Stereoselective total synthesis of (-)-spirofungin a by utilising hydrogen-bond controlled spiroketalisation

Article abstract of DOI:10.1002/chem.201002501

The stereoselective total synthesis of the spiroketal containing Streptomyces metabolite (-)-spirofungin A (1) is described. A key step involved a spiroketalisation controlled by an intramolecular H-bond which favoured the desired spiroketal 4 (13:1 ratio

Full text of DOI:10.1002/chem.201002501

FULL PAPER
DOI: 10.1002/chem.201002501
Stereoselective Total Synthesis of
ACHTUNGTRENNUNG
Hydrogen-Bond Controlled AHCTNUGTRENNNUG
John E. Lynch, Shannon D. Zanatta, Jonathan M. White, and Mark A. Rizzacasa*[a]
Abstract: The stereoselective total syn-
thesis of the spiroketal containing
Streptomyces metabolite (À)-spirofun-
gin A (1) is described. A key step in-
volved a spiroketalisation controlled by
an intramolecular H-bond which fav-
oured the desired spiroketal 4 (13:1
ratio). The presence of the intramolec-
ular H-bond in 4 is possibly due to a
1,5-alkyne–oxygen interaction. Other
key steps include an efficient cross-
metathesis to form the spiroketal pre-
cursor, a tin mediated syn-aldol reac-
tion and a Stille cross-coupling reaction
À
to create the C22 C23 bond. A final
Wittig extension followed by deprotec-
Keywords: hydrogen bonds · natu-
ral products · spirofungins · spiroke-
tals · total synthesis
tion gave (À)-spirofungin A (1).
Introduction
The spirofungins A (1) and B (2) are [6,6]-spiroketal con-
taining natural products that were isolated from Streptomy-
ces violaceusniger Tꢀ 4113 collected in the Otway National
Park, Australia.[1] Spirofungin B was originally proposed to
be compound 3, however, this structural assignment was cu-
rious since it is epimeric at the C18 and C19 stereocenters
with 1 which is difficult to rationalise biosynthetically. We
subsequently completed a total synthesis of the proposed
structure 3 for spirofungin B which was not identical to the
natural compound and this allowed for the reassignment of
the structure of spirofungin B to be 2, namely the C15
isomer of 1.[2]
Spirofungins A (1) and B (2) can therefore interconvert
under acidic conditions to afford thermodynamic mixture fa-
vouring the spiroisomer 1 with double anomeric stabilisa-
tion[3] (Scheme 1). However, an unfavourable steric interac-
tion in spirofungin A (1) makes it close in energy to the
single anomeric isomer 2. In fact diastereoisomer 3,[2] the in-
correct originally assigned structure for spirofungin B, would
Scheme 1. Structures of spirofungins A (1) and B (2).
be the most stable. Thus, the stereoselective synthesis of
either spiroketal isomer represents a considerable chal-
lenge.[4]
[a] J. E. Lynch, Dr. S. D. Zanatta, Prof. Dr. J. M. White,
Prof. Dr. M. A. Rizzacasa
School of Chemistry, The Bio21 Molecular Science
and Biotechnology Institute, The University of Melbourne
Melbourne, Victoria 3010 (Australia)
Fax : (+61)3-9347-8396
This structural assignment was confirmed by the total syn-
thesis of spirofungins A (1) and B (2) in which the two spi-
roketals were synthesised as a mixture via acid-catalysed
spiroketalisation and separated.[5] The previous results also
demonstrated that spirofungin A (1) and B (2) interconvert
upon acid treatment as expected. A second stereoselective
E-mail: masr@unimelb.edu.au
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002501.
Chem. Eur. J. 2011, 17, 297 – 304
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
297

synthesis of spirofungin A (1) was reported in which the
C15 stereochemistry was controlled in an elegant manner
using a conformational lock in the guise of a cyclic silane.[6]
A stereocontrolled kinetic approach to the single anomeric
spiroketal present in spirofungin B (2) has also been report-
ed[7] whilst several approaches to the spiroketal cores of 1
and 2 have been described.[8]
The spirofungins possess antifungal activity against Candi-
da albicans (MIC 15 mgmLÀ1)[1] and synthetic spirofungin A
(1) was shown to possess activity against several human
cancer cells lines with IC50 values ranging from 0.64–
6.4 mm.[6] Compound 1 also specifically inhibits the activity
of isoleucyl-tRNA synthase[6] in a similar manner to that re-
ported for the structurally related natural product reveromy-
cin A.[9]
Scheme 3. Synthesis of spiroketal precursor 5.
Results and Discussion
Treatment of 5 with PPTS in CH2Cl2/MeOH induced se-
lective TES group removal and spiroketal formation to give
a separable mixture of the double anomeric spirofungin A
type spiroketal 11 and the single anomeric isomer 12 in a
We envisaged that a simple solution to the synthesis of the
spirofungin A (1) spiroketal core would be to adjust the sub-
stituents such that a thermodynamic equilibrium would bias
the formation of the double anomeric spiroketal. Retrosyn-
thetically, spirofungin A (1) could arise from the intermedi-
ate spiroketal 4 via the bond constructions shown in
Scheme 2. Spiroketal 4 possesses a sterically small C19
alkyne substituent that would allow for introduction of the
1:2 ratio favouring the spirofungin
B spiroketal 12
(Scheme 4). In this case, the steric demand of the axial ben-
zyloxymethyl substituent makes the double anomeric isomer
11 less stable than the single anomeric isomer 12[12] and ex-
posure of either 11 or 12 to PPTS in CH2Cl2 at RT gave a
similar ratio. In any event, the mixture was subjected to de-
benzylation and conversion[13] into the terminal alkynes 13
and 14. When this mixture was equilibrated under mild
acidic conditions, the ratio now favoured the double ano-
À
C20 C24 diene and a C11 hydroxyethyl side chain for the
À
formation of the C1 C11 triene. The spiroketal precursor
ketone 5 could then be accessed via a cross-metathesis[10] be-
tween enone 6 and alkene 7.
ACHUTNGERNmNUG erAHCTUNGTRNENiUGN c isomer 13 as predicted but in a somewhat disappoint-
ing ratio of 3:1. All equilibrations were conducted until
NMR spectroscopic analysis no change in the ratios.
Scheme 2. Retrosynthetic analysis of spirofungin A (1).
Scheme 4. Synthesis of spiroketals 13 and 14. PPTS=Pyridinium p-tolu-
AHCTUNGTREGUNeNN nesulfonate.
The synthesis of the spirofungin A (1) began with the
preparation of the ketone precursor
5 as shown in
Scheme 3. Treatment of Weinreb amide 8[2] with vinylmag-
nesium bromide afforded enone 6. Cross-metathesis be-
tween 1.0 equiv of the type II[10b] alkene 6 and 1.2 equiv of
type I alkene 7, prepared by TES protection of the known
alcohol 9,[11] using Grubbs II catalyst (2.5 mol%) and subse-
quent reduction of the resultant enone 10 afforded the
ketone 5 in excellent yield over the two steps.
Gratifyingly, treatment of the mixture of 13 and 14 with
CSA in CH2Cl2/MeOH resulted in clean TBS group removal
and further isomerisation to give the desired spiroketal 4
and the single anomeric isomer 15 in a higher ratio (9:1)
after separation by flash chromatography (Scheme 5). This
ratio could be further increased to 13:1 (93:7) upon equili-
298
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Chem. Eur. J. 2011, 17, 297 – 304

Total Synthesis of (À)-Spirofungin A
FULL PAPER
per ppm).[16] This difference could simply arise from the
steric interaction of the alkyne and hydroxyethyl group in 4
which results in a conformation favouring the H-bond. Al-
ternatively, a higher electron density in the oxygen atom H-
bond acceptor of spiroketal 4 could be due to the close
proximity of the axial alkyne group. As seen in the X-ray
data shown in Figure 1, the alkyne carbon (C14) and ketal
oxygen atom (O1) are 2.94(2) ꢂ apart which is within the
sum of the van der Waals radii. Furthermore, the alkyne
À ꢁ
carbon is directed towards the oxygen atom with the C C
C bond angle perturbed to 174.8(1)8. This distortion is indi-
cative of a (1,5) attractive electrophile/nucleophile interac-
tion between the alkyne carbon and oxygen atoms.[17]
Scheme 5. Equilibration of spiroketal isomers 4 and 14 and formation of
spiroketals 16 and 17. CSA=10-Camphorsulphonic acid.
X-ray analysis and calculations conducted on tolan (di-
phenylethyne) derivatives indicate an increased “lone-pair”
density on an oxygen atom and depletions in valence shell
charge on the alkyne carbon atom.[18] A subtle increase in
the electron density of the oxygen atom by this type of at-
tractive interaction could account for the formation of an
stronger intramolecular H-bond in isomer 4. The influence
of the alkyne is further supported by the fact that there is
no thermodynamic preference for spiroketal 16 (with a ben-
zyloxymethyl group in place of the alkyne) indicating an ab-
sence of an H-bond effect as seen in 4 (Scheme 5). Intramo-
lecular H-bonding has been utilised to control spiroketal iso-
merisations but the hydroxyl group is always located on a
ring carbon.[19] To our knowledge, this is the only example
where the H-bond involves a flexible hydroxyethyl side
chain and this should prove useful in the production of re-
lated labile spiroketal systems.
The completion of the total synthesis of spirofungin A (1)
is shown in Schemes 6 and 7. Oxidation of the alcohol in 4
followed by consecutive Wittig extensions gave the a,b,g,d-
unsaturated ester 18 (Scheme 6). Conversion of 18 into the
labile aldehyde 19 by reduction and oxidation then allowed
for a aldol reaction[20] using the tin enolate derived from ox-
azolidine-2-thione 20 to afford adduct 21 in good yield over
bration of either spiroketal 4 or 15 with CSA in CH2Cl2 at
RT. Therefore, after one recycle, the spirofungin A spiroke-
tal 4 was obtained almost exclusively (>99:1). Equilibration
with CSA in the hydrogen-bonding solvent DMSO[14] gave 4
and 15 in a lower ratio of 3:1 respectively.
For comparison, treatment of ketone 5 with CSA resulted
in spiroketalisation and concomitant removal of the TBS
group to afford the two spiroketal alcohol isomers 16 and
17, slightly favouring the single anomeric isomer 17 in a
ratio of 1.4:1. This ratio is similar to that for the TBS-pro-
tected spiroketals 12 and 11 (see Scheme 4) showing that
the free alcohol has little influence in this system. Equilibra-
tion with CSA in CH2Cl2 gave 16 and 17 in a 1:1 ratio. This
clearly indicates that the combination of the free alcohol
and axial alkyne substituent in 4 is key to the thermodynam-
ic preference for this spiroisomer.
Both compounds 4 and 15 were crystalline and X-ray[15]
analysis combined with NMR spectroscopy as well the
above experimental results indicated an intramolecular H-
bond as possible explanation for the increased thermody-
namic preference for isomer 4. As shown in Figure 1, spiro-
ketal 4 has an intramolecular H-bond [2.06(2) ꢂ] between
the primary alcohol and the spiro oxygen atom in the solid
state. This H-bond is also present in solution with a hydroxyl
resonance observed at d=3.14 ppm (t, J=5.2 Hz, OH; un-
1
changed on dilution) in the H NMR spectrum of 4. In the
isomer 15, no intramolecular H-bond is indicated in the X-
ray structure and the resonance for the hydroxyl proton ap-
pears at d=2.16 ppm. Therefore, the H-bond in 4 increases
the stability of this isomer over spiroketal 15 (ꢀ6.3 kJmolÀ1
Scheme 6. Synthesis of the diol 20. DMP=Dess–Martin periodinane.
NEP=N-Ethylpiperidine.
Figure 1. X-ray ORTEP figures of spiroketal isomers 4 and 15 (ellipsoids
have a probability of 50%).
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299

M. A. Rizzacasa et al.
the three steps. Reductive removal of the oxazolidine-2-
thione auxiliary followed by protection of the resultant diol
22 and selective deprotection gave alcohol 23. The other
product of the deprotection was the diol 22 which could
easily be recycled.
Experimental Section
General: Proton nuclear magnetic resonance spectra (1H NMR,
400 MHz, 500 MHz) and proton decoupled carbon nuclear magnetic res-
onance spectra (13C NMR, 100 MHz, 125 MHz and 200 MHz) were mea-
sured in deuterochloroform with residual chloroform as internal standard
unless otherwise stated. Optical rotations were recorded for 1 mL solu-
tions and units are degcm2 gÀ1. Flash chromatography was carried out on
silica gel 60. Analytical thin layer chromatography was conducted on alu-
minium-backed 2 mm thick silica gel 60 GF254 and chromatograms were
visualised with 20% w/w phosphomolybdic acid in ethanol. High resolu-
tion mass spectra (HRMS) were obtained by ionising samples via elec-
tron spray ionisation (ESI). Anhydrous THF, Et2O CH2Cl2 were dried
using a solvent cartridge system. Dry methanol was distilled from magne-
sium methoxide. All other solvents were purified by standard methods.
Petrol used refers to petroleum ether 40–608C boiling range. All other
commercially available reagents were used as received.
Alkene 7: To a solution of the alcohol 9[11] (14.70 g, 71.3 mmol) in DMF
(130 mL) at 08C was added imidazole (9.70 g, 141.1 mmol), and TESCl
(14.7 mL, 88.2 mmol) and the mixture stirred for 30 min. Pentane and
water were added and the aqueous phase extracted with pentane. The
combined organic extracts were washed with water, brine, dried and the
solvent was removed. The residue was purified by flash chromatography
with 5% EtOAc/petrol as eluent to give 7 (19.6 g, 86%) as a colourless
oil. [a]2D2 =À4.7 (c=1.13, CH2Cl2); 1H NMR (500 MHz): d=0.61 (q, J=
8.0 Hz, 6H), 0.95 (t, J=8.0 Hz, 9H), 1.01 (d, J=7.2 Hz, 3H), 2.41 (dd,
J=15.0, 6.3 Hz, 1H), 3.37 (dd, J=9.0, 6.5 Hz, 1H), 3.47 (dd, J=12.0,
6.5 Hz, 1H), 3.73 (m, 1H), 4.56 (ABq, J=12.2 Hz, 2H), 4.97–5.85 (m,
2H), 5.81 (m, 1H), 7.27 ppm (m, 5H); 13C NMR (75 MHz): d=5.0, 6.9,
14.6, 41.4, 73.1, 73.2, 74.9, 114.2, 127.4, 127.6, 128.2, 138.4, 141.4 ppm; IR
(film): nmax =3069, 3032, 2958, 2911, 2878 cmÀ1; HRMS (ESI): m/z: calcd
for C19H32NaO2Si: 343.2069, found 343.2065 [M+Na]+.
The final steps to the target spirofungin A (1) began with
the selective hydrostannylation of the alkyne in 23
(Scheme 7). Pd-catalysed hydrostannylation using the origi-
nal conditions[21] gave poor regioselectivity and large
amounts of the undesired regiosiomeric stannane along with
the reduced alkene by-product. Application of a modified
procedure[22] involving in situ Pd catalyst formation using a
HBF4 phosphine salt with excess amine base gave the E-
vinyl stannane 24 in excellent yield. Stille coupling with
vinyl iodide 25 proceeded smoothly under Farina condi-
tions[23] to give ester 26. Oxidation of the primary alcohol
and Wittig reaction afforded the fully protected spirofungin
A diester 27, the data of which was identical to that report-
ed.[5,6] Final hydrolysis and TBS group removal[5] afforded a
good yield of spirofungin A (1) ([a]1D6 =À123.6, c=0.22,
CH2Cl2) which was identical to the reported data for natu-
ral[1] and synthetic 1 ([a]D22 =À125.8, c=0.28, CHCl3),[5]
([a]D22 =À122.8, c=0.2, CH2Cl2)[6] in all respects.
Enone 6: To a solution of Weinreb amide 8[2] (15.2 g, 33.9 mmol) in dry
THF (300 mL) was added
a solution of vinyl magnesium bromide
(120 mL, 120 mmol) at 08C. The reaction mixture was stirred at 08C for
90 min. The reaction was poured into 5% HCl in ethanol at 08C and the
mixture was partitioned between brine and diethyl ether/dichlorome-
thane 1:1. The organic extract was dried with Na2SO4 and the solvent was
removed. The residue was purified by flash chromatography with 5%
EtOAc/petrol as eluent to give 6 (12.55 g, 86%) as a pale yellow oil.
[a]2D2 =+13.6 (c=1.16, CH2Cl2); 1H NMR (500 MHz): d=0.038 (s, 3H),
0.042 (s, 3H), 0.59 (q, J=7.8 Hz, 6H), 0.89 (s, 9H), 0.894 (d, J=7.3 Hz,
3H), 0.95 (t, J=8.0 Hz, 9H), 1.42 (m, 1H), 1.59 (m, 2H), 1.66 (m, 2H),
2.60 (m, 2H), 3.67 (m, 2H), 3.78 (m, 1H), 5.81 (dd, J=10.6, 1.1 Hz, 1H),
6.21 (dd, J=17.7, 1.1 Hz, 1H), 6.35 ppm (dd, J=17.7, 10.6 Hz, 1H);
13C NMR (125 MHz): d=À5.18, À5.16, 5.3, 7.1, 14.4, 18.4, 26.1, 27.0, 35.4,
37.9, 38.5, 60.2, 72.3, 128.0, 136.6, 201.0 ppm; IR (film): nmax =2858, 1687,
1614, 1462, 1387, 1256 cmÀ1; HRMS (ESI): m/z: calcd for C22H46NaO3Si2:
437.2877, found 437.2878 [M+Na]+.
Enone 10: A solution of enone 6 (5.10 g, 11.9 mmol) and alkene 7
(4.55 g, 14.2 mmol) and Grubbs II catalyst (0.25 g, 0.295 mmol,
2.5 mol%) in CH2Cl2 (100 mL) was heated under reflux under nitrogen
for 12 h. The reaction mixture was then concentrated under and the resi-
due was purified by flash chromatography with 2% EtOAc/petrol as
eluent to give 10 (7.20 g, 86%) as a colourless oil. [a]2D3 =+14.9 (c=0.78,
CH2Cl2); 1H NMR (500 MHz): d=0.037 (s, 3H), 0.041 (s, 3H), 0.58 (m,
12H), 0.88 (d, J=6.8 Hz, 3H), 0.89 (s, 9H), 0.94 (m, 18H), 1.05 (d, J=
6.8 Hz, 3H), 1.38 (m, 2H), 1.64 (m, 2H), 2.45 (m, 1H), 2.57 (m, 2H),
3.36 (dd, J=9.6, 5.6 Hz, 1H), 3.41 (dd, J=9.7, 5.4 Hz, 1H), 3.65 (m, 2H),
3.79 (m, 2H,), 4.49 (s, 2H), 6.08 (dd, J=16.0, 1.2 Hz, 1H), 6.83 (dd, J=
16.0, 7.6 Hz, 1H), 7.34 ppm (m, 5H); 13C NMR (125 MHz): d=À5.17,
À5.14, 5.2, 5.3, 7.0, 7.1, 13.9, 14.4, 18.4, 26.1, 27.1, 35.4, 38.3, 38.7, 40.5,
60.3, 72.5, 72.9, 73.5, 74.2, 127.76, 127.82, 128.5, 129.9, 138.3, 149.6,
Scheme 7. Completion of the total synthesis of spirofungin A (1). DMP=
Dess–Martin periodinane. DMPU=1,3-Dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone. [Pd
2ACHTUNGTRENUN(NG dba)3]=Tris(dibenzylideneacetone)dipalladi-
um(0). (furyl)3P=Tri-2-furylphosphine.
Conclusion
In summary, we have achieved a stereoselective synthesis of
spirofungin A (1) which utilises a thermodynamically con-
trolled isomerisation mediated by an interesting H-bond in-
teraction to give the desired spiroketal 4. This was then car-
ried through an efficient sequence to give the natural prod-
uct 1.[24] We are currently investigating the H-bond con-
trolled spiroketalisation for the synthesis of related spiroke-
tals.
200.7 ppm; IR (film): nmax =2956, 2877, 1698, 1678, 1629, 1461, 1255 cmÀ1
;
HRMS (ESI): m/z: calcd for C39H74NaO5Si3: 729. 4736, found 729.4737
[M+Na]+.
Ketone 5: To a solution of the unsaturated ketone 10 (7.20 g 10.2 mmol)
in EtOAc (70 mL) was added Lindlar catalyst (600 mg) and the suspen-
300
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Chem. Eur. J. 2011, 17, 297 – 304

Total Synthesis of (À)-Spirofungin A
FULL PAPER
sion was stirred under 1 atm of hydrogen gas for 18 h. The catalyst was
removed by filtration and the filtrate was concentrated and the residue
was purified by flash chromatography with 5% EtOAc/petrol as eluent
to give 5 (7.02 g, 97%) as a colourless oil. [a]2D3 =+7.1 (c=1.28, CH2Cl2);
1H NMR (500 MHz): d=0.038 (s, 3H), 0.042 (s, 3H), 0.59 (m, 12H), 0.84
(d, J=6.8 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H), 0.89 (s, 9H), 0.94 (m, 18H),
1.39 (m, 2H), 1.56 (m, 2H), 1.62 (m, 2H), 1.71 (m, 1H), 2.40 (m, 4H),
3.40 (m, 2H), 3.66 (m, 2H), 3.76 (m, 2H), 4.56 (ABq, J=12.0 Hz, 2H),
7.34 ppm (m, 5H); 13C NMR (125 MHz): d=À5.23, À5.19, 5.23, 5.25, 7.0,
7.1, 13.9, 14.3, 18.3, 26.0, 26.8, 27.5, 35.3, 36.3, 38.6, 41.0, 41.1, 60.2, 72.3,
73.1, 73.4, 74.5, 127.6, 127.7, 128.4, 129.9, 138.5, 211.2 ppm; IR (film):
nmax =2955, 2877, 1717, 1461, 1414, 1380, 1254 cmÀ1; HRMS (ESI): m/z:
calcd for C19H32NaO2Si: 731.4893, found 731.4893 [M+Na]+.
10.9, 3.1 Hz, 1H), 3.61 (dd, J=11.2, 8.4 Hz, 1H), 3.72–3.82 (m, 2H),
4.26 ppm (m, 1H); 13C NMR (125 MHz): d=À5.33, À5.23, 11.6, 17.4,
18.2, 22.8, 25.8, 25.9, 28.3, 29.5, 35.0, 36.4, 36.8, 59.6, 64.5, 72.7, 74.6,
97.3 ppm; IR (film): nmax =3423, 2954, 2929, 1641, 1460 cmÀ1; HRMS
(ESI): m/z: calcd for C20H40NaO4Si: 395.2594, found 395.2589 [M+Na]+.
To
a solution of the above alcohols (2.16 g, 5.81 mmol) in CH2Cl2
(60 mL), was added pyridine (1.40 mL, 17.4 mmol) followed by Dess–
Martin periodinane (3.64 g, 8.72 mmol) and the mixture stirred at RT for
18 h. Et2O, saturated aqueous NaHCO3 and 1.5m aqueous Na2S2O3 were
added and the mixture was stirred until two clear layers formed. The
aqueous phase was extracted with Et2O and the combined organic ex-
tracts were washed with saturated aqueous CuSO4, water, brine dried
and the solvent was removed. To the crude aldehyde (2.1 g) in methanol
(80 mL) was added dimethyl-1-diazo-2-oxopropylphosphonate (3.32 g,
17.4 mmol) followed by K2CO3 (7.14 mg, 51.7 mmol) and the mixture
stirred at RT for 24 h. Et2O and water were added and the aqueous
phase extracted with Et2O. The combined organic extracts were washed
with water, brine, dried and the solvent was removed. The crude product
was purified by flash chromatography with 1% EtOAc/petrol as eluent
to give the alkyne 13 (0.49 g, 23%) as a colourless oil. [a]1D5 =+42.0 (c=
0.50, CH2Cl2); 1H NMR (500 MHz): d=0.06 (s, 6H), 0.87 (d, J=6.5 Hz,
3H), 0.90 (s, 9H), 0.97 (d, J=6.4 Hz, 3H), 1.36 (m, 1H), 1.43–1.49 (m,
3H), 1.56 (m, 1H), 1.65–1.74 (m, 2H), 1.80–1.93 (m, 2H), 2.28 (d, J=
2.4 Hz, 1H), 3.68 (m, 1H), 3.74 (dt, J=9.9, 5.9 Hz, 1H), 3.83 (dt, J=9.9,
5.4 Hz, 1H), 4.48 ppm (m, 1H); 13C NMR (125 MHz): d=À5.16, À5.14,
17.5, 18.0, 18.4, 23.3, 26.0, 27.8, 33.7, 34.0, 33.9, 35.9, 36.7, 36.8, 60.0, 66.8,
72.7, 73.2, 82.5, 95.3 ppm; IR (film): nmax =3311, 2954, 2929, 2858, 2108,
1643 cmÀ1; HRMS (ESI): m/z: calcd for C21H38NaO3Si: 389.2488, found
389.2477 [M+Na]+.
Spiroketals 11 and 12: To a solution of the ketone 5 (7.02 g, 9.89 mmol)
in CH2Cl2 (70 mL) and MeOH (25 mL) at 08C was added PPTS (230 mg,
0.92 mmol) and the solution stirred for 3 h. Saturated aqueous NaHCO3,
Et2O and water were added and the aqueous phase extracted with Et2O.
The combined organic extracts were washed with saturated NaHCO3,
water, brine, dried and the solvent removed. The residue was purified by
flash chromatography with 1% EtOAc/petrol as eluent to give the spiro-
ketal 11 (1.22 g, 27%) as a yellow oil. [a]1D3 =+30.2 (c=0.75, CH2Cl2);
1H NMR (500 MHz): d=0.081 (s, 3H), 0.087 (s, 3H), 0.83 (d, J=6.3 Hz,
3H), 0.90 (s, 9H), 0.94 (d, J=7.1 Hz, 3H), 1.19–1.57 (m, 5H), 1.66–1.89
(m, 4H), 2.15 (m, 1H), 2.20 (m, 1H), 3.53 (m, 1H), 3.74 (m, 2H), 3.80
(m, 1H), 3.84 (m, 2H), 4.56 (ABq, J=12.0 Hz, 2H), 7.30 ppm (m, 5H);
13C NMR (125 MHz): d=À5.23, À5.18, 13.0, 17.9, 18.4, 26.0, 26.7, 27.4,
29.5, 30.4, 32.4, 34.9, 36.5, 59.5, 71.5, 72.4, 73.3, 74.4, 96.7, 124.4, 128.3,
138.6 ppm; IR (film): nmax =2952, 2927, 1643, 1454, 1249 cmÀ1; HRMS
(ESI): m/z: calcd for C27H46NaO4Si: 485.3063, found 485.3060 [M+Na]+.
Further elution gave 12 (2.44 g, 53%) as pale yellow oil. [a]1D3 =+32.1
(c=0.81, CH2Cl2); 1H NMR (500 MHz): d=0.05 (s, 6H), 0.85 (d, J=
6.5 Hz, 3H), 0.88 (s, 9H), 0.90 (d, J=6.0 Hz, 3H), 1.25–1.42 (m, 3H),
1.51–1.71 (m, 3H), 1.75–1.93 (m, 4H), 2.01 (m, 1H), 2.06 (m, 1H), 3.24
(dt, J=9.0, 2.3 Hz, 1H), 3.36 (dd, J=9.0, 8.3 Hz, 1H), 3.49 (dd, J=9,
6.2 Hz, 1H), 3.79 (m, 2H), 4.41 (m, 1H), 4.54 (ABq, J=12.0 Hz, 2H),
7.30 ppm (m, 5H); 13C NMR (125 MHz): d=À5.3, À5.2, 11.0, 17.4, 18.2,
22.6, 25.4, 25.9, 27.8, 29.5, 34.8, 36.4, 36.7, 59.7, 70.4, 70.8, 73.3, 74.7, 97.4,
127.5, 127.8, 128.3, 138.4 ppm; IR (film): nmax =2925, 2977, 2858, 1454,
1093 cmÀ1; HRMS (ESI): m/z: calcd for C27H46NaO4Si: 485.3063, found
485.3058 [M+Na]+.
Further elution gave alkyne 14 (1.00 g, 47%) as a colourless oil. [a]D16
=
1
+69.8 (c=0.41, CH2Cl2); H NMR (500 MHz): d=0.047 (s, 3H), 0.049 (s,
3H), 0.83 (d, J=6.6 Hz, 3H), 0.89 (s, 9H), 1.16 (d, J=7.1 Hz, 3H), 1.22–
1.33 (m, 2H), 1.39–1.47, (m, 2H), 1.60 (m, 1H), 1.64–1.72 (m, 2H), 1.85–
1.92 (m, 3H), 1.98–2.02 (m, 2H), 2.42 (d, J=2.3 Hz, 1H), 3.23 (dt, J=
9.7, 2.4 Hz, 1H), 3.73–3.83 (m, 2H), 5.03 ppm (t, J=2.4 Hz, 1H);
13C NMR (125 MHz): d=À5.3, À5.2, 12.3, 17.4, 18.2, 22.0, 24.4, 25.9, 29.4,
31.2, 34.8, 36.3, 36.7, 59.5, 64.3, 73.4, 74.9, 82.8, 97.9 ppm; IR (film):
nmax =3313, 2954, 2929, 2858, 2123 cmÀ1; HRMS (ESI): m/z: calcd for
C21H38NaO3Si: 389.2488, found 389.2486 [M+Na]+.
Isomerisation of spiroketal 14: To
a stirred solution of 14 (20 mg,
Isomerisation of spiroketal 11 in CH2Cl2: To a stirred solution of 11
(20 mg, 43.2 mmol) in DCM (300 mL) at room temperature was added
PPTS (1.0 mg, 4.2 mmol) and the mixture stirred at 08C for 24 h. Et2O
and saturated aqueous NaHCO3 were added and the mixture was stirred
until two clear layers formed. The aqueous phase was extracted with
Et2O and the combined organic extracts were washed with, water, brine,
dried and the solvent removed affording a 1:1.9 mixture of 11 and 12 (by
1H NMR integration) as a yellow oil.
54.6 mmol) in DCM (100 mL) at room temperature was added PPTS
(1.4 mg, 5.46 mmol) and the mixture stirred at RT for 18 h. Et2O and satu-
rated aqueous NaHCO3 were added and the mixture was stirred until
two clear layers formed. The aqueous phase was extracted with Et2O and
the combined organic extracts were washed with, water, brine, dried and
the solvent removed affording a 1:3 mixture of 14 and 13 (by 1H NMR
integration) as a colourless oil.
Spiroketal alcohols 4 and 15: To a solution of spiroketals 13 and 14
(1.49 g, 5.53 mmol) in CH2Cl2 (25 mL) was added CSA (137.1 mg,
0.596 mmol) and the mixture stirred at RT for 18 h. Et2O and saturated
aqueous NaHCO3 were added and the mixture was stirred until two clear
layers formed. The aqueous phase was extracted with Et2O and the com-
bined organic extracts were washed with, water, brine, dried and the sol-
vent removed. The residue was purified by flash chromatography with
1% EtOAc/petrol as eluent to give the alcohol 4 (0.79 g, 77%) as a col-
ourless solid. [a]1D6 =+46.9 (c=0.33, CH2Cl2); 1H NMR (500 MHz): d=
0.80 (d, J=6 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.38 (m, 1H), 1.43–1.51
(m, 2H), 1.53 (m, 1H), 1.57 (m, 1H), 1.60 (m, 1H), 1.64 (m, 1H), 1.69
(m, 1H), 1.73 (m, 1H), 1.81 (m, 1H), 1.95 (m, 1H), 2.00 (m, 1H), 2.37
(dd, J=2.5, 0.8 Hz, 1H), 3.18 (t, J=4.5 Hz, 1H), 3.79 (q, J=4.5 Hz, 2H),
3.92 (ddd, J=13.1, 8.0, 3.2 Hz, 1H), 4.49 ppm (m, 1H); 13C NMR
(125 MHz): d=17.6, 18.1, 23.4, 27.4, 33.8, 34.0, 34.1, 36.9, 37.0, 60.8, 67.1,
73.5, 76.9, 82.0, 95.6 ppm; IR (film): nmax =3421, 3305, 2241, 2108,
1639 cmÀ1; HRMS (ESI): m/z: calcd for C15H24NaO3: 275.1623, found
275.1621 [M+Na]+.
Alkynes 13 and 14: To a solution of the spiroketals 11 and 12 (3.66 g,
7.91 mmol) in EtOAc (60 mL) was added Pd(OH)2 on C, (20 wt% Pd
dry basis, 1.50 g) and the suspension was stirred under a hydrogen atmos-
phere for 2 h. The catalyst was removed by filtration, the filtrate concen-
trated and the crude product was purified by flash chromatography with
1% EtOAc/petrol as eluent to give the double anomeric alcohol (0.79 g,
27%) as
a
colourless oil. [a]D19 =+41.6 (c=2.07, CH2Cl2); 1H NMR
(500 MHz): d=0.081 (s, 3H), 0.087 (s, 3H), 0.86 (d, J=6.5 Hz, 3H), 0.91
(s, 9H), 0.94 (d, J=7.0 Hz, 3H), 1.27–1.34 (m, 1H), 1.42–1.53 (m, 4H),
1.67–1.88 (m, 4H), 1.96 (m, 1H), 2.00 (m, 1H), 2.71 (t, J=6.4 Hz, 1H),
3.52 (m, 1H), 3.66–3.74 (m, 3H), 3.75–3.82 ppm (m, 2H); 13C NMR
(125 MHz): d=À5.3, À5.2, 14.9, 18.0, 26.0, 27.7, 30.5, 33.0, 34.2, 34.8,
36.4, 59.4, 63.3, 72.5, 76.9, 96.2 ppm; IR (film): nmax =3425, 2929, 2858,
1255, 1087 cmÀ1; HRMS (ESI): m/z: calcd for C20H40NaO4Si: 395.2594,
found 395.2594 [M+Na]+.
Further elution gave the single anomeric alcohol (1.57 g, 53%) as a col-
1
ourless oil. [a]1D3 =+14.0 (c=2.04, CH2Cl2); H NMR (500 MHz): d=0.01
(s, 6H), 0.80 (d, J=6.4 Hz, 3H), 0.85 (s, 9H), 0.88 (d, J=7.2 Hz, 3H),
1.23–1.41 (m, 3H), 1.52–1.76 (m, 4H), 1.80–1.96 (m, 3H), 2.04 (m, 1H),
2.13 (m, 1H), 2.37 (brs, 1H), 3.22 (dt, J=9.8, 2.3 Hz, 1H), 3.46 (dd, J=
Further elution gave alcohol 15 (0.087 g, 9%) as a colourless solid.
[a]1D6 =+51.3 (c=0.52, CH2Cl2); 1H NMR (500 MHz): d=0.84 (d, J=
6.4 Hz, 3H), 1.16 (d, J=6.8 Hz, 3H), 1.28 (m, 1H), 1.42–1.51 (m, 3H),
Chem. Eur. J. 2011, 17, 297 – 304
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
301

M. A. Rizzacasa et al.
1.64 (m, 1H), 1.68–175 (m, 2H), 1.81–1.98 (m, 3H), 2.02 (m, 1H), 2.05
(m, 1H), 2.22 (brs, 1H), 2.43 (d, J=2.4 Hz, 1H), 3.30 (dt, J=8 2.8 Hz,
1H), 3.79–3.85 (m, 2H), 4.91 ppm (t, J=8.0, 2.8 Hz, 1H); 13C NMR
(125 MHz): d=12.2, 17.4, 22.0, 24.5, 29.1, 31.0, 34.8, 35.6, 36.3, 60.7, 64.6,
73.6, 77.9, 82.3, 98.3 ppm; IR (film): nmax =3458, 3253, 2962, 2862,
2119 cmÀ1; HRMS (ESI): m/z: calcd for C15H24NaO3: 275.1623, found
275.1621 [M+Na]+.
(810 mg) in toluene (30 mL), was added 2-(triphenylphosphoranylidene)-
propionaldehyde (3.18 g, 10.0 mmol) and the mixture heated at 1058C for
24 h, then another portion of 2-(triphenylphosphoranylidene)propional-
dehyde (1.59 g, 5.00 mmol) was added and the mixture heated at 1058C
for 24 h. The solvent was removed under reduced pressure and the resi-
due was purified by filtration through silica with 10% EtOAc/petrol as
eluent to give the aldehyde (820 mg). To a solution of the aldehyde in
toluene (30 mL) was added methyl(triphenylphosphoranylidene)acetate
(3.34 g, 10.0 mmol) the reaction was heated at 1058C for 24 h. The sol-
vent was removed under reduced pressure and the residue purified by
flash chromatography with 5% EtOAc/petrol as eluent to give the
methyl ester 18 (917 mg, 79%) as a yellow oil. [a]1D4 =+19.9 (c=0.22,
CH2Cl2); 1H NMR (500 MHz): d=0.83 (d, J=6.6 Hz, 3H), 0.98 (d, J=
6.4 Hz, 3H), 1.31–1.39 (m, 2H), 1.41–1.52 (m, 4H), 1.70 (m, 1H), 1.73
(m, 1H), 1.78 (s, 3H), 1.80–1.89 (m, 2H), 2.25 (d, J=2.5 Hz, 1H), 2.39
(m, 1H), 2.54 (m, 1H), 3.75 (s, 3H), 3.83 (m, 1H), 4.50 (m, 1H), 5.78 (d,
J=15.6 Hz, 1H), 6.16 (t, J=7.4 Hz, 1H), 7.35 ppm (d, J=15.8 Hz, 1H);
13C NMR (125 MHz): d=12.4, 17.6, 17.7, 23.3, 27.9, 31.9, 33.80, 33.84,
36.7, 36.8, 51.4, 66.9, 72.7, 74.5, 82.5, 95.6, 114.7, 133.3, 139.3, 150.2,
168.1 ppm; IR (film): nmax =3265, 2929, 2868, 1718, 1622 cmÀ1; HRMS
(ESI): m/z: calcd for C21H33NaO4: 369.2042, found 369.2041 [M+Na]+.
Isomerisation of spiroketal alcohol 15 in CH2Cl2: To a stirred solution of
15 (20 mg, 79.2 mmol) in DCM (100 mL) at room temperature was added
CSA (1.8 mg, 7.92 mmol) and the mixture stirred at RT for 18 h. Et2O
and saturated aqueous NaHCO3 were added and the mixture was stirred
until two clear layers formed. The aqueous phase was extracted with
Et2O and the combined organic extracts were washed with, water, brine,
dried and the solvent removed affording a 1:13 mixture of 15 and 4 (by
1H NMR integration) as a colourless oil.
Isomerisation of spiroketal alcohol 15 in DMSO: To a stirred solution of
15 (28 mg, 110.0 mmol) in DMSO (140 mL) at room temperature was
added CSA (2.6 mg, 11.0 mmol) and the mixture stirred at RT for 24 h.
Et2O and saturated aqueous NaHCO3 were added and the mixture was
stirred until two clear layers formed. The aqueous phase was extracted
with Et2O and the combined organic extracts were washed with, water,
brine, dried and the solvent removed affording a 1:3 mixture of 15 and 4
Aldol adduct 21: To a solution of methyl ester 18 (200 mg, 0.577 mmol)
in CH2Cl2 (15 mL) at À788C was added DiBALH (1.0m in CH2Cl2,
2.36 mL, 2.36 mmol) and the mixture stirred for 25 min, then warmed to
RT, and Et2O, aqueous 0.5m (+)-sodium tartrate, water and EtOAc
added, and the mixture stirred for a further 30 min at RT. The aqueous
phase was extracted with Et2O, and the combined organic extracts were
washed with water, brine, and dried. The solvent was removed under re-
duced pressure to give the alcohol (195 mg), which was dissolved in
CH2Cl2 (15 mL) and pyridine (142 mL, 1.73 mmol) and Dess–Martin per-
1
(by H NMR integration) as a colourless oil.
Spiroketal alcohols 16 and 17: To a solution of the ketone 5 (180 mg,
254 mmol) in CH2Cl2 (1.8 mL) and MeOH (0.6 mL) at 08C was added
CSA (6 mg, 26 mmol) and the solution stirred for 1 h. Saturated aqueous
NaHCO3, Et2O and water were added and the aqueous phase extracted
with Et2O. The combined organic extracts were washed with saturated
NaHCO3, water, brine, dried and the solvent removed. The residue was
purified by flash chromatography with 12.5% EtOAc/petrol as eluent to
give the spiroketal 16 (34 mg, 38%) as a yellow oil. [a]2D2 =+10.7 (c=
1.01, CH2Cl2); 1H NMR (500 MHz): d=0.82 (d, J=6.5 Hz, 3H), 0.91 (d,
J=7.1 Hz, 3H), 1.24–1.36 (m, 2H), 1.39–1.73 (m, 7H), 1.81–1.92 (m,
2H), 2.09 (dt, J=13.6, 3.3 Hz, 1H), 3.24 (brs, 1H), 3.53 (dd, J=10.1,
AHCTUNGERTGiNNUN odinane (364 mg, 0.863 mmol) were added and the mixture stirred for
35 min at RT. Et2O, saturated aqueous NaHCO3 and 1.5m aqueous
Na2S2O3, were added and the mixture was stirred until two clear layers
formed. The aqueous phase was extracted with Et2O and the combined
organic extracts were washed with saturated aqueous CuSO4 solution,
water, brine and dried. The solvent was removed under reduced pressure
to give the crude aldehyde 19 (188 mg), which was used without further
5.1 Hz, 1H), 3.68 (dd, J=10.1, 7.4 Hz, 1H), 3.73ACTHNUTRGNE(NUG m, 1H), 3.80 (m, 1H),
3.88 (ddd, J=7.4, 5.1, 3.9 Hz, 1H), 3.95 (ddd, J=11.8, 8.9, 3.0 Hz, 1H),
4.57 (s, 2H), 7.34 ppm (m, 5H); 13C NMR (125 MHz): d=14.0, 17.9, 26.2,
27.4, 30.2, 31.9, 33.6, 34.76, 34.81, 61.3, 71.0, 73.2, 74.6, 76.8, 96.9, 127.7,
128.5, 138.6 ppm; IR (film): nmax =3444, 2926, 2864, 1455, 1383,
1260 cmÀ1; HRMS (ESI): m/z: calcd for C21H32NaO4: 371.2193, found
371.2193 [M+Na]+.
purification. To a suspension of SnACHTUNTRGNEUNG(OTf)2 (964 mg, 2.31 mmol) in CH2Cl2
(15 mL) at À458C was added freshly distilled N-ethylpiperidine (321 mL,
2.31 mmol). A solution of oxazolidine-2-thione 20[25] (464 mg, 2.31 mmol)
in CH2Cl2 (15 mL) was then added via cannula and the mixture stirred
for 1 h at À458C then cooled to À788C and a solution of the aldehyde 19
(188 mg) in CH2Cl2 (10 mL) was added via cannula. The resulting mix-
ture stirred for 30 min at À788C then warmed to RT and added to pH 7
buffer and stirred for 10 min. The mixture was then filtered through a
Celite plug and the filtrate was extracted with CH2Cl2. The combined or-
ganic extracts were then washed with brine, dried and the solvent re-
moved. The residue was purified by flash chromatography with 20%
EtOAc/petrol as eluent to give the aldol adduct 21 (258.8 mg, 75%) as a
yellow oil. [a]1D4 =+105.8 (c=0.24, CH2Cl2); 1H NMR (500 MHz): d=
0.82 (d, J=6.5 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H), 0.92 (d, J=6.7 Hz, 3H),
0.97 (d, J=6.5 Hz, 3H), 1.20 (d, J=6.9 Hz, 3H), 1.36 (m, 1H), 1.43 (m,
1H), 1.45–1.51 (m, 2H), 1.55 (m, 1H), 1.70 (m, 1H), 1.74 (s, 3H), 1.78–
1.86 (m, 2H), 1.91 (m, 1H), 2.27 (d, J=2.5 Hz, 1H), 2.32 (m, 1H), 2.48
(m, 1H), 2.58 (d, J=3.6 Hz, 1H), 3.79 (m, 1H), 4.38 (d, J=5.6 Hz, 2H),
4.49 (m, 1H), 4.65 (t, J=5.3 Hz, 1H), 4.76 (dd, J=8.0, 5.6 Hz, 1H), 5.05
(m, 1H), 5.57 (dd, J=16.0, 6.4 Hz, 1H), 5.67 (t, J=6.8 Hz, 1H), 6.33 ppm
(d, J=16.0 Hz, 1H); 13C NMR (125 MHz): d=11.6, 12.8, 15.0, 17.7, 17.9,
18.4, 23.4, 28.0, 29.2, 31.4, 33.8, 33.9, 36.8, 36.9, 43.0, 63.4, 67.1, 67.5, 72.8,
74.0, 74.9, 82.6, 95.7, 124.8, 130.7, 133.3, 137.5, 176.9, 186.3 ppm; IR
(film): nmax =3450, 3301, 2929, 2875, 1697 cmÀ1; HRMS (ESI): m/z: calcd
for C29H43NaO5S: 540.2760, found 540.2765 [M+Na]+.
Further elution gave spiroketal 17 (47 mg, 53%) as yellow oil. [a]D22
=
+4.2 (c=0.99, CH2Cl2); 1H NMR (500 MHz): d=0.84 (d, J=6.6 Hz,
3H), 0.90 (d, J=7.2 Hz, 3H), 1.25–1.34 (m, 1H), 1.37–1.52 (m, 3H),
1.58–1.77 (m, 4H), 1.84–1.95 (m, 3H), 2.06 (dt, J=13.9, 2.9 Hz, 1H), 2.55
(brs, 1H), 3.31 (dt, J=9.6, 2.7 Hz, 1H), 3.35 (dd, J=9.7, 6.9 Hz, 1H),
3.47 (dd, J=9.6, 6.4 Hz, 1H), 3.83 (m, 2H), 4.29 (dt, J=6.7, 2.5 Hz, 1H),
4.53 (ABq, J=12.1 Hz, 2H), 7.32 ppm (m, 5H); 13C NMR (125 MHz):
d=11.2, 17.6, 22.9, 25.7, 28.0, 29.2, 34.9, 35.6, 36.5, 61.2, 71.0, 73.3, 78.4,
98.0, 127.6, 127.9, 128.4, 138.5 ppm; IR (film): nmax =3430, 2924, 2860,
1454, 1380, 1276, 1261 cmÀ1; HRMS (ESI): m/z: calcd for C21H32NaO4:
371.2193, found 371.2194 [M+Na]+.
Isomerisation of spiroketal alcohol 17 in CH2Cl2: To a stirred solution of
17 (47 mg, 13.5 mmol) in DCM (300 mL) at room temperature was added
CSA (3 mg, 1.35 mmol) and the mixture stirred at RT for 24 h. Et2O and
saturated aqueous NaHCO3 were added and the mixture was stirred until
two clear layers formed. The aqueous phase was extracted with Et2O and
the combined organic extracts were washed with, water, brine, dried and
the solvent removed affording a 1:1 mixture of 16 and 17 (by 1H NMR
integration) as a colourless oil.
Methyl ester 18: To a solution of the alcohol 4 (845 mg, 3.35 mmol) in
CH2Cl2 (35 mL), was added pyridine (810 mL, 10.01 mmol) followed by
Dess–Martin periodinane (2.13 g, 5.03 mmol) and the mixture stirred at
RT for 8 h. Et2O, saturated aqueous NaHCO3 and 1.5m aqueous Na2S2O3
were added and the mixture was stirred until two clear layers formed.
The aqueous phase was extracted with Et2O and the combined organic
extracts were washed with saturated aqueous CuSO4, water, brine dried
and the solvent was removed. To a solution of the crude aldehyde
Diol 22: To a solution of the aldol adduct 21 (245 mg, 0.473 mmol) in
THF (15 mL) and water (1.5 mL) was added NaBH4 (59 mg, 1.54 mmol)
and the mixture stirred for 1 h at RT. Et2O and water were added and
the aqueous phase extracted with Et2O and the combined organic ex-
tracts were washed with water, brine, dried and the solvent was removed.
The residue was purified by flash chromatography with 20% EtOAc/
petrol as eluent to give the diol 22 (123.0 mg, 69%) as a colourless oil.
302
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 297 – 304

Total Synthesis of (À)-Spirofungin A
FULL PAPER
[a]1D5 =+20.1 (c=0.20, CH2Cl2); 1H NMR (500 MHz): d=0.82 (d, J=
6.4 Hz, 3H), 0.90 (d, J=7.2 Hz, 3H), 0.97 (d, J=6.4 Hz, 3H), 1.25 (m,
1H), 1.36 (m, 1H), 1.43–1.52 (m, 2H), 1.55–1.62 (m, 2H), 1.71 (m, 1H),
1.75 (m, 1H), 1.76 (s, 3H), 1.86 (m, 1H), 2.01 (m, 1H), 2.21 (brs, 1H),
2.25 (d, J=2.4 Hz, 1H), 2.35 (m, 1H), 2.47 (m, 1H), 3.67–3.74 (m, 2H),
3.80 (m, 1H), 4.33 (dd, J=6.9, 3.8 Hz, 1H), 4.49 (m, 1H), 5.61 (dd, J=
16.0, 7.2 Hz, 1H), 5.74 (t, J=6.8 Hz, 1H), 6.30 ppm (d, J=16.0 Hz, 1H);
13C NMR (125 MHz): d=11.8, 12.8, 17.7, 17.9, 23.4, 28.0, 31.4, 33.8, 33.9,
36.8, 36.9, 40.4, 66.5, 67.0, 72.8, 74.9, 76.7, 82.6, 95.7, 125.8, 130.4, 133.3,
137.2 ppm; IR (film): nmax =3307, 2929, 2883, 1443, 1205 cmÀ1; HRMS
(ESI): m/z: calcd for C29H43NaO5S: 399.2511, found 399.2524 [M+Na]+.
washed with water, brine, and dried. The solvent was removed under re-
duced pressure and the residue was purified by flash chromatography
with 30% EtOAc/petrol as eluent to give the methyl ester 26 (25.4 mg,
82%) as
a
colourless oil. [a]D21 =À74.7 (c=0.21, CH2Cl2); 1H NMR
(500 MHz): d=0.03 (s, 3H), 0.08 (s, 3H), 0.76 (d, J=7.0 Hz, 3H), 0.79
(d, J=7.5 Hz, 3H), 0.81 (d, J=7.1 Hz, 3H), 0.90 (s, 9H), 1.35–1.38 (m,
2H), 1.43–1.50 (m, 3H), 1.56 (m, 1H), 1.59 (m, 1H,), 1.72 (s, 3H), 1.74
(m,1H), 1.83 (m, 1H), 1.91 (m, 1H), 2.03 (m, 1H), 2.31 (d, J=1.1 Hz,
3H), 2.38 (m, 2H), 2.93 (brs, 1H), 3.49 (m, 1H), 3.67 (t, J=9.6 Hz, 1H),
3.72 (s, 3H), 4.17 (dd, J=9.1, 5.2 Hz, 1H), 4.29 (m, J=7.1, 3.9 Hz, 1H),
5.57 (dd, J=15.7, 7.3 Hz, 1H), 5.59 (t, J=6.3 Hz, 1H), 5.79 (s, 1H), 6.19
(d, J=15.8 Hz, 1H), 6.23 (d, J=15.7 Hz, 1H), 6.47 ppm (dd, J=15.6,
9.0 Hz, 1H); 13C NMR (125 MHz): d=À4.9, À4.0, 12.7, 13.0, 14.5, 17.1,
17.4, 17.6, 18.3, 24.1, 26.0, 27.7, 29.9, 32.2, 33.3, 33.8, 35.6, 36.1, 41.6, 51.2,
66.2, 74.6, 76.7, 78.2, 78.8, 95.9, 119.1, 125.9, 128.5, 134.2, 135.1, 136.4,
136.6, 152.3, 167.6 ppm; IR (film): nmax =3395, 2918, 2848, 2144, 1713,
1594, 1355 cmÀ1; HRMS (ESI): m/z: calcd for C34H58NaO6Si 613.3895,
found 613.3893 [M+Na]+.
Alcohol 23: To a solution of the diol 22 (150 mg, 0.398 mmol) in DMF
(5 mL) was added imidazole (321 mg, 4.77 mmol) followed by TBSCl
(430 mg, 2.79 mmol) and stirred at RT for 24 h. Et2O and water were
added and the aqueous phase extracted with Et2O. The combined organic
extracts were washed with water, brine, dried and the solvent was re-
moved. The residue was purified by flash chromatography with 1%
EtOAc/petrol as eluent to give the bisTBS-ether (195 mg, 81%) as a col-
ourless oil. [a]2D0 =+25.7 (c=0.42, CH2Cl2); 1H NMR (500 MHz): d=
À0.01 (s, 3H), 0.02 (s, 3H), 0.03 (s, 3H), 0.05 (s, 3H), 0.84 (d, J=6.8 Hz,
3H), 0.86 (d, J=7.2 Hz, 3H), 0.889 (s, 9H), 0.894 (s, 9H), 0.97 (d, J=
6.8 Hz, 3H), 1.38 (m, 1H), 1.43–1.49 (m, 3H), 1.56–1.67 (m, 2H), 1.72 (s,
3H), 1.74 (m, 1H), 1.78–1.91 (m, 2H), 2.23 (d, J=2.8 Hz, 1H), 2.25–2.32
(m, 2H), 2.50 (m, 1H), 3.39 (dd, J=12.0, 6.4 Hz, 1H), 3.57 (dd, J=8.0,
6.4 Hz, 1H), 3.78 (m, 1H), 4.23 (dd, J=8.0, 4.0 Hz, 1H), 4.49 (m, 1H),
5.48 (dd, J=16.0, 7.2 Hz, 1H), 5.64 (t, J=7.2 Hz, 1H), 6.12 ppm (d, J=
16.0 Hz, 1H); 13C NMR (125 MHz): d=À5.18, À5.13, À4.8, À3.8, 11.6,
12.8, 17.7, 18.0, 18.40, 18.44, 23.4, 26.1, 28.0, 31.9, 34.0, 34.4, 36.9, 37.0,
43.3, 65.3, 67.1, 73.0, 74.1, 74.1, 75.0, 82.5, 95.7, 128.75, 128.80, 133.5,
Dimethyl ester 27: To a solution of the alcohol 26 (12.5 mg, 21.5 mmol) in
CH2Cl2 (0.5 mL), was added pyridine (10 mL, 88 mmol) followed by Dess–
Martin periodinane (18 mg, 44 mmol) and the solution was stirred at RT
for 1 h. Et2O, saturated aqueous NaHCO3 and 1.5m aqueous Na2S2O3
were added and the mixture stirred until two clear layers formed. The
aqueous phase was extracted with Et2O and the combined organic ex-
tracts were washed with saturated aqueous CuSO4, water, brine, dried
and the solvent was removed to give the crude aldehyde (12.5 mg). To a
solution of the aldehyde in CH2Cl2 (0.3 mL) was added methyl(triphenyl-
phosphoranylidene)acetate (30 mg, 90 mmol) and the mixture stirred at
RT for 24 h. The solvent was removed under reduced pressure and the
residue was purified by filtration through silica eluting with 5% EtOAc/
petrol followed by flash chromatography with 1% EtOAc/petrol eluent
135.1 ppm; IR (film): nmax =3307, 2954, 2929, 2858, 2895, 1471 cmÀ1
;
HRMS (ESI): m/z: calcd for C35H64NaO4Si2: 627.4241, found 627.4230
[M+Na]+.
to give the dimethyl ester 27 (11.4 mg, 84%) as a colourless oil. [a]D16
=
À145.4 (c=0.21, CH2Cl2), lit.[5] ([a]D22 =À124.0, c=0.81, CHCl3), lit.[6]
([a]2D5 =À148.36, c=0.11, CH2Cl2); 1H NMR (500 MHz, CD2Cl2): d=0.01
(s, 3H), 0.03 (s, 3H), 0.75 (d, J=6.9 Hz, 3H), 0.77 (d, J=6.5 Hz, 3H),
0.89 (s, 9H), 1.03 (d, J=6.8 Hz, 3H), 1.40 (m, 4H), 1.51 (m, 3H), 1.72
(m, 5H), 1.87 (m, 1H), 2.29 (d, J=1.4 Hz, 3H), 2.34 (m, 1H), 2.51 (m,
1H), 3.48 (m, 1H), 3.67 (s, 3H), 3.68 (s, 3H), 4.14 (m, 2H), 5.45 (dd, J=
15.6, 7.2 Hz, 1H), 5.59 (t, J=7.4 Hz, 1H), 5.78 (s, 1H), 5.79 (dd, J=15.8,
1.4 Hz, 1H), 6.17 (d, J=15.3 Hz, 1H), 6.23 (dd, J=15.7, 0.7 Hz, 1H),
6.45 (dd, J=15.6, 8.8 Hz, 1H), 6.97 ppm (dd, J=15.9, 7.2 Hz, 1H);
13C NMR (125 MHz, CD2Cl2): d=À4.8, À4.0, 12.9, 12.7, 14.42, 14.44,
16.8, 17.8, 18.5, 24.5, 26.0, 28.0, 32.3, 33.5, 36.0, 51.2, 51.5, 74.9, 77.3, 78.7,
96.2, 119.1, 121.0, 127.5, 128.8, 134.6, 135.6, 136.2, 136.4, 152.0, 152.5,
To a solution of the above bis-TBS ether (120 mg, 0.198 mmol) in THF
(8 mL) was added pyridine (568 mL, 7.04 mmol) followed by HF·pyridine
(100 mg, 5.00 mmol) and the mixture was stirred at 08C for 18 h. Saturat-
ed aqueous NaHCO3, was added carefully followed by Et2O and water.
The aqueous phase was extracted with Et2O and the combined organic
extracts were washed with saturated aqueous CuSO4, water, brine, and
dried. The solvent was removed under reduced pressure and the residue
was purified by flash chromatography with 10% EtOAc/petrol as eluent
to give alcohol 23 (70.1 mg, 72%) as a colourless oil. [a]1D6 =+22.5 (c=
0.78, CH2Cl2); 1H NMR (500 MHz): d=0.03 (s, 3H), 0.08 (s, 3H), 0.78
(d, J=7.2 Hz, 3H), 0.84 (d, J=6.5 Hz, 3H), 0.89 (s, 9H), 0.97 (d, J=
6.4 Hz, 3H), 1.35–1.38 (m, 2H), 1.43–1.50 (m, 3H), 1.56 (m, 1H), 1.59
(m, 1H,), 1.72 (s, 3H), 1.74 (m,1H), 1.83 (m, 1H), 1.91 (m, 1H), 2.03 (m,
1H), 2.23 (d, J=2.4 Hz, 1H), 2.30 (m, 1H), 2.50 (m, 1H), 2.93 (dd, J=
7.3, 3.2 Hz, 1H), 3.49 (m, 1H), 3.67 (t, J=9.6 Hz, 1H), 3.78 (m, 1H), 4.29
(dd, J=8, 4 Hz, 1H), 4.49 (m, 1H), 5.54 (dd, J=16, 6.8 Hz, 1H), 5.70 (t,
J=7.2 Hz, 1H), 6.18 ppm (d, J=16 Hz, 1H); 13C NMR (125 MHz): d=
À4.9, À4.0, 12.7, 12.9, 17.7, 17.9, 18.3, 23.8, 26.0, 27.9, 31.8, 33.9, 34.3,
36.86, 36.94, 41.5, 66.1, 66.9, 73.0, 74.9, 78.2, 82.5, 95.7, 125.4, 129.9, 133.2,
136.8 ppm; IR (film): nmax =3340, 3307, 2929, 2858, 1460 cmÀ1; HRMS
(ESI): m/z: calcd for C35H64NaO4Si: 513.3376, found 513.3374 [M+Na]+.
167.2, 167.6 ppm; IR (film): nmax =2970, 2952, 1737, 1612, 1365 cmÀ1
;
HRMS (ESI): m/z: calcd for C37H60NaO7Si: 667.4001, found 667.4091
[M+Na]+.
Spirofungin A (1): To a solution of dimethyl ester 27 (8.6 mg, 13.4 mmol)
in THF/H2O/MeOH (0.3/0.1/0.1 mL) was added LiOH (4.1 mg,
171.2 mmol). The reaction mixture was stirred for 96 h and cooled to 08C
and diluted with EtOAc (1 mL) was added and then treated with aque-
ous HCl (1 N in water, 0.17 mL, 171.2 mmol), saturated NH4Cl (1 mL)
and the aqueous layer was extracted twice with EtOAc. The combined
organic layer was washed with H2O, brine, dried (MgSO4), and the sol-
vent was removed under reduced pressure to afford dicarboxylic acid
(8.0 mg) as a yellow oil. A solution of acid (8.0 mg, 13.0 mmol) in DMPU
(8 mL) was treated with TBAF (78 mL, 1m in THF, 78 mmol). The THF
was evaporated and the reaction mixture was maintained for 24 h at
room temp. Et2O was added and the reaction mixture was cooled to 08C
and treated with HCl (1 N in water, 78 mL, 78 mmol) and saturated
NH4Cl (1 mL). The aqueous layer was extracted twice with EtOAc and
then the organic layers were combined, washed with water, brine, dried
with MgSO4 and concentrated. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography with 66%
EtOAc/petrol containing 1% AcOH as eluent to give spirofungin A (1)
(5.3 mg, 80%). [a]D16 =À123.6 (c=0.22, CH2Cl2), lit.[5] ([a]2D2 =À125.8, c=
Methyl ester 26: Tris(dibenzylideneacetone)dipalladium(0) (0.27 mg,
0.308 mmol), tricyclohexylphosphonium tetrafluoroborate (0.45 mg,
1.22 mmol) and diisopropylethylamine (0.32 mg, 2.44 mmol) were added
with CH2Cl2 (400 mL) and the resulting mixture was stirred at RT for
10 min. Alcohol 23 (30 mg, 61 mmol) was added in CH2Cl2 (300 mL) and
then cooled to 08C. Bu3SnH (31.9 mg, 110.3 mmol) diluted in CH2Cl2
(200 mL) was added dropwise. The reaction was then allowed to stir at
08C for 8 h. The reaction mixture was concentrated and purified by flash
chromatography with 5% EtOAc/petrol containing 1% NEt3 as eluent to
afford the vinylstannane 24 (35 mg, 85%), which were used immediately
in the next step. To a freeze–thaw, degassed solution of the stannane 24
and the iodide 25[26] (13 mg, 57.7 mmol) in NMP (1 mL) was added tri-2-
furylphosphine (2.8 mg, 12.1 mmol) and [Pd2dba3] (2.7 mg, 29.5 mmol) and
the mixture heated at 558C for 24 h. Et2O and water were added and the
aqueous phase extracted with Et2O. The combined organic extracts were
1
0.28, CHCl3), lit.[6] ([a]D22 =À122.8 (c=0.2, CH2Cl2); H NMR (500 MHz):
d=0.76 (d, J=7.0 Hz, 3H), 0.78 (d, J=6.6 Hz, 3H), 1.11 (d, J=7.0 Hz,
3H), 1.30–1.54 (m, 7H), 1.67–1.78 (m, 5H), 1.89 (m, 1H), 2.23 (s, 3H),
Chem. Eur. J. 2011, 17, 297 – 304
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M. A. Rizzacasa et al.
2.33 (m, 2H), 2.59 (q, J=6.3 Hz, 1H), 3.41 (dt, J=9.6, 4.4 Hz, 1H), 4.12
(m, 1H), 4.15 (dd, J=8.9, 5.0 Hz, 1H), 5.492 (t, J=6.2 Hz, 1H), 5.494
(dd, J=15.7, 7.8 Hz, 1H), 5.82 (s, 1H), 5.87 (d, J=16.0 Hz, 1H), 6.20 (d,
J=15.6 Hz, 1H), 6.28 (d, J=15.6 Hz, 1H), 6.54 (dd, J=15.6, 9.5 Hz, 1H),
7.09 ppm (dd, J=15.8, 7.3 Hz, 1H); 13C NMR (200 MHz, CD2Cl2): d=
12.2, 13.9, 14.0, 16.5, 17.1, 23.4, 27.5, 32.5, 32.8, 34.4, 35.4, 35.7, 42.3, 77.4,
75.8, 77.9, 95.4, 117.7, 120.6, 125.5, 129.9, 133.2, 135.7, 135.9, 137.1, 152.9,
154.6, 170.7, 171.2 ppm; IR (film): nmax =3300, 2928, 3859, 1721, 1613,
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541.2562, found 541.2568 [M+Na]+.
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Acknowledgements
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Received: August 30, 2010
Published online: December 10, 2010
304
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Chem. Eur. J. 2011, 17, 297 – 304