First total synthesis of Aspinolide B, a new pentaketide produced by Aspergillus ochraceus

Article abstract of DOI:10.1021/jo000327i

The first asymmetric total synthesis of Aspinolide B (1), a new 10-membered lactone discovered by chemical screening methods in the cultures of Aspergillus ochraceus, has been accomplished. The key steps included a selective Felkin-type addition of TMS-acetylene to aldehyde 3a and a Nozaki-Hiyama-Kishi coupling reaction to build the required 10-membered ring. This synthesis confirmed the absolute stereochemistry of aspinolide B, established through Helmchen's method and corrected its previously reported specific optical rotation.

Full text of DOI:10.1021/jo000327i

5910
J . Org. Chem. 2000, 65, 5910-5916
F ir st Tota l Syn th esis of Asp in olid e B, a New P en ta k etid e
P r od u ced by Asper gillu s och r a ceu s
Ronaldo A. Pilli,*,† Mauricio M. Victor,† and Armin de Meijere‡
Instituto de Quı´mica, Unicamp, Cx. Postal 6154, 13083-970 Campinas, SP Brazil and Institut fu¨r
Organische Chemie, Georg-August Universita¨t, Tammannstrasse 2, Go¨ttingen, Germany
pilli@iqm.unicamp.br
Received March 7, 2000
The first asymmetric total synthesis of Aspinolide B (1), a new 10-membered lactone discovered by
chemical screening methods in the cultures of Aspergillus ochraceus, has been accomplished. The
key steps included a selective Felkin-type addition of TMS-acetylene to aldehyde 3a and a Nozaki-
Hiyama-Kishi coupling reaction to build the required 10-membered ring. This synthesis confirmed
the absolute stereochemistry of aspinolide B, established through Helmchen’s method and corrected
its previously reported specific optical rotation.
In tr od u ction
Aspinolide B (1) is a new decanolide produced from
cultures of Aspergillus ochraceus,1 a class of lactones that
has received special attention over the last years.2 While
the relative stereochemistry was established by X-ray
analysis,1 its absolute stereochemistry was assigned after
establishing its 4S configuration by Helmchen’s method.3
Other representative members of the 10-membered lac-
tones are decarestrictine D,4 phoracantolide I,5 and
achaetolide (Figure 1).6
The synthesis of medium-sized lactones may be a
difficult challenge particularly in cases in which desta-
bilizing nonbonded, transannular interactions, and un-
favorable entropic factors must be overcome.7 Taking into
account that the previous approaches to 10-membered
lactones have generally relied on esterification/lacton-
ization strategy to construct the macrolide core, we
considered a novel strategy to 10-membered lactones
based on the formation of a C-C bond as the final
maneuver in the formation of the macrolide.8 Recent
success in the simultaneous formation of the C6-C7 bond
and installation of the correct configuration at C7 in the
total synthesis of decarestrictine D9 prompted the deci-
sion to employ the intramolecular Nozaki-Hiyama-
Kishi reaction in the formation of the C7-C8 bond in the
synthesis of aspinolide 1. Vinylic iodide 2 was conceived
F igu r e 1. Some ten-membered lactone natural products.
to undergo an intramolecular Nozaki-Hiyama-Kishi
reaction to provide the decanolide moiety of aspinolide
B (1). Access to this intermediate would be secured by
esterification of the corresponding carboxylic acid and a
secondary alcohol derived from (R)-lactic acid. The C1-
C7 fragment was planned to be prepared from aldehyde
3a or 3b by a stereocontrolled addition of a two-carbon
fragment in order to set the proper configuration at C5.
Finally, aldehydes 3a and 3b would be obtained from
optically pure lactone 4 (Scheme 1).
Resu lts a n d Discu ssion
† Instituto de Qu´ımica.
The synthesis of the C1-C7 carboxylic acid fragment
of 1 requires the preparation of a glycol, which may be
approached through the Felkin-type addition of lithiated
TMS-acetylene or an equivalent vinylic species to an
R-hydroxy aldehyde under nonchelation control.10
Protection of lactone 411 as its p-methoxybenzyl (PMB)
ether12 was performed in Et2O with triflic acid (TfOH)
as a catalyst (81% yield). Reduction of PMB ether 5 with
LiAlH4 afforded the monoprotected triol 6a in 93% yield
‡ Institut fu¨r Organische Chemie.
(1) Fuchser, J .; Zeeck, A. Liebigs Ann. Recueil 1997, 87.
(2) For recent reviews see: (a) Dra¨ger, G.; Kirschning, A.; Thiericke,
R.; Zerlin, M. Nat. Prod. Rep. 1996, 13, 365. (b) Collins, I. J . Chem.
Soc., Perkin. Trans. 1 1999, 1377.
(3) Helmchen, G. Tetrahedron Lett. 1974, 16, 1527.
(4) (a) Grabley, S.; Granzer, E.; Hu¨tter, K.; Ludwig, D.; Mayer, M.;
Thiericke, R.; Till, G.; Wink, J .; Phillips, S.; Zeeck, A. J . Antibiot. 1992,
45, 56. (b) Hu¨tter, K.; Thiericke, R.; Kirsch, R.; Kluge, H.; Go¨hrt, A.;
Zeeck, A. J . Antibiot. 1992, 45, 66. (c) Hu¨tter, K.; Thiericke, R.; Kirsch,
R.; Kluge, H.; Grabley, S.; Hammann, P.; Mayer, M.; Zeeck, A. J .
Antibiot. 1992, 45, 1176. (d) Browne, L. M.; Sun, M.; Ayer, W. A. J .
Nat. Prod. 1992, 55, 649.
(5) Moore, B. P.; Brown, W. V. Aust. J . Chem. 1976, 29, 1365.
(6) Bodo, B.; Molho, L.; Davoust, D.; Molho, D. Phytochemistry 1983,
22, 447.
(7) Rousseau, G. Tetrahedron 1995, 21, 2777.
(8) Pilli, R. A.; de Andrade, C. K. Z.; Souto, C. R. O.; de Meijere, A.
J . Org. Chem. 1998, 63, 7811.
(10) Guanti, G.; Banfi, L.; Narisano, E. Gazz. Chim. Ital. 1987, 117,
681.
(11) Obtained from (S)-(+)-glutamic acid in two steps: (i) NaNO2,
HCl, H2O; (ii) Me2S‚BH3, THF. Ravid, U.; Silverstein, R. M.; Smith,
L. R. Tetrahedron 1978, 34, 1449.
(12) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139.
(9) Pilli, R. A.; Victor, M. M. Tetrahedron Lett. 1998, 39, 4421.
10.1021/jo000327i CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/18/2000

Total Synthesis of Aspinolide B
J . Org. Chem., Vol. 65, No. 19, 2000 5911
Ta ble 1. Selectivity in th e Ad d ition of Nu cleop h ile to
Ald eh yd e
Sch em e 1
Sch em e 2a
a
b
Determined by GC analysis. Determined after protection
with TBDPSCl.
to evaluate the addition of the lithium anions of tri-
methylsilylacetylene and trans-1,2-bis(tri-n-butylstan-
nyl)ethylene14 to the TBS- and TBDPS-protected dihy-
droxy aldehydes 3a and 3b. Our results are summarized
above (Table 1).
Our results indicated that the addition of the lithium
derivatives of 1-tri-n-butyl vinylstannane and trimeth-
ylsilylacetylene to 3b (Table 1, entries 3 and 4) can be
used to homologate the carbon chain, but with low
diastereoselection (up to 2:1). Moreover, scrambling of the
TBDPS-silyl protecting group leading to mixtures of silyl
ethers at C3 and C4 was observed, which required
conversion to the corresponding bis-silyl ethers prior to
the determination of the diastereoisomeric ratio. When
the addition was performed to 3a , the lithium derivative
of 1-tri-n-butyl vinylstannane surprisingly gave low anti
selectivity (Table 1, entry 2) while lithium trimethylsi-
lylacetylide (Table 1, entry 1) assured both good yield and
anti selectivity. The reason for the higher selectivity
observed for 3a in comparison with the results described
for lactaldehyde may result from the bulkier nature of
the (CH2)3OTBS group in 3a when compared with the
methyl group in (R)-O-tert-butyldiphenylsilyl lactalde-
hyde. However, the origin of the higher selectivity in the
addition of lithium trimethylsilylacetylide to 3a when
compared to the addition to 3b is not clear at this
moment. The assignment of anti stereochemistry to the
major isomer required the transformation15 of the crude
mixture of diastereoisomers 8a /9a to the corresponding
mixture of ketal 10a and its C5 epimer: a 2.2% increment
in the H4 signal of 10a was observed upon irradiation of
H5 and supported the anti stereochemistry assigned for
the major stereoisomer 8a (Figure 3).The anti relative
stereochemistry of the majors isomers 8b-d was tenta-
tively assigned after 8a .
a
(a) PMB-acetimidate, Et2O, TfOH (cat.) (81%); (b) LiAlH4, THF
(93%); (c) TBSCl, DMF, imidazole (99%); (d) TBSCl, DMAP, Et3N,
CH2Cl2 (93%); (e) TBDPSCl, DMF, imidazole (93%); (f) DDQ,
CH2Cl2:H2O (20:1), 0 °C (92% for 6b; 94% for 6d ); (g) TPAP, NMO,
4A MS, CH2Cl2 (90% for 7a ; 85% for 7b).
F igu r e 2. Nucleophilic addition to aldehydes 3a ,b.
which was converted to the corresponding bis-TBS ether
6b in DMF and imidazole (99% yield). The p-methoxy-
benzyl group in 6b was removed with DDQ to give alcohol
7a in 92% yield. Oxidation with tetrapropylammonium
perruthenate (TPAP)13 afforded aldehyde 3a in 90%
yield. Alternatively, 6a was protected as its mono-TBS
ether 6c in 93% yield when the reaction was carried out
in CH2Cl2. The fully protected triol 6d was obtained in
93% yield from 6c after protection of the secondary
hydroxyl group with TBDPSCl in DMF and converted to
3b (two steps, 80% overall yield) through the same
reaction sequence described for 3a (Scheme 2).
The next step included the diastereoselective addition
of a two-carbon nucleophile to aldehydes 3a and 3b
(Figure 2). According to Guanti et al.,10 under nonchela-
tion control (TBDPS as the protecting group of the
R-hydroxy group) stereoselective anti addition (83:17
ratio) of lithium trimethylsilylacetylide to (R)-O-tert-
butyldiphenylsilyl lactaldehyde was achieved. We decided
(14) Obtained in two steps from acetylene and tributyltin chloride:
(i) acetylene, THF, -78 °C, then n-BuLi and n-Bu3SnCl 78% (Cabezas,
J . A.; Oehlschlager, A. C. Synthesis 1994, 432); (ii) ethynyl(tributyl)-
tin, n-BuSnH, AIBN 96% (Corey, E. J .; Wollenberg, R. H. J . Am. Chem.
Soc. 1974, 96, 5581).
(15) (i) TBSCl, imidazole, DMF; (ii) AgNO3, THF, EtOH, H2O, KCN;
(iii) Ac2O, DMAP, Et3N, CH2Cl2; (iv) TBAF, THF; (v) 2,2-dimethox-
ypropane, DMF, TsOH; (vi) K2CO3, MeOH.
(13) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.

5912 J . Org. Chem., Vol. 65, No. 19, 2000
Pilli et al.
Sch em e 3a
F igu r e 3.
Having selected an attractive methodology to set the
proper configuration at C5 in 8a , protection of the
hydroxyl group with TBSCl afforded the fully silylated
triol 11 in quantitative yield. Treatment of 11 with
AgNO3 in THF/H2O/EtOH, conditions adapted from those
described by Nicolaou and Webber,16 selectively removed
the acetylenic TMS as well as the primary TBS protecting
group. This transformation occurred in 93% yield to
provide acetylenic alcohol 12. The required transforma-
tion of the terminal acetylenic moiety to the correspond-
ing (E)-vinyl iodide was initially carried out under
palladium catalysis [Cl2Pd(PPh3)2],17 as described by
Guibe´ et al.,18 followed by iodide exchange to afford the
product in 69% yield. Unfortunately, the desired (E)-vinyl
iodide was obtained along with its regioisomer and the
corresponding terminal olefin in a 81:10:9 ratio, respec-
tively. The desired transformation was successfully car-
a
(a) TBSCl, DMF, imidazole (100%); (b) AgNO3, EtOH, THF,
H2O, then KCN (93%); (c) HSnBu3, AIBN (cat.), 90 °C (78%); (d)
TBSCl, Et3N, DMAP (cat.), CH2Cl2 (89%); (e) I2, CCl4 then CH2Cl2,
NaOH (86%); (f) J ones reagents, acetone, 0 °C (89%).
Sch em e 4a
n
ried out by radical stannylation with Bu3SnH and AIBN
a
(a) TBSCl, DMF, imidazole (90%); (b) DIBAL-H, CH2Cl2, 0 aC
as catalyst, which afforded vinyl stannane 13 in 78%
yield as a single isomer. Attempts to convert 13 directly
to the corresponding iodide proved difficult. Initially tin-
iodide exchange (I2, CCl4) was performed in low yields
(up to 38%) when 13 was employed, and the separation
of tin-containing side-products was tedious. These prob-
lems were circumvented by protection of the free hydroxyl
group with TBSCl (89% yield) which led to nonpolar
silylated compound 14 and allowed us to employ the tin-
removal protocol with 1 M aqueous NaOH solution.19
Tin-iodide exchange was performed in 86% yield when
14 was employed to give iodide 15, which was converted
to the required carboxylic acid 16 in 89% yield after an
one-pot desilylation-oxidation sequence.20 The conver-
sion of 8a to 16 was carried out with mixtures containing
less than 10% of the minor isomer at the assigned
position (Scheme 3).
The synthesis of lactate derivative 21 containing the
C8-C10 fragment was readily accomplished starting
from (R)-methyl lactate (17). Protection of 17 with TBSCl
(90% yield) afforded silyl ether 18 which was reduced
(DIBAL-H, CH2Cl2, 0 °C) to produce monoprotected diol
19 in 50% yield. Following protection as the p-methoxy-
benzyl 20 (69% yield), desilylation with TBAF in THF
afforded C8-C10 fragment 21 in 91% yield (Scheme 4).
(50%); (c) PMB-trichloroacetimidate, Et2O, TfOH (cat.) (69%); (d)
TBAF, THF (91%).
raphy on silica gel to furnish isomerically pure ester 22
in 71% yield along with the C5 epimer as a minor
component (4% yield). Deprotection of the PMB ether in
22 upon treatment with DDQ afforded alcohol 23 in 84%
yield. At this point we were ready to carry out the key
step in the synthetic plan: Dess-Martin periodinane
oxidation of 23 gave aldehyde 2, which was treated
without prior purification with excess CrCl2 (15 equiv)22
containing 0.5% of NiCl2 in DMF (0.005 M). A smooth
reaction ensued to afford a 1.5:1 mixture of diastereoi-
someric allylic alcohols 24a /24b in 49% yield over two
steps.23 The lack of facial selectivity in the Nozaki-
Hiyama-Kishi reaction was circumvented as the chro-
matographic separation of the 8R-epimer 24b allowed its
conversion to the 8S-epimer 24a by Mitsunobu inver-
sion24 (p-nitrobenzoic acid, triphenylphosphine, and di-
ethyl azodicarboxylate) to give a p-nitrobenzoate ester,
which was hydrolyzed with potassium carbonate in
methanol in 56% overall yield. Esterification of 24a with
crotonic acid (diisopropylcarbodiimide in CH2Cl2) afforded
the corresponding ester 25 in 89% yield. Synthetic (-)-
aspinolide B (1) was obtained after desilylation of 25 upon
treatment with HF‚pyridine complex in THF at room
temperature in 46% yield (Scheme 5). The synthetic
material proved to be spectroscopically identical (1H and
13C NMR and IR) with an authentic sample kindly
provided by Prof. Zeeck. However, the specific optical
rotation of the synthetic sample ([R]D -44.0 (c 1.0,
The coupling of the C1-C7 fragment 16 and the C8-
C10 fragment 21 was initially performed employing
diisopropylcarbodiimide (DIC) in CH2Cl2 which afforded
ester 22 in 61%. However, better results were achieved
under Yamaguchi conditions21 to give crude ester 22,
which required careful purification by flash chromatog-
(16) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453.
(17) Miyaura, N.; Suzuki, A. Org. Synth. 1990, 68, 130.
(18) Zhang, H. X.; Guibe´, F.; Balavoine, G. J . Org. Chem. 1990, 55,
1857.
(19) Renaud, P.; Lacoˆte, E.; Quaranta, L. Tetrahedron Lett. 1998,
39, 2123.
(20) Evans, P. A.; Roseman, J . D.; Garber, L. T. Synth. Commun.
1996, 26, 4685.
(21) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
(22) The Nozaki-Hiyama-Kishi coupling experiments were carried
out with CrCl2 purchased from Merck Schuchardt or Aldrich (>99.9%)
and dried at 1 mmHg and 250 °C for 4 h immediately prior to use.
(23) The stereochemistry at C8 was assigned on basis of 1H NMR
data of aspinolide B which displays H8 at 4.94 ppm as a double dublet
(J ) 9.0, 8.0 Hz), characteristic of trans diaxial orientation. In
comparison, H8 in 24a (δ 3.83 ppm) appears as double triplet (J )
8.5, 8.5, 5.0 Hz) while in 24b (δ 4.30 ppm) as a singlet.
(24) Mitsunobu reaction carried out with crotonic acid instead of
p-NBA was unsucessfull.

Total Synthesis of Aspinolide B
J . Org. Chem., Vol. 65, No. 19, 2000 5913
Sch em e 5a
Go¨ttingen. Column chromatography was performed using
silica gel (70-230 mesh), except when stated otherwise.
(5S)-5-(4-Meth oxyben zyloxym eth yl)tetr a h yd r o-2-fu r a -
n on e (5). To a stirred solution of (5S)-5-hydroxymethyltet-
rahydro-2-furanone 411 (233 mg, 2.01 mmol) and p-methoxy-
benzyl trichloroacetimidate (702 mg, 2.48 mmol) in Et2O (4
mL) was added one drop of a solution of TfOH (0.05 mL) in
Et2O (10 mL). After 1 h the reaction was quenched by the
addition of saturated NaHCO3. The aqueous phase was
extracted twice with Et2O, and the combined organic layers
were washed with brine, dried over Na2SO4, and concentrated.
Column chromatography (AcOEt:hexane 4:6) afforded ether
5 (385 mg, 81%) as a white solid. Mp: 42.5-44 °C; [R]D +10.6
(c 1.0, CHCl3); IR 1779 cm-1 1H NMR (250 MHz, CDCl3) δ
;
7.25 (d, J ) 8.6 Hz, 2H), 6.89 (d, J ) 8.6 Hz, 2H), 4.68-4.64
(m, 1H), 4.51(s, 2H), 3.81 (s, 3H), 3.66 (dd, J ) 10.7, 3.3 Hz,
1H), 3.56 (d, J ) 10.7, 4.2 Hz, 1H), 2.70-2.40 (m, 2H), 2.40-
2.30 (m, 1H), 2.30-2.20 (m, 1H); 13C NMR (62.5 MHz, CDCl3)
δ 177.3, 159.2, 129.6, 129.2, 113.8, 79.0, 73.1, 71.1, 55.2, 28.3,
24.1. Anal. Calcd for C13H16O4: C, 66.07%; H, 6.83%. Found:
C, 65.91%; H, 6.72%.
(4S)-5-(4-Meth oxyben zyloxy)p en ta n e-1,4-d iol (6a ). To
a suspension of LiAlH4 (1.06 g, 27.9 mmol) in THF (110 mL)
at 0 °C was added a solution of PMB ether 5 (2.64 g, 11.2
mmol) in THF (30 mL). The reaction mixture was stirred for
2 h and successively treated at 0 °C with water (1.05 mL),
10% aqueous NaOH (1.05 mL), and water (3.15 mL). The
inorganic solids were filtered and washed with AcOEt. The
organic extracts were dried over MgSO4 and concentrated to
afford 6a (2.49 g, 93%) as a colorless oil. [R]D -8.6 (c 1.0,
EtOH); IR 3317 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.25 (d, J
) 8.6 Hz, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 4.47 (s, 2H), 3.84-
3.79 (m, 1H), 3.80 (s, 3H), 3.66-3.60 (m, 2H), 3.45 (dd, J )
9.3, 3.4 Hz, 1H), 3.31 (dd, J ) 9.3, 7.9 Hz, 1H), 2.86 (br, 2H),
1.70-1.60 (m, 2H), 1.60-1.50 (m, 2H); 13C NMR (62.5 MHz,
CDCl3) δ 159.2, 129.9, 129.4, 113.8, 74.1, 73.0, 70.3, 62.7, 55.2,
30.1, 29.4. Anal. Calcd for C13H20O4: C, 64.96%; H, 8.39%.
Found: C, 64.65%; H, 8.56%.
(2S)-2,5-Bis(ter t-bu tyld im eth ylsilyloxy)-1-(4-m eth oxy-
ben zyloxy)p en ta n e (6b). To a solution of diol 6a (7.15 g, 29.8
mmol) in DMF (14.3 mL) were added imidazole (10.72 g, 157.6
mmol) and TBSCl (10.76 g, 71.3 mmol). The mixture was
stirred for 7.5 h and diluted with Et2O, and the reaction was
quenched by the addition of 70 mL of brine. After phase
separation the aqueous phase was extracted twice with CH2-
Cl2. The combined organic layers were dried over Na2SO4 and
concentrated. Silica gel chromatography (AcOEt:hexane 5:95)
furnished 6b (13.80 g, 99%) as a colorless oil. [R]D -8.0 (c 1.0,
CHCl3); IR 1250 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.27 (d, J
) 8.6 Hz, 2H), 6.88 (d, J ) 8.6 Hz, 2H), 4.46 (s, 2H), 3.81 (s,
3H), 3.90-3.78 (m, 1H), 3.61 (t, J ) 5.7 Hz, 2H), 3.37 (δAB, ∆
) 12.7 Hz, J ) 12.7, 5.5 Hz, 2H), 1.66-1.41 (m, 4H), 0.90 (s,
9H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 9H); 13C NMR (62.5
MHz, CDCl3) δ 159.0, 130.6, 129.2, 113.6, 74.4, 72.9, 71.3, 63.4,
55.2, 31.0, 28.6, 26.0, 25.9, 18.3, 18.2, -4.4, -4.8, -5.3 (×2).
Anal. Calcd for C25H48O4Si2: C, 64.05%; H, 10.32%. Found:
C, 64.01%; H, 10.14%.
a
(a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then 21, DMAP,
benzene (71%); (b) DDQ, CH2Cl2:H2O (20:1), 0 °C (84%); (c) Dess-
Martin periodinane, CH2Cl2, H2O (cat.); (d) CrCl2/NiCl2 (0.5%),
DMF, 0.005 M (49% for two steps); (e) (i) p-NBA, DEAD, PPh3,
benzene; (ii) K2CO3, MeOH (56% over two steps); (f) crotonic acid,
DIC, CH2Cl2 (89%); (g) HF‚pyridine complex, pyridine, THF (46%).
MeOH)) differed from the previously reported value for
natural aspinolide B ([R]D -19.1 (c 1.0, MeOH)).1,25
In conclusion, the first asymmetric total synthesis of
(-)-aspinolide B was achieved in 19 steps and 2.4%
overall yield from 4. Homologation of aldehyde 3a was
performed in good yield and selectivity, efficiently provid-
ing anti-diol 8a . The Nozaki-Hiyama-Kishi coupling
reaction proved to be useful for the construction of 10-
membered ring lactones 24a and 24b, despite the low
facial selectivity. Studies are underway aimed to control
the stereochemical outcome of this reaction when applied
to the formation of medium- and large-ring lactones.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. Unless otherwise
stated, all reactions were run under a nitrogen atmosphere.
Anhydrous solvents were freshly distilled before use: diethyl
ether and tetrahydrofuran (THF) were distilled from sodium
benzophenone ketyl. Benzene was distilled from sodium and
stored over 4A molecular sieve. Methylene chloride and
triethylamine were distilled from CaH2. Dimethylformamide
was treated with P2O5, distilled from CaH2, and stored over
4A molecular sieve. CrCl2 containing 0.5 mol % NiCl2 was
activated 4 h at 250 °C under vacuum (1 mmHg) and weighed
under argon atmosphere in a glovebox. The remaining re-
agents were purchased from commercial suppliers and used
(2S)-2,5-Bis(ter t-bu tyldim eth ylsilyloxy)-1-pen tan ol (7a).
To a stirred solution of 6b (13.8 g, 29.5 mmol) in CH2Cl2 (157
mL) containing water (7.8 mL) at 5 °C was added DDQ (8.69
g, 38.3 mmol). After 2 h the reaction mixture was filtered and
washed with CH2Cl2. The extract was successively washed
with saturated NaHCO3 and brine and then dried over Na2-
SO4. The solvent was evaporated, and the residue was chro-
matographed on a silica gel column (AcOEt:hexane 1:4) to give
alcohol 7a (9.47 g, 92%) as a colorless oil. [R]D +8.5 (c 1.3,
1
without further purification. H NMR spectra were recorded
at 250, 300, or 500 MHz; 13C NMR spectra were recorded at
62.5, 75, or 125 MHz. CHCl3 (δ 7.26) was used as an internal
standard in H NMR spectra. 13C NMR spectra were referenced
1
to CDCl3 at 77.0 ppm. Optical rotations were measured at 25
°C at 589 nm or at 546 nm (mercury line). Combustion
analyses were conducted at the Mikroanalytisches Laborato-
rium des Institut fu¨r Organische Chemie der Universita¨t,
CHCl3); IR 3400 cm-1 1H NMR (250 MHz, CDCl3) δ 3.80-
;
3.72 (m, 1H), 3.62-3.53 (m, 3H), 3.45 (ddd, J ) 11.0, 6.3, 5.5
Hz, 1H), 1.95 (t, J ) 6.3 Hz, 1H), 1.60-1.45 (m, 4H), 0.90 (s,
9H), 0.89 (s, 9H), 0.09 (s, 6H), 0.05 (s, 6H); 13C NMR (62.5
MHz, CDCl3) δ 72.7, 66.2, 63.1, 30.3, 28.5, 25.9, 25.8, 18.3,
18.1, -4.5, -4.6, -5.3 (×2). Anal. Calcd for C17H40O3Si2: C,
58.56%; H, 11.56%. Found: C, 58.58%; H, 11.32%.
(25) After completion of this work, a personal communication from
Prof. A. Zeeck confirmed the specific optical rotation of natural
aspinolide B to be identical to the one found for the synthetic material
([R]D ) -44.0 (c 1.0, MeOH)) and not the one reported in his original
paper ([R]D -19.1 (c 1.0, MeOH)).
(2S)-2,5-Bis(ter t-bu tyld im eth ylsilyloxy)p en ta n a l (3a ).
Solid tetrapropylammonium perruthenate (3.2 mg, 0.0091

5914 J . Org. Chem., Vol. 65, No. 19, 2000
Pilli et al.
mmol) was added in one portion to a stirred mixture of alcohol
7a (85 mg, 0.24 mmol), 4-methylmorpholine N-oxide (32 mg,
0.27 mmol), and powdered 4A molecular sieve (90 mg) in CH2-
Cl2 (0.36 mL). After 1 h the reaction mixture was filtered
through a short pad of silica gel, eluted with AcOEt:hexane
1:4 and concentrated, furnishing the crude aldehyde 3a (75
mg, 90%) as a colorless oil. [R]D -15.8 (c 1.0, CHCl3); IR 2799,
m/z (relative intensity) 315 (10%, [M - C4H9]+), M+ 73 (100%).
HRMS calcd for C15H31O3Si2 [M - C4H9]+: 315.1812. Found:
315.1811.
(4S,5R,6E)-7-Tr ibu tyltin -4,5-bis(ter t-bu tyld im eth ylsi-
lyloxy)-6-h ep ten -1-ol (13). The terminal acetylene 12 (59 mg,
0.16 mmol, 11.5:1 mixture) in HSnBu3 (0.10 mL, 0.11 g,
0.32 mmol) in the presence of a catalytic amount of AIBN (1
mg) was heated at 90-100 °C for 48 h. Column chromatog-
raphy (hexane) furnished stannane 13 (82 mg, 78%) as a
colorless liquid in a 11.5:1 mixture with its C5 epimer. [R]546
-15.4 (c 1.3, CHCl3); IR 3334, 1601 cm-1. 13: 1H NMR (500
MHz, CDCl3) δ 6.10 (dd, J ) 19.3, 1.0 Hz, 1H), 5.94 (dd, J )
19.1, 6.6 Hz, 1H), 3.94 (ddd, J ) 6.6, 4.9, 1.0 Hz, 1H), 3.66-
3.57 (m, 4H), 1.68-1.60 (m, 4H), 1.54-1.45 (m, 6H), 1.30 (sex.,
J ) 7.3 Hz, 6H), 0.91-0.86 (m, 33H), 0.06 (s, 3H), 0.05 (s, 3H),
0.04 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 149.0,
130.1, 80.0, 75.9, 63.3, 29.7, 29.1, 28.4, 27.3, 26.0 (×2), 18.3,
18.2, 13.7, 9.4, -4.0 (×2), -4.5, -4.7; LRMS (EI) m/z (relative
intensity) 607 (55%, [M - C4H9]+), 73 (100%). HRMS calcd for
C27H59O3Si2Sn [M - C4H9]+: 607.3025. Found: 607.3027.
Tr ibu tyl[(E,3R,4S)-3,4,7-tr is(ter t-bu tyldim eth ylsilyloxy)-
1-h ep ten yl]sta n n a n e (14). To a solution of 13 (1.69 g, 2.55
mmol, 11.5:1 mixture) in CH2Cl2 (10 mL) were added at
room-temperature triethylamine (0.43 mL, 3.1 mmol), DMAP
(38 mg, 0.31 mmol), and TBSCl (462 mg, 3.06 mmol). After 16
1
1738 cm-1; H NMR (250 MHz, CDCl3) δ 9.60 (d, J ) 1.6 Hz,
1H), 4.00 (ddd, J ) 6.8, 5.1, 1.6 Hz, 1H), 3.62 (t, J ) 5.9 Hz,
2H), 1.80-1.53 (m, 4H), 0.92 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H),
0.07 (s, 3H), 0.04 (s, 6H); 13C NMR (62.5 MHz, CDCl3) δ 204.1,
77.5, 62.7, 29.1, 27.9, 25.9, 25.7, 18.3, 18.2, -4.6, -4.9, -5.3
(×2).
(4S,5R)-7-Tr im eth ylsilyl-1,4-bis(ter t-bu tyld im eth ylsi-
lyloxy)-6-h ep tyn -5-ol (8a ). n-BuLi (31.2 mL, 2.3 M in hexane,
71.6 mmol) was diluted at 0 °C in THF (92 mL), and
trimethylsilylacetylene (10.1 mL, 7.04 g, 71.7 mmol) was
added. After 30 min, the solution was cooled to -78 °C, and a
solution of the aldehyde 3a (8.28 g, 23.9 mmol) in THF (10
mL) was added via cannula. After the mixture had been stirred
for 1.5 h, the cooling bath was removed and the reaction
quenched at -30 °C by the addition of saturated NH4Cl
solution and extracted twice with CH2Cl2. The organic layer
was washed with brine, dried over MgSO4, and concentrated.
Silica gel chromatography (AcOEt:hexane 1:19) afforded the
addition products 8a and 8b (8.48 g, 81%) as an 11.5:1
inseparable mixture (determined by GC). [R]D -3.0 (c 1.0,
CHCl3); IR 3429, 2175 cm-1. 8a : 1H NMR (250 MHz, CDCl3)
δ 4.31 (dd, J ) 5.6, 3.9 Hz, 1H), 3.80-3.74 (m, 1H), 3.61 (t, J
) 5.6 Hz, 2H), 2.38 (d, J ) 5.6 Hz, 1H), 1.80-1.40 (m, 4H),
0.90 (s, 9H), 0.89 (s, 9H), 0.16 (s, 9H), 0.09 (s, 6H), 0.04 (s,
6H); 13C NMR (62.5 MHz, CDCl3) δ 103.6, 90.9, 74.8, 66.4, 63.2,
28.8, 28.6, 25.9, 25.8, 18.3, 18.1, -0.2, -4.4, -4.5, -5.3 (×2).
Anal. Calcd for C22H48O3Si3: C, 59.40%; H, 10.88%. Found:
C, 59.10%; H, 10.79%.
h
the solution was diluted with Et2O and washed with
saturated NH4Cl solution. The aqueous layer was extracted
with Et2O, and the organic layer was washed with brine, dried
over MgSO4, and concentrated. Silica gel chromatography
(AcOEt:hexane 1:99) gave the fully protected stannane 14 (1.77
g, 89%) as a colorless liquid in a 11.5:1 mixture with its C3
epimer. [R]546 -20.0 (c 1.0, CHCl3); IR 1601 cm-1. 14: 1H NMR
(500 MHz, CDCl3) δ 6.07 (dd, J ) 19.0, 0.7 Hz, 1H), 5.96 (dd,
J ) 19.1, 6.3 Hz, 1H), 3.91 (ddd, J ) 6.3, 4.1, 0.7 Hz, 1H),
3.63-3.55 (m, 3H), 1.65-1.40 (m, 10H), 1.31 (sex., J ) 7.3 Hz,
6H), 0.92-0.86 (m, 48H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s,
3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 149.1, 129.4,
80.3, 76.2, 63.6, 29.7, 29.2, 28.5, 27.3, 26.0 (×2), 26.0, 18.4,
18.3, 18.2, 13.7, 9.4, -3.9, -4.0, -4.5, -4.6, -5.3 (×2); LRMS
(EI) m/z (relative intensity) 721 (10%, [M - C4H9]+), 185
(100%). HRMS calcd for C33H73O3Si3Sn [M - C4H9]+: 721.3890.
Found: 721.3890.
(E,3R,4S)-1-Iod o-3,4,7-tr is(ter t-bu tyld im eth ylsilyloxy)-
1-h ep ten e (15). To a stirred solution of the stannane 14 (1.69
g, 2.17 mmol, 11.5:1 mixture) in CCl4 (25 mL) was added
I2 (1.38 g, 5.43 mmol). After 2 h the mixture was diluted with
Et2O and washed with 10% aqueous NaHSO3. The aqueous
layer was extracted with Et2O, and the organic layer was
concentrated. The crude product mixture was redissolved in
CH2Cl2 (10 mL), aqueous 1 M NaOH (10 mL) was added, and
the mixture was vigorously stirred for 1 h. The organic phase
was separated, washed successively with aqueous 1 M NaOH
and brine, and dried over MgSO4. Column chromatography
(hexane) afforded the iodide 15 (1.14 g, 86%) as a colorless
viscous oil in a 11.5:1 mixture with its C3 epimer. [R]546 -20.0
(c 1.0, CHCl3); IR 1608 cm-1. 15: 1H NMR (500 MHz, CDCl3)
δ 6.50 (dd, J ) 14.5, 7.2 Hz, 1H), 6.20 (dd, J ) 14.6, 1.0 Hz,
1H), 3.91 (ddd, J ) 7.1, 5.4, 1.0 Hz, 1H), 3.62-3.54 (m, 3H),
1.58-1.50 (m, 4H), 0.89 (s, 9H), 0.87 (s, 9H), 0.86 (s, 9H), 0.06
(s, 3H), 0.05 (s, 3H), 0.04 (s, 9H), 0.03 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 147.3, 78.5, 77.6, 75.3, 63.4, 29.8, 27.9, 26.0,
25.9, 25.9, 18.3, 18.2, 18.1, -4.1, -4.3, -4.5, -4.7, -5.3 (×2);
LRMS (EI) m/z (relative intensity) 557 (8%, [M - C4H9]+), 73
(100%). HRMS calcd for C21H46O3Si3I [M - C4H9]+: 557.1800.
Found: 557.1801.
Tr im eth yl[(3R,4S)-3,4,7-tr is(ter t-bu tyldim eth ylsilyloxy)-
1-h ep tyn yl]sila n e (11). To a solution of alcohol 8a (4.2 g, 9.4
mmol, 11.5:1 mixture) in DMF (10.2 mL) were added imid-
azole (2.06 g, 30.3 mmol) and TBSCl (2.06 g, 13.7 mmol). The
mixture was stirred for 48 h and diluted with CH2Cl2, and the
reaction was quenched by the addition of brine. After phase
separation the aqueous phase was extracted twice with CH2-
Cl2. The combined organic layers were dried over Na2SO4 and
concentrated. Silica gel chromatography (AcOEt:hexane 1:99)
furnished the fully protected silane 11 (5.25 g) as a colorless
oil in a 11.5:1 mixture with its C3 epimer in quantitative yield.
[R]D -20.3 (c 1.0, CHCl3); IR 2175 cm-1. 11: 1H NMR (250
MHz, CDCl3) δ 4.15 (d, J ) 6.2 Hz, 1H), 3.75-3.68 (m, 1H),
3.59 (t, J ) 5.5 Hz, 2H), 1.74-1.52 (m, 4H), 0.89 (s, 18H), 0.88
(s, 9H), 0.14 (s, 9H), 0.07 (s, 6H), 0.03 (s, 12H); 13C NMR (62.5
MHz, CDCl3) δ 107.0, 89.6, 75.3, 67.0, 63.5, 29.4, 27.5, 26.0
(×2), 25.8, 18.3, 18.2, 18.2, -0.2, -4.1, -4.3, -4.4, -5.0, -5.3
(×2); LRMS (EI) m/z (relative intensity) 501 (35%, [M -
C4H9]+), M+ 185 (100%). HRMS calcd for C24H53O3Si4 [M -
C4H9]+: 501.3072. Found: 501.3072.
(4S,5R)-4,5-Bis(ter t-b u t yld im et h ylsilyloxy)-6-h ep t yn -
1-ol (12). Compound 11 (5.18 g, 9.26 mmol, 11.5:1 mixture)
was dissolved in ethanol (74 mL) and THF (45 mL) and cooled
to 0 °C. To this magnetically stirred solution was added
dropwise a solution of silver nitrate (6.30 g, 37.1 mmol) in
ethanol (103 mL) and water (103 mL) over a period of 2 h.
After the addition was complete, this mixture was stirred at
room-temperature overnight. After 16 h a solution of potas-
sium cyanide (17.4 g, 267 mmol) in water (56 mL) was added,
and the mixture was extracted with Et2O, and the extracts
were dried over MgSO4 and concentrated. Purification by
column chromatography (AcOEt:hexane 1:4) gave the depro-
tected alcohol 12 (3.20 g, 93%) as a colorless oil in a 11.5:1
mixture with its C5 epimer. [R]D -29.9 (c 1.0, CHCl3); IR 3312,
2362 cm-1. 12: 1H NMR (250 MHz, CDCl3) δ 4.25 (dd, J )
5.3, 2.2 Hz, 1H), 3.80-3.72 (m, 1H), 3.70-3.58 (m, 2H), 2.35
(d, J ) 2.1 Hz, 1H), 1.80-1.55 (m, 5H), 0.90 (s, 9H), 0.89 (s,
9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H); 13C
NMR (62.5 MHz, CDCl3) δ 84.2, 75.4, 73.5, 66.5, 63.2, 29.2,
27.9, 25.9, 25.8, 18.2 (×2), -4.2, -4.4, -4.5, -5.1; LRMS (EI)
(4S,5R,6E)-7-Iod o-4,5-bis(ter t-bu tyld im eth ylsilyloxy)-
6-h ep ten oic Acid (16). A stirred ice-cold acetone solution (66
mL) of iodide 15 (1.06 g, 1.72 mmol, 11.5:1 mixture) was
treated dropwise with 8 M J ones reagent (ca. 1.5 mL). The
excess of the J ones reagent was quenched by the addition of
2-propanol, and the mixture was allowed to reach room
temperature. The clear greenish solution was decanted, and
the remaining chromium salts were extracted four times with
Et2O. The combined extracts were washed with brine and dried
over MgSO4. The solvents were removed in vacuo, and the

Total Synthesis of Aspinolide B
J . Org. Chem., Vol. 65, No. 19, 2000 5915
remaining crude product was purified by column chromatog-
raphy (AcOEt:hexane 5:95) to give the carboxylic acid 16 (791
mg, 89%) as a white solid in a 11.5:1 mixture with its C5
epimer. Mp: 91-93 °C; [R]546 -30.0 (c 1.0, CHCl3); IR 3300-
2600, 1705, 1610 cm-1. 16: 1H NMR (500 MHz, CDCl3) δ 6.48
(dd, J ) 14.4, 7.1 Hz, 1H), 6.24 (dd, J ) 14.5, 0.9 Hz, 1H),
3.88 (ddd, J ) 7.1, 5.4, 1.0 Hz, 1H), 3.61 (q, J ) 5.3 Hz, 1H),
2.43-2.37 (m, 2H), 1.90-1.80 (m, 2H), 0.88 (s, 9H), 0.87 (s,
9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 179.3, 146.8, 78.3, 78.2, 74.0, 29.1,
27.9, 25.9, 25.8, 18.1, 18.0, -4.1, -4.3, -4.7, -4.9; LRMS (EI)
m/z (relative intensity) 457 (16%, [M - C4H9]+), 73 (100%).
HRMS calcd for C15H30O3Si3I [M - C4H9]+: 457.0727. Found:
457.0728.
Meth yl (2R)-2-(ter t-Bu tyld im eth ylsilyloxy)p r op a n oa te
(18). Using the conditions described for the conversion of 6a
to 6b, the silylated compound 18 was obtained from (R)-methyl
lactate 17 in 90% as a colorless liquid. [R]D +27.2 (c 1.89, CCl4);
lit.26 (2S)-18 [R]D -26.9 (c 1.89, CCl4); IR 1760, 1740 cm-1; 1H
NMR (250 MHz, CDCl3) δ 4.27 (q, J ) 6.7 Hz, 1H), 3.66 (s,
3H); 1.33 (d, J ) 6.8 Hz, 3H), 0.84 (s, 9H), 0.04 (s, 3H), 0.02
(s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 174.4, 68.2, 51.7, 25.6,
21.2, 18.2, -5.1, -5.4.
0.056 mmol) and Et3N (9 µL, 0.06 mmol) at room temperature.
After 16 h, the precipitate was filtered off, and the filtrate was
evaporated in vacuo to leave a solid, which was taken up in
benzene (1.4 mL). A solution of alcohol 21 (12 mg, 0.062 mmol)
and DMAP (15 mg, 0.12 mmol) in benzene (0.6 mL) was added
to the above solution, and stirring was continued for 2 h at
room temperature. The reaction mixture was diluted with Et2O
and washed successively with saturated aqueous NaHCO3 and
brine, dried over MgSO4, and concentrated to leave an oil,
which was flash chromatographed on silica gel (AcOEt:hexane
1:24) to give ester 22 (27.6 mg, 71%) as a colorless viscous oil.
[R]546 -16.1 (c 0.93, CHCl3); IR 1738, 1612 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.28-7.22 (m, 2H), 6.90-6.85 (m, 2H), 6.49
(dd, J ) 14.5, 7.2 Hz, 1H), 6.23 (d, J ) 14.6 Hz, 1H), 5.16-
5.04 (m, 1H), 4.47 (δAB, ∆ ) 17.2 Hz, J ) 11.7 Hz, 2H), 3.88
(t, J ) 6.0 Hz, 1H), 3.80 (s, 3H), 3.61 (q, J ) 5.1 Hz, 1H), 3.48
(dd, J ) 10.3, 5.8 Hz, 1H), 3.41 (dd, J ) 10.4, 4.6 Hz, 1H),
2.40-2.35 (m,2H), 1.88-1.78 (m, 2H), 1.22 (d, J ) 6.6 Hz, 3H),
0.88 (s, 18H), 0.05 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 173.1, 159.2, 146.8, 130.1, 129.2, 113.8,
78.5, 78.1, 74.3, 72.8, 72.1, 69.3, 55.2, 29.7, 28.3, 25.9, 25.8,
18.2, 18.1, 16.8, -4.1, -4.3, -4.6, -4.9; LRMS (EI) m/z
(relative intensity) 635 (0.3%, [M - C4H9]+), 121 (100%).
HRMS calcd for C26H44O6Si2I [M - C4H9]+: 635.1721. Found:
635.1721.
(1R,4S,5R,6E)-2-H yd r oxy)-1-m et h ylet h yl 7-Iod o-4,5-
bis(ter t-bu tyld im eth ylsilyloxy)-6-h ep ten oa te (23). Using
the conditions described for the conversion of 6b to 7a , ester
23 was obtained from PMB ether 22 in 84% as a colorless
viscous oil. [R]546 -30.8 (c 1.3, CHCl3); IR 3460, 1732, 1608
cm-1; 1H NMR (300 MHz, CDCl3) δ 6.49 (dd, J ) 14.4, 6.9 Hz,
1H), 6.24 (d, J ) 14.4 Hz, 1H), 4.99 (quintd, J ) 6.6, 3.6 Hz,
1H), 3.89 (dd, J ) 6.9, 5.5 Hz, 1H), 3.70-3.66 (m, 3H), 2.44-
2.35 (m, 2H), 1.83 (td, J ) 7.9, 5.2 Hz, 2H), 1.90-1.80 (br,
1H), 1.23 (d, J ) 6.5 Hz, 3H), 0.88 (s, 18H), 0.06 (s, 6H), 0.05
(s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.1, 146.8,
78.4, 78.2, 74.1, 72.0, 66.1, 29.6, 28.3, 25.9, 25.8, 18.2, 18.1,
16.2, -4.1, -4.3, -4.6, -4.9; LRMS (EI) m/z (relative intensity)
515 (23%, [M - C4H9]+), 73 (100%). HRMS calcd for C18H36O5-
Si2I [M - C4H9]+: 515.1146. Found: 515.1146.
(2R)-2-(ter t-Bu tyld im eth ylsilyloxy)p r op a n -1-ol (19). A
toluene solution (4.8 mL) of ester 18 (1.04 g, 4.8 mmol) was
cooled to -78 °C, treated with DIBAL (11.9 mL, 1.0 M in
hexane, 11.9 mmol), stirred at -78 °C for 40 min, and then
allowed to reach room temperature. After 2 h the reaction was
quenched by the addition of AcOEt. Then, a saturated solution
of sodium potassium tartrate was added, and the mixture was
stirred overnight. The layers were separated, and the aqueous
layer was extracted with Et2O. The combined organic layers
were washed with brine, dried over MgSO4, and concentrated
to afford the alcohol 19 (457 mg, 50%) as a colorless oil. [R]D
-23.1 (c 1.18, CHCl3); IR 3394 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 3.90 (quintd, J ) 6.3, 3.7 Hz, 1H), 3.49 (ddd, J )
11.0, 7.4, 3.7 Hz, 1H), 3.35 (ddd, J ) 10.9, 6.4, 5.0 Hz, 1H),
2.01 (dd, J ) 7.4, 5.2 Hz, 1H); 1.10 (d, J ) 6.2 Hz, 3H), 0.89
(s, 9H), 0.07 (s, 6H); 13C NMR (62.5 MHz, CDCl3) δ 69.0, 68.1,
25.8, 19.8, 18.0, -4.4, -4.8. LRMS (EI) m/z (relative intensity)
133 (7%, [M - C4H9]+), 75 (100%). HRMS calcd for C5H13O2Si
[M - C4H9]+: 133.0685. Found: 133.0684.
(5S,6R,9R/S,10R)-9-Hyd r oxy-5,6-bis(ter t-bu tyld im eth -
ylsilyloxy)-10-m eth yl-3,4,5,6,9,10-h exa h yd r o-2H-2-oxeci-
n on e (24a a n d 24b). To a suspension of Dess-Martin
periodinane (201 mg, 0.474 mmol) in CH2Cl2 (5.2 mL) was
added a solution of alcohol 23 (136 mg, 0.237 mmol) in CH2-
Cl2 (1.4 mL). To this suspension was added water (8.5 µL, 0.47
mmol). The reaction mixture was stirred for 25 min, and it
was diluted with AcOEt. After the addition of saturated
NaHCO3 solution, the organic layer was separated and the
aqueous layer was extracted twice with AcOEt. The combined
organic layers were washed successively with aqueous 1 M
NaHSO3 and brine and dried over MgSO4. Concentration
produced crude aldehyde 2 (135 mg, quantitative) which was
used in the next step without further purification.
(2R)-2-(ter t-Bu tyld im eth ylsilyloxy)-1-(4-m etoxyben zyl-
oxy)p r op a n e (20). Using the conditions described for the
conversion of 4 to 5, PMB ether 20 was obtained from alcohol
19 in 69% as a colorless oil. [R]546 +5.0 (c 2.0, CHCl3); IR 1614
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.28-7.24 (m, 2H), 6.90-
6.85 (m, 2H), 4.47 (s, 2H), 3.97 (sex., J ) 6.0 Hz, 1H), 3.80 (s,
3H), 3.38 (dd, J ) 9.5, 5.9 Hz, 1H), 3.28 (dd, J ) 9.5, 5.5 Hz,
1H), 1.16 (d, J ) 6.2 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 159.0, 130.6, 129.1, 113.6, 75.9, 72.9,
67.7, 55.2, 25.8, 20.9, 18.2, -4.7, -4.8.
(2R)-1-(4-Metoxyben zyloxy)pr opan -2-ol (21). To a stirred
solution of 20 (717 mg, 2.31 mmol) in THF (6 mL) was added
TBAF (906 mg, 3.47 mmol). After 5 h the mixture was diluted
with Et2O and successively washed with saturated NH4Cl and
brine, dried over MgSO4, and concentrated. Silica gel chro-
matography (AcOEt:hexane 1:3) afforded alcohol 21 (412 mg,
91%) as a colorless liquid. [R]546 -12.8 (c 1.28, CHCl3); IR 3440
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.27-7.25 (m, 2H), 6.90-
6.86 (m, 2H), 4.48 (s, 2H), 3.97 (dqd, J ) 8.2, 6.4, 3.0 Hz, 1H),
3.80 (s, 3H), 3.43 (dd, J ) 9.4, 3.1 Hz, 1H), 3.25 (dd, J ) 9.2,
8.4 Hz, 1H), 2.25 (br, 1H), 1.13 (d, J ) 6.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 159.2, 130.0, 129.3, 113.8, 75.5, 72.9, 66.4,
55.2, 18.6; LRMS (EI) m/z (relative intensity) 196 (10%, M+),
To a suspension of CrCl2 (347 mg, 2.82 mmol) containing
0.5 mol % of NiCl2 in degassed DMF (40 mL) was added via
cannula, under cooling with an ice bath, a solution of the
aldehyde above (135 mg, azeotroped with 2 × 0.5 mL of
benzene in vacuum) in degassed DMF (7.5 mL). The reaction
mixture was stirred overnight at room temperature, and the
solvent was distilled off under vacuum (0.1 mmHg). The
residue was taken up in saturated NH4Cl and extracted with
Et2O and AcOEt. The combined organic layers were washed
with brine and dried over MgSO4. The crude product was
purified by flash chromatography (AcOEt:hexane 1:19) to yield
a 1.5:1 mixture of 24a and 24b (51.9 mg, 49% for two steps).
Apolar isomer 24a (white solid): Rf 0.40 (AcOEt:hexane 1:4);
mp: 137-140 °C; [R]546 -31.6 (c 0.95, CHCl3); IR 3504, 1720
121 (100%). HRMS calcd for
Found: 196.1100.
C
11H16O3 (M+): 196.1099.
(1R,4S,5R,6E)-2-(4-Meth oxyben zyloxy)-1-m eth yleth yl
7-Iod o-4,5-b is(t er t -b u t yld im e t h ylsilyloxy)-6-h e p t e n -
oa te (22). 2,4,6-Trichlorobenzoyl chloride (10 µL, 0.06 mmol)
was added to a stirred THF (1 mL) solution of acid 16 (29 mg,
1
cm-1; H NMR (500 MHz, CDCl3) δ 5.64 (ddd, J ) 15.4, 8.8,
2.2 Hz, 1H), 5.48 (dd, J ) 15.4, 1.7 Hz, 1H), 4.83 (dq, J ) 8.5,
4.9 Hz, 1H), 4.36 (s, 1H), 3.83 (td, J ) 8.5, 4.9 Hz, 1H), 3.54
(d, J ) 10.0 Hz, 1H), 2.60 (dtd, J ) 14.9, 10.3, 0.9 Hz, 1H),
2.41 (ddd, J ) 14.6, 10.5, 1.0 Hz, 1H), 1.97 (dd, J ) 14.4, 11.2
Hz, 1H), 1.71 (d, J ) 5.1 Hz, 1H), 1.46-1.40 (m, 1H), 1.38 (d,
J ) 6.4 Hz, 3H), 0.95 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.06 (s,
(26) Stammen, B.; Berlage, U.; Kindermann, R.; Kaiser, M.; Gu¨nther,
M.; Sheldrick, W. S.; Welzel, P.; Roth, W. R. J . Org. Chem. 1992, 57,
6566.

5916 J . Org. Chem., Vol. 65, No. 19, 2000
Pilli et al.
6H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 174.5, 132.8,
130.4, 79.4, 78.2, 74.4, 72.9, 33.7, 28.0, 26.1, 25.9, 18.4, 18.3,
17.0, -4.4, -4.6-4.8, -4.9; LRMS (EI) m/z (relative intensity)
387 (0.5%, [M - C4H9]+), 73 (100%). HRMS calcd for C18H35O5-
Si2 [M - C4H9]+: 387.2023. Found: 387.2022. Polar isomer
24b (viscous oil): Rf 0.35 (AcOEt:hexane 1:4); [R]546 -21.1 (c
8.5 Hz, 1H), 4.38 (s, 1H), 3.56 (d, J ) 10.0 Hz, 1H), 2.60 (dt,
J ) 14.8, 10.6 Hz, 1H), 2.43 (dd, J ) 14.7, 9.8 Hz, 1H), 2.00
(dd, J ) 14.7, 11.2 Hz, 1H), 1.90 (dd, J ) 6.8, 1.7 Hz, 3H),
1.43 (dd, J ) 14.5, 10.4 Hz, 1H), 1.29 (d, J ) 6.1 Hz, 3H), 0.93
(s, 9H), 0.89 (s, 9H), 0.08 (s, 3H), 0.06 (s, 6H), 0.00 (s, 3H); 13
C
NMR (125 MHz, CDCl3) δ 174.4, 165.6, 145.4, 133.8, 127.1,
122.3, 79.1, 78.1, 74.3, 70.4, 33.6, 28.0, 26.0, 25.9, 18.4, 18.3,
18.0, 16.9, -4.5, -4.6-4.9, -5.0; LRMS (EI) m/z (relative
intensity) 455 (6%, [M - C4H9]+), 69 (100%). HRMS calcd for
1
0.71, CHCl3); IR 3467, 1738, 1722, 1712 cm-1; H NMR (500
MHz, CDCl3) δ 5.80-5.69 (m, 2H), 5.21-5.10 (m, 1H), 4.41 (s,
1H), 4.30 (s, 1H), 3.61 (d, J ) 10.0 Hz, 1H), 2.58 (dt, J ) 14.7,
10.8 Hz, 1H), 2.41 (dd, J ) 14.7, 10.0 Hz, 1H), 2.04 (dd, J )
14.6, 10.4 Hz, 1H), 1.68 (br, 1H), 1.46-1.40 (m, 1H), 1.38 (d,
J ) 6.3 Hz, 3H), 0.94 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s,
6H), 0.01 (s, 3H); LRMS (EI) m/z (relative intensity) 387 (0.5%,
[M - C4H9]+), 73 (100%). HRMS calcd for C18H35O5Si2 [M -
C4H9]+: 387.2023. Found: 387.2023.
(5S,6R,9R,10R)-9-Hyd r oxy-5,6-bis(ter t-bu tyld im eth yl-
silyloxy)-10-m eth yl-3,4,5,6,9,10-h exa h yd r o-2H-2-oxecin o-
n e (24a ). To a solution of 24b (11.2 mg, 0.0252 mmol), PPh3
(33 mg, 0.13 mmol), and p-nitrobenzoic acid (18.4 mg, 0.110
mmol) in benzene (0.5 mL) was added at 0 °C diethyl
azodicarboxylate (20 µL, 0.13 mmol). The ice-bath was re-
moved, and the mixture was stirred overnight at room tem-
perature. The solvent was removed in vacuo, the crude
p-nitrobenzoate derivative was dissolved in MeOH (0.2 mL)
and water (30 µL), and K2CO3 (21 mg, 0.15 mmol) was added.
The mixture was stirred for 2 h at room temperature, the
solvent was removed, and the crude mixture diluted with Et2O
and water. The layers were separated, and the aqueous phase
was extracted twice with Et2O. The combined organic phases
were washed with brine, dried over MgSO4, and concentrated
under reduced pressure. Silica gel chromatography (AcOEt:
hexane 1:19) of the crude product afforded 24a (6.2 mg, 56%)
as a white solid.
(5S,6R,9S,10R)-5,6-Bis(ter t-bu tyld im eth ylsilyloxy)-10-
m eth yl-2-oxo-3,4,5,6,9,10-h exa h yd r o-2H-9-oxecin yl (E)-2-
Bu ten oa te (25). To a solution of crotonic acid (5.8 mg, 0.068
mmol) in CH2Cl2 (1 mL) were added DMAP (1.4 mg, 0.011
mmol) and diisopropylcarbodiimide (13 µL, 11 mg, 0.078
mmol). After 30 min, a solution of alcohol 24a (25.1 mg, 0.0564
mmol) in CH2Cl2 (1.5 mL) was added via cannula. Within 30
min a precipitate was formed, and stirring was continued for
20 h. An additional solution of crotonic acid (5.8 mg, 0.068
mmol), DMAP (1.4 mg, 0.011 mmol), and DIC (13 µL, 11 mg,
0.078 mmol) in CH2Cl2 (1 mL) was stirred for 1 h and added
to the reaction mixture via cannula. After 36 h the solvent
was removed, and the crude product was purified by flash
chromatography (AcOEt:hexane 1:99) to give TBS-protected
Aspinolide 25 (25.4 mg, 89%) as a colorless oil. [R]546 -33.3 (c
0.45, CHCl3); IR 1745, 1728 cm-1; 1H NMR (500 MHz, CDCl3)
δ 6.99 (dq, J ) 15.5, 6.8 Hz, 1H), 5.85 (dd, J ) 15.6, 1.7 Hz,
1H), 5.61 (dd, J ) 15.4, 2.0 Hz, 1H), 5.54 (ddd, J ) 15.4, 8.4,
2.1 Hz, 1H), 5.05 (dq, J ) 9.1, 6.2 Hz, 1H), 4.95 (dd, J ) 9.0,
C
22H39O6Si2 [M - C4H9]+: 455.2285. Found: 455.2284.
Asp in olid e B (1). To a solution of 25 (14 mg, 0.027 mmol)
in THF (0.40 mL) in a Nalgene tube was added freshly
prepared buffered pyridinium hydrofluoride (stock solution
prepared from 342 mg of Aldrich pyridinium hydrofluoride in
0.77 mL of pyridine). After 40 h at room temperature, the
reaction mixture was diluted with Et2O and neutralized by
dropwise addition of saturated NaHCO3. The layers were
separated, the aqueous layer was extracted successively with
Et2O and AcOEt, and the combined organic layers were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Silica gel chromatography (AcOEt:hexane
1:1) afforded Aspinolide B 1 (3.5 mg, 46%) as a white solid.
Mp: 102-3 °C; [R]D -44.0 (c 1.0, MeOH); lit.:1,25 mp ) 106
°C; [R]D -44.0 (c 1.0, MeOH). 1H NMR (500 MHz, CDCl3) δ
7.01 (dq, J ) 15.5, 6.9 Hz, 1H), 5.86 (dd, J ) 15.6, 1.7 Hz,
1H), 5.67 (dd, J ) 16.0, 1.9 Hz, 1H), 5.58 (ddd, J ) 15.9, 8.3,
2.4 Hz, 1H), 5.10 (dq, J ) 9.3, 6.4 Hz, 1H), 4.97 (dd, J ) 9.0,
8.6 Hz, 1H), 4.55-4.50 (m, 1H), 3.68-3.62 (m, 1H), 2.47 (ddd,
J ) 15.6, 9.8, 1.0 Hz, 1H), 2.34-2.25 (m, 1H), 2.16 (d, J ) 7.6
Hz, 1H), 2.09 (dd, J ) 14.9, 11.7 Hz, 1H), 1.96 (d, J ) 7.6 Hz,
1H), 1.90 (dd, J ) 6.9, 1.6 Hz, 3H), 1.81-1.74 (m, 1H), 1.33
(d, J ) 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.5, 165.5,
145.9, 131.2, 127.8, 122.1, 78.6, 75.2, 72.9, 72.0, 32.5, 27.3, 18.0,
16.7.
Ack n ow led gm en t. The authors are in debt to
Volkswagen Stiftung, Germany and FAPESP, Brazil, for
financial support, to Professor A. Zeeck (Go¨ttingen,
Germany) for providing an authentic sample of (-)-
aspinolide B, and to Professor Timothy J . Brocksom
(UFSCar, Brazil) for optical rotation measurements
with Perkin-Elmer 241 polarimeter. R.A.P. and M.M.V.
are grateful to CNPq, Brazil, and M.M.V. to Alfa
Program, European Commission for fellowships.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds 8a , 15, 22, 23, 24a , 25, and 1
and 1H NMR spectra for compound 24b. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O000327I