thus, a successful outcome of the reaction results
essentially as a compromise of two effects: an effective
weakening of the push-pull-substituted bond in the three-
membered ring by coordinating the in situ generated alde-
hyde moiety and the ability not to attack the enol ether
system after its generation. Therefore, the kind of Lewis acid
that has been added as a catalyst is crucial.
With a reliable procedure in our hands we examined the
spiroketal formation of other cyclopropanated carbohy-
drate derivatives. As starting materials we used the exocyclic
enol ether systems depicted in Table 2. Our choice comprises
five- and six-membered exocyclic enol ethers as well as
different protecting groups for hydroxyl functionalities such
as isopropylidene, cyclohexylidene, and benzyl ethers. Also
two examples of non-carbohydrate-derived enol ethers were
chosen (entries 8 and 9). For all educts 13 cyclopropanation
led to a mixture of cyclopropyl derivatives 12a-12d that
were reduced by LiAlH4 to the corresponding alcohols
16a-16d. In the case of enol ether 21 we observed a highly
substrate-controlled product formation because one of the
Our investigations of different diastereomers revealed that
the configuration of the spirocenter is not conserved during the
transformation when only IBX or IBX in the presence of
Yb(OTf)3 was used as oxidizing agent. As previously assumed,
the creation of the thermodynamically more stable spiroketal
is favored. Mechanistically, these results suggest that a con-
certed mechanism does not take place or only takes place to a
minor extent (Scheme 5, left), whereas the main reaction
pathway leads via a zwitterionic intermediate such as the
open-chain compound 54 (Scheme 5, right). In the latter case,
the stereochemistry at the spirocenter is not conserved. All four
cyclopropyl stereoisomers would afford the same product or
the same product ratio of spiroketals, respectively. To our
surprise, a different outcome was observed when Dess-
Martin periodinane was utilized to perform the ring enlarge-
ment. In general, the yields obtained with DMP were rather
poor (see also Table 1); however, in two cases (entries 4 and 6)
better results were obtained. As exemplified by entry 6, the
oxidation of cyclopropyl derivative 39d afforded only the less
thermodynamically stable spiroketal without anomeric effect
in operation. Such an outcome is only plausible if a concerted24
rather than a zwitterionic mechanism takes place when DMP is
employed. In contrast to the oxidation by IBX, different ratios
of spiroketals 28a/28b and 32a/32b, respectively, were ob-
tained when Dess-Martin periodinane was used. Whereas
the 5:1 ratio of the corresponding spiroketals achieved by the
action of IBX does not mirror the distribution of the starting
material, the 2:1 ratio (after the oxidation using Dess-Martin
periodinane) is similar to it. Experiments to equilibrate the
different stereoisomeric spiroketals under the reaction condi-
tions or with exposure to Yb(OTf)3 were in vain.
(23) To the best of our knowledge, the highly diastereoselective cyclo-
propanation of exocyclic enol ethers is an unsolved problem. Initial experi-
ments using bisoxazoline ligands did not reveal significant preferences for
distinct stereoisomers.
(24) A concerted mechanism for the rearrangement of a vinylcyclopro-
pylcarbaldehyde to afford a five-membered enol ether was discussed by DFT
calculations: Sperling, D.; Reissig, H.-U.; Fabian, J. Eur. J. Org. Chem.
1999, 1107–1114.
8782 J. Org. Chem. Vol. 74, No. 22, 2009

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TABLE 2. Oxidative Spiroketal Formation
aCombined yield for the different stereoisomers; the first value gives the yield of the cyclopropanation reaction; the second the yield of the reduction.
For detailed information on cyclopropanation yields and product distribution, as well as yields of reduction, see Supporting Information. bYield of
spiroketal formation (see also Supporting Information for details). cIBX (1.2 equiv), Yb(OTf)3 (0.1 equiv), DMSO, rt, 8 h. dIBX (1.2 equiv), DMSO, rt,
8 h. eDess-Martin periodinane (1.1 equiv), CH2Cl2, rt, 12 h. f19b was oxidized. g23a and 23b were oxidized as a mixture and separately with the same
yield. hA mixture of all four diastereomers was oxidized. i35a was oxidized. j39a as well as 39d was oxidized with the same yield. k43c was oxidized; there
l
was a poorer yield with 43d. 47a and 47b were oxidized separately with the same yield. m5:1 ratio (a:b) when IBX was used, 2:1 ratio (a:b) when
Dess-Martin periodinane was used. nObtained as racemic mixture of both enantiomers.
J. Org. Chem. Vol. 74, No. 22, 2009 8783

Brand et al.
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SCHEME 5. Potential Mechanism of Spiroketal Formation via
a Concerted Mechanism (left) and an Open-Chain Intermediate
54 (right)
FIGURE 2. Most important NOE effects for determination of
stereochemistry of 28a (left) and 28b (right).
molecular structures25,26 and to confirm the stereochemistry
at the spirocenter also assigned by NOESY investigations.
Two structures are depicted in Figure 3. An elucidation of
the geometrical properties within the cyclopropane moiety
shows an almost perpendicular arrangement (74.4°) of the
ester group to the plane of the three-membered ring. Such a
behavior is suggested by the Walsh model of cyclopropane.27
Also the bond lengths are in accordance with this model: the
shortest bond (1.488 A compared to 1.523 and 1.508 A) is
found opposite to the electron-withdrawing ester group. The
longest bond (1.523 A) is located between the donor- and the
acceptor-substituted carbon atoms. As anticipated by the
Walsh model, such geometrical features were not observed
for the cyclopropyl alcohols 43 and 51 bearing the hydroxy
methyl instead of the ester moiety.
Finally, we subjected the benzyl-protected [6,5]-spiroke-
tals 28, 32, 36, and 40 to hydrogenolysis using Pearlman0s
catalyst (Table 3). Cleavage of all benzyl groups and the
reduction of the enol ether double bond was achieved,
affording the fully deprotected spiroketals 57a-60 in very
good to quantitative yield.
A proper analysis of the 13C NMR spectra of protected
and deprotected [6,5]-spiroketals revealed an interesting
tendency of the chemical shift of the spiro carbon atom.
All spiroketals that are anomerically favored (in our nomen-
clature in Table 4 assigned as a) showed a lower-frequency
resonance than the corresponding stereoisomers that are not
stabilized by the anomeric affect (assigned in Table 4 as b).4
In general, we found resonance frequencies of 109-111 ppm
when anomeric effects are operating and resonance frequen-
cies of 111-112 ppm without this effect in operation. We
assume that this slight difference in chemical shift may be
attributed to the np(O) f σ*(C-O) interaction that increases
the electron density around the spiro carbon atom, whereas
such an interaction cannot take place in the other anomer. As
a result of the increased electron density the spiro carbon
atoms are more shielded. This observation, which has also
been demonstrated in recent literature,28 may be also useful
for the elucidation of the stereochemistry of unknown
spiroketal structures and may give a further indication of
their geometrical feature besides extensive spectroscopic
investigations such as NOE spectroscopy.
The identity of all diastereomers was unequivocally deter-
mined by extensive 2D-NMR spectroscopic techniques as
well as NOESY investigations. The major NOE correlation
effects for the determination of the configuration at the
spirocenter of spiroketals is exemplarily depicted in Figure 2
for 28a and 28b. In the case of 28b we found a strong NOE
correlation between H-2 and one hydrogen of the methylene
unit in the five-membered ring, whereas such NOE correla-
tion could not be observed in the case of the other diastereo-
mer 28a, but for H-3.
For three of the cyclopropane derivatives, the ester 38d
and the alcohols 43b and 51, we were able to grow single
crystals suitable for X-ray crystallography to elucidate their
ꢀ
(26) For the XDLSM program see: Koritsanszky, T.; Richter, T.;
Macchi, P.; Volkov, A.; Gatti, C.; Howard, S.; Mallinson, P. R.; Farrugia,
L.; Su, Z.; Hansen, N. K. XD;A Computer Program Package for Multipole
Refinement and Analysis of Electron Densities from Diffraction Data
(25) The diffractometer was equipped with a molybdenum microsource.
Diffraction data also allowed an invariom refinement using the XDLSM
program, which led to significant improvements in the figures of merit, bond
lengths, and the physical significance of the anisotropic displacement para-
meters (ADPs). For the method of invariom refinement, see: (a) Dittrich, B.;
€
(Handbook), Freie Universitat: Berlin, 2003.
(27) (a) Walsh, A. D. Nature (London) 1947, 159, 712–713. (b) Sugden,
T. M. Nature (London) 1947, 160, 367–368. (c) Walsh, A. D. Trans. Faraday
Soc. 1949, 45, 179–190.
ꢀ
Koritsanszky, T.; Luger, P. Angew. Chem. 2004, 116, 2773–2776. Angew.
€
(28) (a) Pothier, N.; Goldstein, S.; Deslongchamps, P. Helv. Chim. Acta
1992, 75, 604–620. (b) Zanatta, S. D.; White, J. M.; Rizzacasa, M. A. Org.
Lett. 2004, 6, 1041–1044. (c) de Oliveira, L. G.; Dias, L. C.; Sakauchi, H.;
Kiyota, H. Tetrahedron Lett. 2006, 47, 2413–2418.
Chem., Int. Ed. 2004, 43, 2718-2721. (b) Dittrich, B.; Hubschle, C. B.;
Messerschmidt, M.; Kalinowski, R.; Girnt, D.; Luger, P. Acta Crystallogr.
2005, A61, 314–320.
8784 J. Org. Chem. Vol. 74, No. 22, 2009

Brand et al.
JOCArticle
TABLE 3. Hydrogenolysis of Protected [6,5]-Spiroketals of Type 55 To
Afford Deprotected Spiroketals of Type 56
FIGURE 3. ORTEP plots (50% ellipsoid probability) of the mole-
cular structures of 38d (top) and 51 (bottom). Oxygen atoms are
shown in red. In the case of 38d hydrogen atoms are omitted for the
sake of clarity.
Conclusions
In summary, we have developed a concise and original
method for the formation of [n,5]-spiroketals (n = 5, 6). The
key step of the synthetic sequence is the ring enlargement of
donor-acceptor-substituted cyclopropane derivatives into
five-membered enol ether systems. Starting materials are
easily available exocyclic enol ethers that are converted by
a sequence of cyclopropanation using ethyl diazoacetate and
subsequent reduction with LiAlH4 into the corresponding
alcohols. The hydroxy functionality was oxidized by hyper-
valent iodine reagents to the cyclopropyl aldehyde that
underwent ring enlargement to the desired compounds. In
most cases best results were achieved by the use of IBX. The
soft Lewis acid Yb(OTf)3 proved to be a useful additive to
increase the yield of the desired transformation. In general,
stereoisomeric mixtures of cyclopropyl derivatives could be
employed because of a zwitterionic mechanism leading to the
corresponding products via an open-chain intermediate. Sur-
prisingly, the use of Dess-Martin periodinane conserved the
stereochemistry of the spirocenter during the transformation.
This method for spiroketal formation proves to be an elegant
way to access [n,5]-spiroketals with an enol ether double bond in
the five-membered ring that are difficult to obtain by common
methods of spiroketal formation. The versatility of our three-
step approach has been demonstrated by the preparation of
several monosaccharide-derived spiroketals.
TABLE 4. Comparison of the Chemical Shift of Spiro Carbon Atom
δ(Cspiro) [ppm] in [6,5]-Spiroketals with and without Anomeric Stabiliza-
tion
δ(Cspiro) With Anomeric
Stabilization (a)
δ(Cspiro) Without Anomeric
Stabilization (b)
Spiroketal
28a
32a
36a
40a
44a
57b
58b
59b
60b
109.1
109.3
109.7
109.6
110.9
108.9
109.3
109.3
-
111.4
112.0
-
111.9
-
111.1
111.8
-
111.9
aRelative to δ(CDCl3) = 77.0 ppm; measured in CDCl3. bRelative to
δ(CD3OD) = 49.2 ppm; measured in CD3OD.
Experimental Section
was added and heated to 70 °C. Over a period of 12 h a solu-
tion of ethyl diazoacetate (4.29 g, 35.9 mmol, 4.0 equiv) in
anhydrous toluene (10 mL) was added via syringe pump. After
completed addition, the solution was stirred for 30 min at 70 °C.
Formation of the Cyclopropyl Ester 18a-18d. Compound
1720n (1.57 g, 8.43 mmol, 1.0 equiv) was dissolved in anhydrous
toluene (12 mL). Cu powder (0.269 g, 4.22 mmol, 0.5 equiv)
J. Org. Chem. Vol. 74, No. 22, 2009 8785

Brand et al.
JOCArticle
Evaporation of the solvent and purification by column chro-
matography (SiO2, pentane/EtOAc, 5:1) afforded four diaster-
eoisomers 18a-18d as colorless oils with an overall yield of 1.90
g (83%). HPLC (hexane/isopropyl alcohol 98:2, 3 mL/min)
afforded pure samples of 18c and 18d.
Analytical Data of Mixture of 18a and 18b. Yield: 54%. Rf:
0.30 (hexane/EtOAc, 5:1). 1H NMR (300 MHz, CDCl3): δ 1.24
(t, J = 7.1 Hz, 3.6 H), 1.47-1.55 (m, 2.4 H), 1.89 (dd, J = 9.5,
7.3 Hz, 1 H), 2.15 (dd, J = 9.4, 6.8 Hz, 0.2 H), 3.28 (s, 0.6 H),
3.31 (s, 3 H), 4.03-4.23 (m, 2.6 H), 4.56 (d, J = 5.9 Hz, 1 H),
4.62 (d, J = 5.9 Hz, 0.2 H), 4.70 (d, J = 5.9 Hz, 0.2 H), 4.77
(d, J = 5.9 Hz, 1 H), 4.91 (s, 0.2 H), 4.94 (s, 1 H). 13C NMR
(125 MHz, CDCl3): δ 13.2, 13.2, 14.2, 14.4, 20.1, 20.9, 25.5,
25.7, 26.4, 26.5, 26.9, 54.9, 55.0, 60.7, 60.8, 72.2, 73.0, 79.0,
82.0, 84.8, 107.8, 107.9, 112.4, 112.5, 170.8, 171.1. IR (film):
ν~ (cm-1) = 2986, 2939, 2836, 1722, 1447, 1383. UV (CH3CN):
CDCl3): δ 0.63 (t, J = 6.5 Hz, 1 H), 0.95 (dd, J = 10.1, 6.0
Hz, 1 H), 1.31 (s, 3 H), 1.52 (s, 3 H), 1.67-1.77 (m, 1 H),
2.99-3.16 (m, 2 H), 3.27 (s, 3 H), 3.98 (dt, J = 12.0, 5.1 Hz, 1 H),
4.59 (d, J = 6.0 Hz, 1 H), 4.70 (d, J = 6.0 Hz, 1 H), 4.91 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ 16.8, 20.5, 25.0, 26.3, 54.8, 64.2,
70.1, 83.1, 85.6, 107.8, 112.6. IR (film): ν~ (cm-1) = 3338, 2992,
1374, 1264. UV (CH3CN): λmax [nm] (log ε) = 194.0 (2.767).
HRMS (ESI): m/z calcd for C11H18O5Na: 253.10464; found
253.10459.
Formation of Spiroketal 20. A 10 mL flask was charged with a
solution of 19b (60 mg, 0.26 mmol, 1.0 equiv) in dry DMSO
(3 mL). IBX (88 mg, 0.31 mmol, 1.2 equiv) and Yb(OTf)3
(16 mg, 0.03 mmol, 0.1 equiv) were sequentially added, and
the resulting mixture was stirred at room temperature for 8 h.
The reaction was stopped by addition of water (5 mL). Et2O
(10 mL) was added, and the layers were separated. The water
layer was extracted with Et2O (3 ꢀ 5 mL), and the combined
organic phases were washed with brine (10 mL), dried over
Na2SO4, filtrated, and concentrated in vacuo. Purification by
column chromatography (SiO2, pentane/Et2O, 6:1) afforded 20
(33 mg, 55%) as a colorless oil: Rf: 0.30 (hexane/Et2O, 6:1).
[R] = 4.0° (c 1.05, CHCl3). 1H NMR (600 MHz, CDCl3): δ 1.29
(s, 3 H), 1.40 (s, 3 H), 2.54 (dt, J = 17.5, 2.4 Hz, 1 H), 3.06 (dt,
J = 17.5, 2.5 Hz, 1 H), 3.35 (s, 3 H), 4.65 (d, J = 5.8 Hz, 1 H),
4.69 (d, J = 5.8 Hz, 1 H), 4.96 (dd, J = 5.3, 2.8 Hz, 1 H), 4.98
(s, 1 H), 6.27 (dt, J = 2.8, 2.0 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): δ 25.2, 26.4, 35.5, 55.0, 84.1, 84.7, 99.5, 108.9, 112.6,
119.1, 143.3. IR (film): ν~ (cm-1) = 2989, 1623, 1374, 1198.
UV (CH3CN): λmax [nm] (log ε) = no absorption in the range
of 190 - 350 nm. HRMS (ESI): m/z calcd for C11H16O5Na:
251.08899; found 251.08904.
λ
max [nm] (log ε) = no absorption in the range of 190-350 nm.
HRMS (ESI): m/z calcd for C13H20O6Na: 295.11521; found
295.11521.
Analytical Data of 18c. Yield: 16%. Rf: 0.18 (hexane/EtOAc,
5:1). [R] = 107.5° (c 0.20, CHCl3). 1H NMR (600 MHz, CDCl3): δ
1.18 (dd, J = 9.2, 5.9 Hz, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.32 (s, 3
H), 1.46 (s, 3 H), 1.66 (dd, J = 7.0, 5.9 Hz, 1 H), 2.08 (dd, J = 9.1,
7.0Hz, 1H), 3.33(s, 3H), 4.18(q, J= 7.2 Hz, 2 H), 4.38 (d, J=5.8
Hz, 1 H), 4.62 (d, J = 5.8 Hz, 1 H), 5.00 (s, 1 H). 13C NMR (125
MHz, CDCl3): δ 14.3, 19.1, 20.5, 26.1, 26.6, 54.8, 60.8, 71.6, 83.7,
84.7, 107.4, 113.1, 169.3. IR (film): ν~ (cm-1) = 2986, 2836, 1736,
1449, 1384, 1330. UV (CH3CN): λmax [nm] (log ε) = no absorption
in the range of 190-350 nm. HPLC: tR (hexane/isopropyl
alcohol 98:2, 3 mL/min) = 12.2 min. HRMS (ESI): m/z calcd
for C13H20O6Na: 295.1152; found 295.1158.
Analytical Data of 18d. Yield: 13%. Rf: 0.18 (hexane/EtOAc,
5:1). [R] = 90.0° (c 0.22, CHCl3). 1H NMR (600 MHz, CDCl3):
δ 1.26 (t, J = 6.9 Hz, 3 H), 1.30 (s, 3 H), 1.37 (dd, J = 8.6,
6.3 Hz, 1 H), 1.47 (s, 3 H), 1.78-1.89 (m, 2 H), 3.20 (s, 3 H),
4.01-4.23 (m, 2 H), 4.40 (d, J = 6.0 Hz, 1 H), 4.63 (d, J = 6.0
Hz, 1 H), 4.95 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ 11.6,
14.4, 25.7, 26.4, 27.2, 55.7, 60.6, 72.9, 84.3, 84.7, 108.8, 112.9,
169.1. IR (film): ν~ (cm-1) = 2985, 2938, 2838, 1731, 1455, 1402,
1383. UV (CH3CN): λmax [nm] (log ε) = no absorption in the
range of 190-350 nm. HPLC: tR (hexane/isopropyl alcohol
98:2, 3 mL/min) = 13.3 min. HRMS (ESI): m/z calcd for
C13H20O6Na: 295.1152; found 295.1163.
Formation of the Cyclopropyl Alcohols 19a and 19b. To a
solution of LiAlH4 (0.045 g, 1.2 mmol, 1.2 equiv) in dry THF
(8 mL) was slowly added a solution of a mixture of 18a and 18b
(0.27 g, 0.99 mmol, 1.0 equiv) in dry THF (5 mL), and the
mixture was stirred at room temperature for 2 h. The reaction
was stopped by addition of MeOH. Evaporation of the solvent
and purification by column chromatography (SiO2, pentane/
EtOAc, 2:1) afforded 19a and 19b as colorless oils with an
overall yield of (0.184 g, 81%).
Analytical Data of 19a. Yield: 66%. Rf: 0.18 (hexane/EtOAc,
2:1). [R] = 19.0° (c 0.6, CHCl3). 1H NMR (300 MHz, CDCl3):
δ 0.78 (t, J = 7.0 Hz, 1 H), 1.22 (dd, J = 10.0, 6.9 Hz, 1 H), 1.32
(s, 3 H), 1.35-1.46 (m, 1 H), 1.49 (s, 3 H), 1.65 (bs, 1 H), 3.21
(t, J = 10.6 Hz, 1 H), 3.32 (s, 3 H), 3.90 (dd, J = 11.3, 5.7 Hz,
1 H), 4.57 (d, J = 5.9 Hz, 1 H), 4.66 (d, J = 5.9 Hz, 1 H), 4.91
(s, 1 H). 13C NMR (125 MHz, CDCl3): δ 9.9, 25.4, 26.3, 26.4,
55.0, 62.9, 69.2, 79.9, 85.3, 107.4, 112.4. IR (film): ν~ (cm-1) =
3435, 2935, 1729, 1454, 1373. UV (CH3CN): λmax [nm] (log ε) =
228.5 (3.482). HRMS (ESI): m/z calcd for C11H18O5Na:
253.1046; found 253.1045.
Hydrogenation and Deprotection of Spiroketal 28a To Afford
57a. To a solution of 28a (32.0 mg, 0.055 mmol, 1.0 equiv) in a
mixture of MeOH/CH2Cl2 (3:1, 3 mL) was added Pd(OH)2/C
(Pearlman’s catalyst, 25 mg). The reaction mixture was stirred
under a hydrogen atmosphere of 1 bar for 16 h at room
temperature. Filtration over Celite afforded 57a (12.1 mg,
quant) as a colorless solid: [R] = 58.1° (c 1.46, MeOH). 1H
NMR (300 MHz, CD3OD): δ 1.79-2.23 (m, 4 H), 3.26-3.38
(m, 2 H), 3.53-3.67 (m, 3 H), 3.76 (dd, J = 11.5, 2.4 Hz, 1 H),
3.90-3.97 (m, 2 H). 13C NMR (125 MHz, CD3OD): δ 24.8, 34.6,
62.8, 69.4, 71.9, 74.1, 74.3, 76.6, 108.9. IR (film): ν~ (cm-1) =
3423, 2933, 2509, 1647, 1441, 1195, 1165. UV (CH3CN): λmax
[nm] (log ε) = no absorption in the range of 190-350 nm.
HRMS (ESI): m/z calcd for C9H16O6Na: 243.08391; found
243.08408.
Acknowledgment. We are grateful to the Deutsche
Forschungsgemeinschaft (DFG) and the Fonds der Chemi-
schen Industrie (FCI) for financial support (Emmy Noether
Fellowships to B.D. and D.B.W as well as Liebig Fellowship
to D.B.W.). M.Z. thanks the European Union for an Eras-
mus Fellowship. We thank Prof. Lutz F. Tietze for helpful
discussions and generous support of our work.
Supporting Information Available: Experimental proce-
1
dures and analytical data for all new compounds. H and 13C
NMR spectra of all new compounds. CIF files of 38d, 43b, and
51.29 This material is available free of charge via the Internet at
http://pubs.acs.org.
(29) Cif files have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publications no. CCDC-746262 (38d),
CCDC-746263 (43b), and CCDC-746264 (51). Copies can be obtained via
email: data_request@ccdc.cam.ac.uk.
Analytical Data of 19b. Yield: 15%. Rf: 0.28 (hexane/EtOAc,
2:1). [R] = -37.9° (c 0.39, CHCl3). 1H NMR (300 MHz,
8786 J. Org. Chem. Vol. 74, No. 22, 2009