Total synthesis and proof of relative stereochemistry of (-)-aureonitol

Article abstract of DOI:10.1021/jo801338t

(Chemical Equation Presented) Two trisubstituted epimeric tetrahydrofurans, 1 and 2, have been synthesized in order to confirm the relative stereochemistry in the natural product aureonitol. The key step in the synthesis of 1 and 2 involved a stereoselective intramolecular allylation of an allylsilane with an aldehyde, which introduced the stereotriad in the five-membered ring. The major tetrahydrofuran diastereoisomer 18 from this cyclization reaction was subsequently elaborated to tetrahydrofuran 1. Its 3-epimer (2) was then prepared from 1 via an oxidation-reduction sequence. Compound 1 exhibits identical ¹H NMR data to those reported for aureonitol, which was isolated from Helichrysum aureonitons by Bohlmann in 1979, whereas the ¹H NMR data for 2 are markedly different. The ¹H NMR data (in CDCl₃, CD₃OD, and C₆D₆) and ¹³C NMR data (in CDCl₃) for 1 are also identical with those reported for a natural product isolated from various Chaetomium sp. by Abraham, Seto, and Teuscher. These findings support Abraham's conclusion that the structure of aureonitol should be revised from 2 to 1. The enantioselective synthesis of 1 has also confirmed that (-)-aureonitol isolated by Abraham contains the (2S,3R,4S) absolute configuration of stereocenters on the tetrahydrofuran ring.

Full text of DOI:10.1021/jo801338t

Total Synthesis and Proof of Relative Stereochemistry of
(-)-Aureonitol
Peter J. Jervis and Liam R. Cox*
School of Chemistry, The UniVersity of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
l.r.cox@bham.ac.uk
ReceiVed June 20, 2008
Two trisubstituted epimeric tetrahydrofurans, 1 and 2, have been synthesized in order to confirm the
relative stereochemistry in the natural product aureonitol. The key step in the synthesis of 1 and 2 involved
a stereoselective intramolecular allylation of an allylsilane with an aldehyde, which introduced the
stereotriad in the five-membered ring. The major tetrahydrofuran diastereoisomer 18 from this cyclization
reaction was subsequently elaborated to tetrahydrofuran 1. Its 3-epimer (2) was then prepared from 1 via
1
an oxidation-reduction sequence. Compound 1 exhibits identical H NMR data to those reported for
1
aureonitol, which was isolated from Helichrysum aureonitons by Bohlmann in 1979, whereas the H
NMR data for 2 are markedly different. The 1H NMR data (in CDCl3, CD3OD, and C6D6) and 13C NMR
data (in CDCl3) for 1 are also identical with those reported for a natural product isolated from various
Chaetomium sp. by Abraham, Seto, and Teuscher. These findings support Abraham’s conclusion that the
structure of aureonitol should be revised from 2 to 1. The enantioselective synthesis of 1 has also confirmed
that (-)-aureonitol isolated by Abraham contains the (2S,3R,4S) absolute configuration of stereocenters
on the tetrahydrofuran ring.
Introduction
In 1979, Bohlmann isolated a tetrahydrofuran metabolite from
the plant Helichrysum aureonitens.1,2 He named the compound
aureonitol, and used a combination of 1H NMR, IR, mass, and
UV data to elucidate its basic structure. Although he did not
comment on the absolute stereochemistry, from analysis of the
1H NMR coupling constants, he proposed an all-syn arrangement
of the substituents on the tetrahydrofuran ring (Figure 1). This
compound was structurally similar to one isolated by Burrows
in 1967 from the fungus Chaetomium coarctatum.3,4 At the same
time as Burrows, who reported just the basic structure of the
metabolite, Mason and Vane also published on the same
sample.5 They compared the CD spectrum of their compound
with those of the corresponding cyclopentane derivatives and
* Corresponding author. Phone: +44 (0)121 414 3524. Fax: +44 (0)121 414
4403.
FIGURE 1. Proposed structures of aureonitol.
(1) Bohlmann, F.; Ziesche, J. Phytochemistry 1979, 18, 664–665.
(2) Helichrysum aureonitens is a hairy perennial herb that grows in the
Kwazulu-Natal province of South Africa. It belongs to a large genus of about
500 species. According to folklore, it has been used for centuries by the people
of this province against infection. In 1995, Meyer (Meyer, J. J. M.; Afolayan,
A. J. J. Ethnopharmacol. 1995, 47, 109–111.) found that the dichloromethane
extract of H. aureonitens was active against a wide range of gram-positive
bacteria, yet inactive against all gram-negative bacteria tested (including
Escherichia coli).
concluded that there was an anti relationship between the two
dienyl arms (Figure 1). Seto and co-workers later investigated
the biosynthesis of this compound (isolated again from C.
coarctatum) using labeling studies and showed it to be a
polyketide metabolite. While the group again confirmed the
basic structure, they too did not comment on the relative
7616 J. Org. Chem. 2008, 73, 7616–7624
10.1021/jo801338t CCC: $40.75 2008 American Chemical Society
Published on Web 09/06/2008

Total Synthesis and of (-)-Aureonitol
FIGURE 2. Targets for total synthesis.
SCHEME 1. Stereoselective Synthesis of 2,3,4-Trisubstituted
Tetrahydrofurans
stereochemistry in the tetrahydrofuran core.6 Since Bohlmann
did not refer to these reports in his paper, it was unknown at
that time whether or not Bohlmann had isolated the same
diastereoisomeric product from his plant source as Burrows,
Mason and Vane, and Seto had from their fungal source.
In 1992, Abraham reported the isolation of a tetrahydrofuran
derivative from the fungus C. cochlioides.7 Since the 1H NMR
data were identical with those reported by Bohlmann for
aureonitol, Abraham concluded that he had isolated the same
molecule. Abraham used a Mosher ester analysis to elucidate
the absolute stereochemistry at the 3-position of the tetrahy-
drofuran ring. From NOE experiments he also showed that the
molecule contained the “down-up-down” relative stereochem-
istry. He reasoned that as the data for this compound were
identical with those of Bohlmann’s aureonitol, the structure of
aureonitol should be revised (Figure 1). Abraham also fermented
C. coarctatum to isolate the tetrahydrofuran reported earlier by
SCHEME 2. Retrosynthesis of (-)-Aureonitol
Burrows,3 Mason and Vane,5 and Seto.6 The 1H NMR and 13
C
NMR spectra of the tetrahydrofuran isolated from C. coarctatum
were identical with those for the “aureonitol” obtained from C.
cochlioides, suggesting that the structure proposed by Mason
and Vane in 1967 should also be revised, and that Burrows had
indeed isolated aureonitol. In 2005, Teuscher isolated the same
molecule as Abraham from C. globosum.8
Despite Abraham’s findings and report,7 aureonitol is still
described on the Chemical Database as having the all-syn
relative stereochemistry suggested originally by Bohlmann.1
Independent total syntheses of (2S,3R,4S)-2-(buta-1′,3′-dienyl)-
3-hydroxy-4-(penta-1′′,3′′-dienyl)tetrahydrofuran,1,and(2S,3S,4S)-
2-(buta-1′,3′-dienyl)-3-hydroxy-4-(penta-1′′,3′′-dienyl)tetrahy-
drofuran, 2, (Figure 2) would, once and for all, prove the relative
stereochemistry of this interesting natural product.
As part of a research program investigating the use of silyl
nucleophiles in cyclization strategies,9 we have used an
intramolecular allylation of an allylsilane with an aldehyde
to synthesize a number of oxygen-containing heterocycles.
We recently reported that the intramolecular allylation of
aldehyde 3 generates two (out of a possible four) 2,3,4-
trisubstituted tetrahydrofuran products 4 and 5 (Scheme 1).9c
Significantly, the major diastereoisomer 4 contains the same
relative stereochemistry as that proposed by Abraham for
aureonitol.7 We therefore identified this tetrahydrofuran as
a possible precursor to the structure of aureonitol as proposed
by Abraham. Furthermore, having also shown previously that
the major diastereoisomer 4 from our intramolecular allylation
can be converted to its 3-epimer 6 via an oxidation-reduction
sequence,9c we argued that a similar approach could be em-
ployed to obtain the all-syn diastereoisomer 2 (the structure
proposed by Bohlmann1) from 1.
(3) Burrows, B. F. J. Chem. Soc., Chem. Commun. 1967, 597.
(4) Chaetomium spp. are filamentous fungi found in soil, air, and plant debris.
As well as being a contaminant, Chaetomium spp. are also causative agents of
infections in humans. The Chaetomium genus contains over 100 species, with
the most common being C. atrobrunneum, C. funicola, C. globosum, and C.
strumarium.
(5) Mason, S. F.; Vane, G. W. J. Chem. Soc., Chem. Commun. 1967, 598.
(6) (a) Seto, H.; Saito, M.; Uzawa, J.; Yonehara, H. Heterocycles 1979, 13,
247–253. (b) Saito, M.; Seto, H.; Yonehara, H. Agric. Biol. Chem. 1983, 47,
2935–2937.
(7) Abraham, W. R.; Arfmann, H. A. Phytochemistry 1992, 31, 2405–2408.
(8) Teuscher, F. Ph.D. thesis, Heinrich-Heine-Universita¨t, Germany, 2005.
(9) (a) Beignet, J.; Jervis, P. J.; Cox, L. R. J. Org. Chem. 2008, 73, 5462–
5475. (b) Ramalho, R.; Jervis, P. J.; Kariuki, B. M.; Humphries, A. C.; Cox,
L. R. J. Org. Chem. 2008, 73, 1631–1634. (c) Jervis, P. J.; Kariuki, B. M.; Cox,
L. R. Tetrahedron Lett. 2008, 49, 2514–2518. (d) Jervis, P. J.; Cox, L. R. Beilstein
J. Org. Chem. 2007, 3, 6. (e) Jervis, P. J.; Kariuki, B. M.; Cox, L. R. Org. Lett.
2006, 8, 4649–4652. (f) Ramalho, R.; Beignet, J.; Humphries, A. C.; Cox, L. R.
Synthesis 2005, 3389–3397. (g) Simpkins, S. M. E.; Kariuki, B. M.; Arico´, C. S.;
Cox, L. R. Org. Lett. 2003, 5, 3971–3974. (h) Beignet, J.; Cox, L. R. Org. Lett.
2003, 5, 4231–4234.
Results and Discussion
The retrosynthesis of our first tetrahydrofuran target 1 is
shown in Scheme 2. This compound should also provide a route
to its 3-epimer 2 via an oxidation-reduction sequence. Although
we did not expect particularly serious stability problems, the
C-2 dienyl unit in tetrahydrofuran 1 was deemed to be the most
labile portion of the molecule10 and therefore was disconnected
first to provide aldehyde 7; various olefination strategies exist
for elaborating an aldehyde into a diene. From aldehyde 7, a
change of oxidation state and protection of the resulting alcohol
(10) Activation of the ring oxygen could potentially result in the opening of
the tetrahydrofuran ring at C-2 to generate a stabilized pentadienyl cation.
J. Org. Chem. Vol. 73, No. 19, 2008 7617

Jervis and Cox
SCHEME 3. Diastereo- and Enantioselective Synthesis of
Tetrahydrofuran 9 from (S)-Serine
excellent selectivity, using Raney-nickel (Ra-Ni) under a
hydrogen atmosphere, to provide alkene 16 (along with traces
of the corresponding over-reduction product). Diisobutylalu-
minum hydride (DIBALH) reduction of the ester in 16
proceeded uneventfully to provide the desired cyclization
precursor 11 in excellent yield. Compound 11 reacted with
MeSO3H under our optimized conditions9c to provide an 8:1
mixture of diastereoisomers 18 and 17 in high yield.13 The
relative stereochemistry in cyclization product 18 was assigned
by analogy with other similarly substituted tetrahydrofurans
prepared previously by us using this methodology.9c The
multiplicity and chemical shifts of the proton resonances
attached directly to the ring are particularly characteristic of a
tetrahydrofuran containing a “down-up-down” relationship of
substituents around the ring.9c While separation of the two
diastereoisomers at this stage proved impossible, TBDPS
protection of the remaining secondary alcohol afforded the
corresponding silyl ethers, which were now separable by HPLC.
Having successfully assembled the trisubstituted tetrahydro-
furan, all that remained was to install the two dienyl side chains.
This proved to be more challenging than we had expected. In
a first approach to introducing the right-hand pentadienyl side
chain, we sought to employ the vinyl substituent in 9 in a cross-
metathesis reaction. To this end, commercially available (E)-
1,3-pentadiene 19 was identified as a potential cross-metathesis
partner, as this would potentially deliver the required diene 8
in a single step. There is precedent for this type of diene cross-
metathesis,14 although previous examples all involve a mono-
substituted olefin partner that is considerably less sterically
hindered than that in tetrahydrofuran 9. In these cases, the
reaction of a sterically unhindered monosubstituted olefin partner
(a type I olefin in Grubbs’ classification15) with a relatively
unreactive diene partner (a type III olefin in Grubbs’ classifica-
tion15) gives rise to the cross-metathesis product efficiently. This
would not necessarily be the case with the two reacting olefins
which we wanted to employ since both are relatively unreactive
cross-metathesis partners (two type III olefins according to
Grubbs’ classification), and as such, we expected this to be a
more difficult metathesis reaction. Unfortunately these predic-
tions were borne out: heating a solution of tetrahydrofuran 9 in
toluene at reflux for 48 h with 4 equiv of diene 19 in the
presence of 10 mol % Grubbs II catalyst in a sealed tube16 led
to no consumption of the starting material, although a number
of volatile nonpolar homodimers from the starting diene were
tentatively identified (Scheme 4). The use of catalysts 20 and
21 led to no improvement.17
affords tetrahydrofuran 8. We envisaged that the right-hand
dienyl arm could be installed either by a cross-metathesis of
vinyl tetrahydrofuran 9 or by an olefination procedure from
aldehyde 10, which could be accessed from vinyl tetrahydro-
furan 9 by oxidative cleavage of the double bond. Tetrahydro-
furan 9 would be accessed from aldehyde 11, which in turn
could be prepared from (S)-ethyl glycerate 12. In this way, we
would also have an enantioselective synthesis of aureonitol,
which would allow us to confirm the absolute stereochemistry
of the natural product isolated by Abraham.7
(S)-Ethyl glycerate 12 was prepared in a two-step procedure,11
involving a stereospecific substitution of the amine group in
(S)-serine with a hydroxyl group to afford (S)-glyceric acid,
followed by Fischer esterification of the carboxylic acid with
p-toluenesulfonic acid (pTSA) as the catalyst (Scheme 3).12
Selective protection of the less hindered primary hydroxyl group
with tert-butyldiphenylsilyl chloride (TBDPSCl) afforded silyl
ether 13 in good yield, which was primed for attaching the
allylsilane nucleophile. A nonbasic etherification procedure was
used to avoid potential epimerization of the stereogenic center.
Thus trichloroacetimidate 14 was prepared as described
previously,9e and then reacted with R-hydroxy ester 13 in the
presence of TMSOTf to provide ether 15. Partial hydrogenation
of the triple bond in the resulting alkyne was achieved with
To circumvent this problem, we next employed a masked
diene metathesis partner, which we expected would be more
reactive toward cross-metathesis and bring us back to a system
where a reactive alkene is reacting with a less-reactive alkene,
and therefore a much better substrate set for obtaining a high-
yielding cross-metathesis product. To this end, we envisaged
cross-metathesis of alkenes 22-24 with vinyl tetrahydrofuran
(13) Confirmation that no loss of stereochemical integrity had occurred along
the synthetic sequence was confirmed by chiral HPLC analysis of 18 and
comparison with a racemic sample (see the Supporting Information).
(14) (a) Dewi, P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005, 46, 577–
580. (b) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187–190.
(c) Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5–8.
(15) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
(11) (a) Goubert, M.; Toupet, L.; Sinibaldi, M. E.; Canet, I. Tetrahedron
2007, 63, 8255–8266. (b) Yokokawa, F.; Inaizumi, A.; Shioiri, T. Tetrahedron
Lett. 2001, 42, 5903–5908.
(16) A sealed tube was employed owing to the volatility of diene 19 (bp
42 °C).
(17) Metathesis catalyst 20 and 21 were provided by Dr. David Lindsay,
University of Reading, UK.
(12) Fischer, E.; Speier, A. Chem. Ber. 1895, 28, 3252–3258.
7618 J. Org. Chem. Vol. 73, No. 19, 2008

Total Synthesis and of (-)-Aureonitol
SCHEME 4. Attempted Cross-Metathesis Route to Diene 8
SCHEME 6. Installation of the Right-Hand Pentadienyl
Unit
SCHEME 5. Attempted Cross-Metathesis Routes to Diene 8
Using a Masked Diene Metathesis Partner
reaction was observed and the starting material was recovered
intact, or the starting material decomposed under the reaction
conditions. This was also the case with acetate 26 and tosylate
28 (prepared from alcohol 27). Attempted dehydration of alcohol
27 by using the Burgess reagent19 also led to decomposition of
the starting material.
At this juncture, we reluctantly abandoned our cross-
metathesis approach and switched our attention to olefination
strategies involving aldehyde 10, which was readily prepared
from 9 in a two-step dihydroxylation-periodate cleavage
operation (Scheme 6).20 Attempts to carry out this reaction
sequence in a one-pot operation following a procedure reported
by Jin et al.21 resulted in a much lower yield of the desired
aldehyde (15%). Horner-Wadsworth-Emmons olefination of
aldehyde 10 with (E)-diethyl crotylphosphonate gave only trace
amounts of any diene product, and instead led to preferential
elimination of the ꢀ-siloxy group in the starting aldehyde to
provide an enal product (see the Supporting Information).22 The
corresponding Wittig reaction was more successful;23 however,
the desired (E,E)-diene product was formed as the minor
stereoisomer (2:1 ratio of (Z,E)-8 to (E,E)-8). In light of these
disappointing results, we turned our attention to the Julia-
Kocienski olefination, which often proceeds with high levels
of (E)-stereoselectivity,24 although the stereochemical outcome
9 would provide an alkene product and the required diene 8
after elimination (Scheme 5). Heating a solution of tetrahydro-
furan 9 and 4 equiv of alkene 22 in the presence of Grubbs’ II
catalyst provided alkene 25 in high yield and with complete
(E)-stereoselectivity, along with a large amount of alkene 29
arising from the background homodimerization process (Scheme
5). Homodimer 29 was not a substrate for secondary metathesis;
thus an excess of alkene 22 was crucial to ensure a high
conversion of tetrahydrofuran 9 to product. The reaction where
the 4-nitrobenzoyl (PNBz) group in 22 was replaced by an acetyl
group (23), or where the free homoallylic alcohol (24) was
employed, provided much poorer yields of the corresponding
cross-metathesis products 26 and 27, respectively. Frustratingly,
all attempts to eliminate ester 25 to diene 8 by using various
bases (DBU, KOtBu, LDA)18 were unsuccessful: either no
(19) (a) Hoffmann, R. W.; Scha¨fer, F.; Haeberlin, E.; Rohde, T.; Ko¨rber, K.
Synthesis 2000, 2060–2068. (b) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A.
J. Org. Chem. 1973, 38, 26–31. (c) Burgess, E. M.; Penton, H. R., Jr.; Taylor,
E. A. J. Am. Chem. Soc. 1970, 92, 5224–5226. (d) Atkins, G. M.; Burgess, E. M.
J. Am. Chem. Soc. 1968, 90, 4744–4745.
(20) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973–1976. (b) Betancort, J. M.; Mart´ın, T.; Palazo´n, J. M.; Mart´ın, V. S. J.
Org. Chem. 2003, 68, 3216–3224.
(21) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–
3219.
(22) Wang, Y.; West, F. G. Synthesis 2002, 99–103.
(23) (a) Sodeoka, M.; Yamada, H.; Shibasaki, M. J. Am. Chem. Soc. 1990,
112, 4906–4911. (b) Bestmann, H. J.; Su¨ss, J.; Vostrowsky, O. Liebigs Ann.
Chem. 1981, 2117–2138.
(24) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
(b) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26–28. (c) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365–366.
(18) (a) Yamamoto, K.; Ohta, O.; Tsuji, J. Chem. Lett. 1979, 713–716. (b)
Tucker, J. R.; Riley, D. P. J. Organomet. Chem. 1985, 279, 49–62. (c) Crousse,
B.; Alami, M.; Linstrumelle, G. Tetrahedron Lett. 1997, 38, 5297–5300. (d)
Tuckett, M. W.; Watkins, W. J.; Whitby, R. J. Tetrahedron Lett. 1998, 39, 123–
126.
J. Org. Chem. Vol. 73, No. 19, 2008 7619

Jervis and Cox
SCHEME 7. Installation of the Left-Hand Dienyl Unit
SCHEME 8. Completing the Total Synthesis of Aureonitol
we reasoned that (Z)-1 might still be channeled to our target
(-)-aureonitol if isomerization could be carried out after this
final deprotection step. To this end, silyl ether (Z)-35 was
deprotected in the same way as for its (E)-stereoisomer, to form
(Z)-1 in 90% yield. Pleasingly, heating a solution of this material
in chloroform in the presence of 5 mol % of iodine at reflux
for 30 min provided a 6:1 ratio of (E)-1 [(-)-aureonitol] to (Z)-
1,26 which could be separated by flash column chromatography
to afford pure (-)-aureonitol (Scheme 8).
is admittedly less-predictable when the procedure is used to
install a diene.24 However, encouraged by the work of Omura
j
et al.,25 who used a highly (E)-selective Julia-Kocienski
olefination to install the central diene unit of the natural product
nafuredin, aldehyde 10 was reacted with the anion of sulfone
32 (Scheme 6). This reaction again provided the product as a
mixture of geometric isomers, although now the ratio was 2.5:1
in favor of the required diene, (E,E)-8. Heating a solution of
the two diene stereoisomers in chloroform in the presence of 5
mol % of iodine for 30 min isomerized this diene mixture from
2.5:1 to 4:1 in favor of the required (E,E)-8, which at this stage
was inseparable from (Z,E)-8 (Scheme 6).26
Selective deprotection of the primary TBDPS ether in 8 with
HF-pyridine provided alcohol 33,27,28 which was oxidized to
the corresponding aldehyde 7 by using tetra-n-propylammonium
perruthenate (TPAP) (Scheme 7). Aldehyde 7 proved to be labile
and was therefore used immediately, without further purification,
in a second Julia-Kocienski olefination.24 Thus, deprotonation
of sulfone 34 with potassium hexamethyldisilazane (KHMDS),
followed by treatment with aldehyde 7 provided a mixture of
dienes, (E)-35 and (Z)-35, in a good yield and a 2:1 ratio
(Scheme 7). Attempts to improve this ratio by isomerization in
the presence of iodine were unsuccessful and only led to
decomposition. Fortunately, both (E)-35 and (Z)-35 were
separable by flash column chromatography from one another,
and from residual traces of minor stereoisomers that had been
carried through from earlier steps.
The 1H NMR and 13C NMR spectra of (E)-1 were consistent
with the basic structure of the target molecule. Further evidence
came from COSY and HSQC experiments (which allowed a
full assignment of the resonances) as well as electrospray,
1
HRMS, and IR data. We next compared the H NMR data for
our synthesized (E)-1 with those reported by Bohlmann for the
aureonitol isolated from H. aureonitens.1 The chemical shifts
and coupling constants are identical in the solvent CDCl3 (see
the Supporting Information). Since our synthesized (E)-1 is
known to contain the (2S,3R,4S) relative stereochemistry,
independent synthesis supports Abraham’s conclusion that the
structure of aureonitol should be revised (Abraham also had
matching 1H NMR data with Bohlmann).7 Although at this point
we had shown that the 1H NMR data for the (2S,3R,4S)
diastereoisomer matches those reported for Bohlmann’s aure-
onitol, we had still not disproved the (2S,3S,4S) relative
stereochemistry that was originally proposed for the structure
of aureonitol. To this end, (E)-1 was oxidized to ketone 36 in
good yield with Dess-Martin periodinane (Scheme 9). Subse-
quent reduction with the bulky reducing agent, L-selectride,
provided the epimerized tetrahydrofuran 2, with high diaste-
reoselectivity (>10:1).29 Comparing the H NMR data of this
1
synthesized all-syn diastereoisomer with the 1H NMR data for
Bohlmann’s Helichrysum aureonitol in CDCl3 revealed marked
differences, with the resonances for the protons situated on the
tetrahydrofuran ring exhibiting particularly large differences in
chemical shift values (see the Supporting Information).1 It was
clear from this comparison that 2 and Bohlmann’s aureonitol
are not the same compound; thus we have proven by indepen-
dent synthesis that aureonitol does not contain the all-syn relative
stereochemistry as is currently listed in the Chemical Database.
In a final step, (E)-35 was treated with TBAF to provide our
target molecule (E)-1 [(-)-aureonitol] in 91% yield (Scheme
8). Although isomerization of (Z)-35 to (E)-35 was unsuccessful,
(25) Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma,
j
R.; Kuwajima, I.; Omura, S. Org. Lett. 2001, 3, 2289–2291.
(26) (a) Paterson, I.; Steven, A.; Luckhurst, C. A. Org. Biomol. Chem. 2004,
2, 3026–3038. (b) Adger, B. J.; Barrett, C.; Brennan, J.; McGuigan, P.;
McKervey, M. A.; Tarbit, B. J. Chem. Soc., Chem. Commun. 1993, 1220–1222.
(27) (a) Chattopadhyay, S. K.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1
2000, 2429–2454. (b) Crouch, R. D. Tetrahedron 2004, 60, 5833–5871.
(28) The ratio of (E,E)-33:(E,Z)-33 improved from 4:1 to 5:1 after purification
by column chromatography.
(29) Brinza, I. M.; Fallis, A. G. J. Org. Chem. 1996, 61, 3580–3581.
7620 J. Org. Chem. Vol. 73, No. 19, 2008

Total Synthesis and of (-)-Aureonitol
SCHEME 9. Epimerization of (E)-1
Conclusions
(-)-Aureonitol ((E)-1) has been synthesized for the first time
as a single enantiomer in 14 steps from (S)-serine. The key step
involved a Brønsted acid-promoted intramolecular allylation of
aldehyde 11. This reaction provided the required tetrahydrofuran
framework with good diastereoselectivity, with the major
diastereoisomer 18 containing the desired relative stereochem-
istry around the ring. Subsequent elaboration of the tetrahydro-
furan 18 allowed the dienyl arms to be installed with moderate
(E)-stereoselectivity. Julia-Kocienski olefination was found to
offer the best stereoselectivity, and this could be further
increased through heating the diene mixture in chloroform in
the presence of iodine at reflux. Our synthesized (-)-aureonitol
displays identical spectral data with those reported for aureonitol
intheliterature,1,6-8whereas2,preparedviaanoxidation-reduction
sequence of 1, was shown to have markedly different NMR
data to those reported in the literature. This comparison of data
conclusively demonstrates that the structure of (-)-aureonitol
is 1 and not its 3-epimer as it is currently described on the
Chemical Database.
Having confirmed that we had prepared the same diastere-
oisomer as Bohlmann, we now wished to confirm that (E)-1
was the same diastereoisomer as the tetrahydrofuran isolated
by Abraham from C. cochlioides.7 Our 1H NMR data are
Experimental Section
(S)-Ethyl 3-tert-Butyldiphenylsilanyloxy-2-hydroxypropanoate
(13). TBDPSCl (8.73 mL, 33.58 mmol) was added dropwise over
15 min to a stirred solution of (S)-ethyl glycerate 12 (4.50 g, 33.58
mmol) and imidazole (6.86 g, 100.75 mmol) in CH2Cl2 (70 mL) at
0 °C. The reaction mixture was warmed to rt, stirred for a further
2 h, and then quenched by the addition of NaHCO3 solution (70
mL). The phases were separated and the aqueous phase was
extracted with CH2Cl2 (2 × 70 mL). The combined organic extracts
were washed with brine (70 mL), dried (MgSO4), and evaporated
to dryness. The residue was purified by flash column chromatog-
raphy (15% EtOAc in hexane) to afford silyl ether 13 as a viscous,
7
identical with those reported by Abraham in CDCl3 and C6D6
and Seto in CDCl3 (see the Supporting Information).6 The 13
C
NMR data in CDCl3 were also identical. We observed the same
NOE data reported by Abraham (performed in C6D6 as the
resonances are more separated in this solvent).7 We also
confirmed that the metabolite isolated by Teuscher in 2005 has
the same relative stereochemistry as our synthesized (E)-1 by
1
1
comparing our crude H NMR spectrum with the H NMR
spectrum of aureonitol isolated from C. globosum in the solvent
CD3OD (see the Supporting Information).8,30
colorless oil (9.74 g, 78%): Rf 0.21 (15% EtOAc in hexane); [R]23
D
The specific rotation for our synthesized aureonitol was -6.9
(c 1, 23 °C, CHCl3), which is in the region of the specific
rotations reported by Abraham (-7.8, c 1, CHCl3) and later by
Teuscher (-8, c 1, CHCl3).7,8 The absolute configuration of
our synthesized aureonitol is known to be (2S,3R,4S) around
the tetrahydrofuran ring as the configuration at the 2-position
is derived from (S)-serine. This supports Abraham’s assignment
of absolute configuration, and that Abraham and Teuscher had
both also isolated the (2S,3R,4S)-enantiomer. More importantly,
we had confirmed that our synthesized molecule was the same
natural product isolated by Abraham and later Teuscher. It
should be noted, however, that the absolute stereochemistry of
the molecule isolated by Abraham and the molecule synthesized
by us is not necessarily the same absolute configuration as that
of the Helichrysum aureonitol, as Bohlmann never reported any
optical rotation data for his isolate.1
+12.4 (c 1.00, CHCl3); νmax (film)/cm-1 3425 s br (OH), 1738 s
(CdO); δH (300 MHz) 1.03 (s, 9H), 1.30 (t, J 6.7, 3H), 3.15 (br s,
1H), 3.91 (A of ABX, JA-B ) 10.4 Hz, JA-X ) 2.9 Hz, 1H), 3.97
(B of ABX, JB-A ) 10.4 Hz, JB-X ) 2.7 Hz, 1H), 4.19-4.33 (stack,
3H), 7.33-7.57 (stack, 6H), 7.60-7.71 (stack, 4H); δC (75 MHz)
14.2 (CH3), 19.2 (C), 26.6 (CH3), 61.6 (CH2), 65.8 (CH2), 127.6
(CH), 127.7 (CH), 129.7 (CH), 132.8 (C), 133.0 (C), 135.4 (CH),
135.5 (CH), 172.8 (C); m/z (TOF ES+) 395.1 ([M + Na]+, 100%);
HRMS calcd for C21H28NaO4Si [M + Na]+ 395.1655, found
395.1664. Anal. Calcd for C21H28O4Si: C, 67.71; H, 7.58. Found:
C, 67.87; H, 7.61.
(S)-Ethyl 3-tert-Butyldiphenylsilanyloxy-2-(4′-trimethylsilanyl-
but-2′-ynyloxy)propanoate (15). TMSOTf (270 µL, 1.5 mmol) was
added to a solution of trichloroacetimidate 149e (4.30 g, 15.0 mmol)
and R-hydroxy ester 13 (8.37 g, 22.5 mmol) in cyclohexane (150
mL) at 0 °C. After warming to rt, the reaction mixture was stirred
for 5 h and then quenched by the addition of NaHCO3 solution
(150 mL). The two phases were separated and the aqueous phase
was extracted with Et2O (2 × 150 mL). The combined organic
extracts were washed with H2O (50 mL) and brine (50 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (6%
EtOAc in hexane) afforded ether 15 as a colorless oil (4.84 g, 65%):
Rf 0.34 (6% EtOAc in hexane); [R]23D -4.5 (c 1.00, CHCl3); νmax
(film)/cm-1 2212 w (Ct C), 1752 s (CdO); δH (300 MHz) 0.07 (s,
9H), 1.03 (s, 9H), 1.28 (t, J ) 7.0 Hz, 3H), 1.47 (t, J ) 2.4 Hz,
2H), 3.87-4.00 (m, 2H), 4.16-4.38 (stack, 5H), 7.32-7.44 (stack,
6H), 7.58-7.68 (stack, 4H); δC (75 MHz) -2.1 (CH3), 7.1 (CH2),
14.2 (CH3), 19.2 (C), 26.6 (CH3), 58.2 (CH2), 60.8 (CH2), 64.6
(CH2), 73.8 (C), 77.5 (CH), 85.8 (C), 127.6 (CH), 129.6 (CH), 133.1
(C), 133.2 (C), 135.50 (CH), 135.55 (CH), 170.6 (C); m/z (TOF
1
Our synthesized (-)-aureonitol also has identical H NMR
and 13C NMR data to those shown by a molecule recently
isolated from Chaetonium sp. by Fatope.31 From the information
available, it would appear that Fatope isolated (+)-aureonitol,
the enantiomer of 1, owing to the specific rotation being of the
opposite sign to that recorded by ourselves, Abraham,7 and
Teuscher.8 In addition, Fatope determined the configuration at
C-3 to be (S) by Mosher ester analysis (cf. Abraham determined
the configuration at C-3 to be (R) by Mosher ester analysis).31
(30) Interestingly, purified aureonitol was insoluble in CD3OD.
(31) Marwah, R. G.; Fatope, M. O.; Deadman, M. L.; Al-Maqbali, Y. M.;
Husband, J. Tetrahedron 2007, 63, 8174–8180.
J. Org. Chem. Vol. 73, No. 19, 2008 7621

Jervis and Cox
ES+) 519.2 ([M + Na]+, 100%); HRMS calcd for C28H40NaO4Si2
[M + Na]+ 519.2363, found 519.2367. Anal. Calcd for C28H40O4Si2:
C, 67.70; H, 8.12. Found: 67.75; H, 7.77.
(C), 26.8 (CH3), 52.2 (CH), 64.4 (CH2), 71.1 (CH2), 77.8 (CH),
84.3 (CH), 117.1 (CH2), 127.62 (CH), 127.64 (CH), 129.6 (CH),
129.7 (CH), 133.0 (C), 133.1 (C), 135.4 (CH), 135.5 (CH), 136.1
(CH); selected data for the minor diastereoisomer 17: δC (75 MHz)
19.1 (C), 26.7 (CH3), 48.3 (CH), 64.5 (CH2), 70.6 (CH2), 75.2 (CH),
86.6 (CH), 118.8 (CH2); m/z (TOF ES+) 405.2 ([M + Na]+, 100%);
HRMS calcd for C23H30NaO3Si [M + Na]+ 405.1862, found
405.1842.
(Z,S)-Ethyl 3-tert-Butyldiphenylsilanyloxy-2-(4′-trimethylsilanyl-
but-2′-enyloxy)propanoate (16). Ra-Ni (a spatula tip) was added
to a solution of alkyne 15 (4.50 g, 9.1 mmol) in EtOH (270 mL)
at rt. The reaction flask was charged with H2 gas (3 × vacuum-H2
flushes) and the resulting suspension stirred for 5 min under an
atmosphere of H2. Filtration through Celite and removal of the
solvent under reduced pressure left a residue, which was purified
by flash column chromatography (6% EtOAc in hexane) to afford
alkene 16 as a colorless oil (4.26 g, 94%): Rf 0.35 (10% EtOAc in
(2S,3R,4S)-3-tert-Butyldiphenylsilanyloxy-2-tert-butyldiphenyl-
silanyloxymethyl-4-vinyltetrahydrofuran (9). TBDPSCl (1.02 mL,
3.93 mmol) was added dropwise over 15 min to a stirred solution
of alcohol 18 (and 17) (1.50 g, 3.93 mmol, 18:17, 8:1) and imidazole
(813 mg, 11.94 mmol) in CH2Cl2 (9 mL) at 0 °C. The reaction
mixture was warmed to rt, stirred for a further 3 h, and then
quenched by the addition of NaHCO3 solution (9 mL). The phases
were separated and the aqueous phase was extracted with CH2Cl2
(2 × 9 mL). The combined organic extracts were washed with brine
(9 mL), dried (MgSO4), and concentrated under reduced pressure.
The residue was purified by flash column chromatography (6% Et2O
in hexane) and then by HPLC to afford silyl ether 9 as a viscous,
hexane); [R]23 -7.8 (c 1.00, CHCl3); νmax (film)/cm-1 1748 s
D
(CdO), 1648 w (CdC); δH (300 MHz) -0.02 (s, 9H), 1.02 (s,
9H), 1.28 (t, J ) 7.0 Hz, 3H), 1.49 (d, J ) 8.8 Hz, 2H), 3.90 (d,
J ) 5.5 Hz, 2H), 3.98-4.26 (stack, 5H), 5.43 (dt, J ) 10.7, 7.0
Hz, 1H), 5.57-5.69 (m, 1H), 7.33-7.43 (stack, 4H), 7.62-7.70
(stack, 6H); δC (75 MHz) -1.9 (CH3), 14.3 (CH3), 19.2 [(CH2),
(C), coincident peaks)], 26.7 (CH3), 60.8 (CH2), 64.7 (CH2), 65.9
(CH2), 79.1 (CH), 123.0 (CH), 127.59 (CH), 127.60 (CH), 129.6
(CH), 130.5 (CH), 133.16 (C), 133.24 (C), 135.6 (CH), 135.7 (CH),
171.1 (C); m/z (TOF ES+) 521.3 ([M + Na]+, 100%); HRMS calcd
for C28H42NaO4Si2 [M + Na]+ 521.2519, found 521.2503.
(Z,S)-3-tert-Butyldiphenylsilanyloxy-2-(4′-trimethylsilanylbut-2′-
enyloxy)propanal (11). DIBALH (5.1 mL of a 1.5 M solution in
toluene, 7.7 mmol) was added dropwise over 30 min to a solution
of ester 16 (3.50 g, 7.0 mmol) in CH2Cl2 (115 mL) at -78 °C.
After 1 h, the reaction was quenched with MeOH (280 µL, 7.0
mmol) and H2O (760 µL, 42 mmol) at -78 °C. The resulting slurry
was warmed to rt and then filtered through MgSO4 and Celite.
Removal of the solvent under reduced pressure provided a yellow
liquid, which was purified by flash column chromatography (8%
EtOAc in hexane) to afford aldehyde 11 as a colorless oil (2.92 g,
92%): Rf 0.24 (8% EtOAc in hexane); [R]23D -6.4 (c 1.00, CHCl3);
νmax (film)/cm-1 1736 s (CdO), 1648 w (CdC); δH (300 MHz)
-0.02 (s, 9H), 1.03 (s, 9H), 1.48 (d, J ) 9.6 Hz, 2H), 3.79-3.86
(m, 1H), 3.88-3.94 (m, 2H), 4.12 (d, J ) 6.6 Hz, 2H), 5.43 (dt, J
) 11.0, 6.6 Hz, 1H), 5.59-5.72 (m, 1H), 7.33-7.45 (stack, 6H),
7.61-7.70 (stack, 4H), 9.74 (d, J ) 1.5 Hz, 1H); δC (75 MHz)
-1.9 (CH3), 19.2 (C), 19.3 (CH2), 26.7 (CH3), 63.4 (CH2), 66.1
(CH2), 83.8 (CH), 122.7 (CH), 127.6 (CH), 127.7 (CH), 129.8 (CH),
131.0 (CH), 132.9 (C), 133.0 (C), 135.57 (CH), 135.61 (CH), 202.9
(CH); m/z (TOF ES+) 509.3 ([M + Na + MeOH]+, 30%), 477.2
(100, [M + Na]+); HRMS calcd for C26H38NaO3Si2 [M + Na]+
477.2257, found 477.2253.
colorless oil (2.05 g, 84%): Rf 0.30 (6% Et2O in hexane); [R]23
D
-43.2 (c 1.00, CHCl3); νmax (film)/cm-1 1642 w (CdC); δH (400
MHz) 1.14 (s, 9H), 1.23 (s, 9H), 2.99-3.09 (m, 1H), 3.58 (A of
ABX, JA-B ) 11.1 Hz, JA-X ) 4.9 Hz, 1H), 3.74 (B of ABX, JB-A
) 11.1 Hz, JB-X unresolved, 1H), 3.88 (app. t, J ) 7.1 Hz, 1H),
4.20-4.29 (stack, 2H, 2-H), 4.39 (s with unresolved fine coupling,
1H), 4.96 (d, J ) 11.5 Hz, 1H), 4.97 (d, J ) 15.5 Hz, 1H),
5.54-5.61 (m, 1H), 7.39-7.55 (stack, 12H), 7.71-7.85 (stack, 8H);
δC (75 MHz) 19.10 (C), 19.11 (C), 26.8 (CH3), 27.0 (CH3), 53.3
(CH), 64.2 (CH2), 71.6 (CH2), 79.4 (CH), 87.2 (CH), 116.2 (CH2),
127.52 (CH), 127.55 (CH), 127.6 (CH), 129.4 (CH), 129.7 (CH),
133.33 (C), 133.37 (C), 133.42 (C), 133.6 (C), 135.6 (CH), 135.8
(CH), 135.9 (CH), 136.8 (CH); m/z (TOF ES+) 643.3 ([M + Na]+,
100%); HRMS calcd for C39H48NaO3Si2 [M + Na]+ 643.3040,
found 643.3030.
(2S,3R,4S)-3-tert-Butyldiphenylsilanyloxy-2-tert-butyldiphenyl-
silanyloxymethyl-4-formyltetrahydrofuran (10). OsO4 (121 µL of
a 4% w/w solution in H2O, 0.019 mmol) was added to a stirred
solution of alkene 9 (600 mg, 0.96 mmol) and NMO (225 mg, 1.92
mmol) in acetone:H2O (5:1, 10 mL) at rt. After 2 h, the reaction
mixture was quenched by the addition of NaHSO3 solution (10 mL)
and then diluted with EtOAc (50 mL) and H2O (35 mL). The phases
were separated and the organic phase was washed with H2O (2 ×
10 mL) and brine (10 mL) and dried over MgSO4. Filtration and
concentration under reduced pressure afforded a viscous, colorless
oil, which was dissolved in THF:H2O (7:3, 10 mL). NaIO4 (411
mg, 1.92 mmol) was added. After being stirred for 15 min at rt,
the reaction mixture was diluted with EtOAc (25 mL) and H2O
(25 mL) and the phases were separated. The aqueous phase was
extracted with EtOAc (2 × 25 mL). The combined organic extracts
were washed with brine (25 mL) and dried over MgSO4. Filtration
and concentration under reduced pressure afforded aldehyde 10 as
a viscous, colorless oil (514 mg, 86% over two steps), which was
used in the next step without further purification: Rf 0.65 (15%
(2S,3R,4S)-2-tert-Butyldiphenylsilanyloxymethyl-3-hydroxy-4-vi-
nyltetrahydrofuran (18) and (2S,3R,4R)-2-tert-Butyldiphenylsila-
nyloxymethyl-3-hydroxy-4-vinyltetrahydrofuran (17). MeSO3H
(0.4 mL, 6.1 mmol) was added to a solution of aldehyde 11 (2.50
g, 5.5 mmol) in CHCl3 (55 mL) at -60 °C. After 5 min, the reaction
was quenched by the addition of NaHCO3 solution (55 mL) at -78
°C. The reaction mixture was warmed to rt over 30 min. The two
phases were then separated and the aqueous phase was extracted
with CH2Cl2 (2 × 55 mL). The combined organic extracts were
washed with H2O (55 mL) and brine (55 mL) and dried over
MgSO4. Filtration and concentration under reduced pressure af-
forded a residue, which was purified by flash column chromatog-
raphy to provide a mixture of alcohol diastereoisomers 18 and 17
(8:1, 18:17) as a colorless oil, which was inseparable by flash
column chromatography (1.81 g, 86%); data on the mixture of
diastereoisomers unless specified otherwise: Rf 0.29 (25% EtOAc
in hexane); [R]23D -5.0 (c 1.00, CH2Cl2); νmax (film)/cm-1 3481 s
br (OH), 1642 w (CdC); major diastereoisomer 18: δH (300 MHz)
1.06 (s, 9H), 1.25 (s, 1H), 2.85 (app. quintet, J ) 8.1 Hz, 1H),
3.69 (app. t, J ) 9.2 Hz, 1H), 3.73 (stack, 3H), 4.03-4.11 (stack,
2H), 5.13 (d, J ) 10.3 Hz, 1H), 5.20 (d, J ) 16.9 Hz, 1H),
5.66-5.80 (m, 1H), 7.31-7.48 (stack, 6H), 7.61-7.71 (stack, 4H);
selected data for minor diastereoisomer 17: δH (300 MHz)
5.81-5.92 (m, 1H); major diastereoisomer 18: δC (75 MHz) 19.1
EtOAc in hexane); [R]23 +4.5 (c 1.00, CHCl3); νmax (film)/cm-1
D
1727s (CdO); δH (300 MHz) 0.92 (s, 9H), 1.05 (s, 9H), 2.85-2.92
(m, 1H), 3.42 (A of ABX, JA-B ) 11.2 Hz, JA-X ) 4.8 Hz, 1H),
3.55 (B of ABX, JB-A ) 11.2 Hz, JB-X ) 3.0 Hz, 1H), 3.98 (app.
q, J ) 4.1 Hz, 1H), 4.05 (A of ABX, JA-B ) 9.2 Hz, JA-X ) 7.0
Hz, 1H), 4.22 (B of ABX, JB-A ) 9.2 Hz, JB-X ) 3.7 Hz, 1H), 4.68
(t, J ) 3.7 Hz, 1H), 7.20-7.48 (stack, 12H), 7.50-7.64 (stack,
8H), 9.04 (d, J ) 1.5 Hz, 1H); δC (75 MHz) 19.08 (C), 19.10 (C),
26.7 (CH3), 26.9 (CH3), 61.4 (CH), 63.4 (CH2), 66.8 (CH2), 74.8
(CH), 87.7 (CH), 127.59 (CH), 127.61 (CH), 127.86 (CH), 127.92
(CH), 129.6 (CH), 130.0 (CH), 130.1 (CH), 132.9 (C), 133.0 (C),
133.1 (C), 133.2 (C), 135.55 (CH), 135.59 (CH), 135.7 (CH), 135.8
(CH), 199.7 (CH); m/z (TOF ES+) 677.3 ([M + MeOH + Na]+,
100%), 645.3 (35, [M + Na]+); HRMS calcd for C38H46NaO4Si2
[M + Na]+ 645.2832, found 645.2844.
7622 J. Org. Chem. Vol. 73, No. 19, 2008

Total Synthesis and of (-)-Aureonitol
(1′E,3′E,2S,3R,4S)-3-tert-Butyldiphenylsilanyloxy-2-tert-butyl-
diphenylsilanyloxymethyl-4-penta-1′,3′-dienyltetrahydrofuran
((E,E)-8) and (1′Z,3′E,2S,3R,4S)-3-tert-Butyldiphenylsilanyloxy-
2-tert-butyldiphenylsilanyloxymethyl-4-penta-1′,3′-dienyltet-
rahydrofuran ((Z,E)-8). KHMDS (140 µL of a 0.5 M solution in
toluene, 0.70 mmol) was added dropwise to a cooled (-78 °C)
solution of (E)-crotyl sulfone 32 (203 mg, 0.77 mmol) in THF (5
mL). After 30 min, a cooled (-78 °C) solution of aldehyde 10
(400 mg, 0.64 mmol) in THF (5 mL) was added dropwise over 1
min. The reaction mixture was stirred at -78 °C for 1 h and then
quenched by the addition of H2O (10 mL). After warming to rt
over 30 min, the phases were separated and the aqueous phase was
extracted with EtOAc (2 × 10 mL). The combined organic extracts
were washed with brine (10 mL) and dried over MgSO4. Filtration
and concentration under reduced pressure afforded dienes (E,E)-8
and (Z,E)-8 as a ∼2.5:1 mixture of geometric isomers, which were
inseparable by flash column chromatography. This mixture was
dissolved in CHCl3 (2 mL) before I2 (16 mg, 0.064 mmol) was
added. The reaction mixture was stirred at reflux for 1 h. After
cooling to rt, the reaction mixture was washed with Na2S2O3
solution (2 × 2 mL) and brine (2 mL) and then dried (MgSO4).
Filtration and concentration under reduced pressure afforded (E,E)-8
and (Z,E)-8 as a ∼4:1 mixture of geometric isomers as a colorless
oil (342 mg, 81%); data for the mixture unless specified otherwise:
Rf 0.27 (6% EtOAc in hexane); νmax (film)/cm-1 1603 w (CdC),
1589 w (CdC); major stereoisomer (E,E)-8: δH (300 MHz) 0.94
(s, 9H), 1.02 (s, 9H), 1.69 (d, J ) 6.6 Hz, 3H), 2.74-2.86 (m,
1H), 3.40 (A of ABX, JA-B ) 11.0 Hz, JA-X ) 4.8 Hz, 1H), 3.54
(B of ABX, JB-A ) 11.0 Hz, JB-X ) 3.3 Hz, 1H), 3.63 (A of ABX,
JA-B ) 8.5 Hz, JA-X ) 6.3 Hz, 1H), 3.97-4.07 (stack, 2H), 4.14
(app. t, J 4.4, 1H), 5.01 (dd, J ) 14.3, 8.8 Hz, 1H), 5.43 (dq, J )
13.6, 6.6 Hz, 1H), 5.55-5.75 (stack, 2H), 7.25-7.42 (stack, 12H),
7.49-7.69 (stack, 8H); selected data for minor stereoisomer (Z,E)-
8: δH (300 MHz) 1.60 (d, J ) 6.6 Hz, 3H); major stereoisomer
(E,E)-8: δC (75 MHz) 18.0 (CH3), 19.1 (C), 19.2 (C), 26.8 (CH3),
26.9 (CH3), 52.4 (CH), 64.2 (CH2), 72.0 (CH2), 79.6 (CH), 87.0
(CH), 127.5 (CH), 127.9 (CH), 129.1 (CH), 129.5 (CH), 129.7 (CH),
131.3 (CH), 132.2 (CH), 133.4 (C), 133.5 (C), 135.6 (CH), 135.9
(CH), 136.1 (CH); m/z (TOF ES+) 683.3 ([M]+, 100%); HRMS
calcd for C42H52NaO3Si2 [M + Na]+ 683.3353, found 683.3381.
(1′E,3′E,2S,3R,4S)-3-tert-Butyldiphenylsilanyloxy-2-hydroxy-
methyl-4-penta-1′,3′-dienyltetrahydrofuran ((E,E)-33) and
(1′Z,3′E,2S,3R,4S)-3-tert-Butyldiphenylsilanyloxy-2-hydroxymethyl-
4-penta-1′,3′-dienyltetrahydrofuran ((Z,E)-33). HF-pyridine
(0.1 mL of a 70% solution in pyridine) was added dropwise over
1 min to a cooled (0 °C) solution of a 4:1 mixture of bis-silyl ethers
(E,E)-8 and (Z,E)-8 (120 mg, 0.18 mmol) in THF/pyridine (1:1, 2
mL). The reaction mixture was stirred at this temperature for 30
min, then diluted with EtOAc (10 mL) and washed with CuSO4
solution (3 × 5 mL), H2O (2 × 5 mL), and brine (5 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure to afford
alcohols (E,E)-33 and (Z,E)-33 as a 4:1 mixture. Purification by
flash column chromatography (20% EtOAc in hexane) increased
the ratio of (E,E)-33 to (Z,E)-33 to 5:1, a mixture that was obtained
as a colorless oil (65 mg, 82%); data for the mixture unless specified
otherwise: Rf 0.28 (20% EtOAc in hexane); νmax(film)/cm-1 3344 s
br (OH), 1662 m (CdC); data for major stereoisomer (E,E)-33: δH
(300 MHz) 1.04 (s, 9H), 1.71 (d, J ) 7.0 Hz, 3H), 3.85-3.94 (m,
1H), 3.18 (A of ABX, JA-B ) 12.2 Hz, JA-X ) 5.1 Hz, 1H), 3.36
(B of ABX, JB-A ) 12.2 Hz, JB-X unresolved, 1H), 3.61 (A of ABX,
JA-B ) 8.5 Hz, JA-X ) 5.9 Hz, 1H), 3.86-3.94 (stack, 2H), 4.05 (B
of ABX, JB-A ) 8.5 Hz, JB-X ) 7.0 Hz, 1H), 5.07 (dd, J ) 14.3,
8.8 Hz, 1H), 5.50 (dq, J ) 13.6, 6.6 Hz, 1H), 5.70-5.85 (stack,
2H), 7.29-7.48 (stack, 6H), 7.57-7.69 (stack, 4H); selected data
for minor stereoisomer (Z,E)-33: δH (300 MHz) 1.62 (d, J ) 6.6
Hz, 3H); data for major stereoisomer (E,E)-33: δC (75 MHz) 18.0
(CH3), 19.1 (C), 26.9 (CH3), 52.1 (CH), 62.3 (CH2), 71.5 (CH2),
79.3 (CH), 86.6 (CH), 127.6 (CH), 127.7 (CH), 128.5 (CH), 128.7
(CH), 129.8 (CH), 129.9 (CH), 131.0 (CH), 132.4 (CH), 133.3 (C),
133.49 (C), 135.9 (CH), 136.0 (CH); m/z (TOF ES+) 445 ([M +
Na]+, 100%); HRMS calcd for C26H34NaO3Si [M + Na]+ 445.2175,
found 445.2182.
(1′E,1′′E,3′′E,3S,3R,4S)-2-Buta-1′,3′-dienyl-3-tert-butyldiphe-
nylsilanyloxy-4-penta-1′′,3′′-dienyltetrahydrofuran ((E)-35) and
(1′Z,1′′E,3′′E,3S,3R,4S)-2-buta-1′,3′-dienyl-3-tert-butyldiphenyl-
silanyloxy-4-penta-1′′,3′′-dienyltetrahydrofuran ((Z)-35). TPAP
(2.9 mg, 0.011 mmol) was added to a cooled (0 °C) solution of
alcohol 33 (46 mg, 0.11 mmol), NMO (26 mg, 0.22 mmol), and 4
Å molecular sieves (50 mg) in CH2Cl2 (1 mL). The reaction mixture
was stirred at this temperature for 30 min and then filtered through
a short silica plug (washing with CH2Cl2). Concentration of the
filtrate under reduced pressure afforded aldehyde 7 (42 mg, quant)
as a colorless oil, which was immediately dissolved in THF (1 mL)
and cooled to -78 °C. KHMDS (220 µL of a 0.5 M solution in
toluene, 0.109 mmol) was added dropwise to a cooled (-78 °C)
solution of allyl sulfone 34 (30 mg, 0.119 mmol) in THF (1 mL).
After 30 min, the cooled (-78 °C) solution of aldehyde 7 (42 mg,
0.100 mmol) in THF (5 mL) was added dropwise over 1 min. The
reaction mixture was stirred at -78 °C for 1 h and then diluted
with EtOAc (9 mL) and quenched by the addition of H2O (10 mL).
After warming to rt over 30 min, the phases were separated and
the aqueous phase was extracted with EtOAc (2 × 10 mL). The
combined organic extracts were washed with brine (10 mL) and
dried over MgSO4. Filtration and concentration under reduced
pressure afforded dienes (E)-35 and (Z)-35 as a 2:1 mixture, which
were separated by flash column chromatography to afford, in order
of elution, major diene (E)-35 as a colorless oil (28 mg, 57%): Rf
0.27 (70% CH2Cl2 in hexane); [R]23D -14.8 (c 1.00, CHCl3); νmax
(film)/cm-1 1605 w (CdC); δH (300 MHz) 1.04 (s, 9H), 1.70 (d,
J ) 6.6 Hz, 3H), 2.75-2.87 (m, 1H), 3.65 (A of ABX, JA-B ) 8.5
Hz, JA-X ) 5.5 Hz, 1H), 3.84 (app. t, J ) 4.4 Hz, 1H), 4.08 (B of
ABX, JB-A ) 8.5 Hz, JB-X ) 7.0 Hz, 1H), 4.26 (dd, J ) 6.6, 4.4
Hz, 1H), 4.99-5.15 (stack, 3H), 5.25 (dd, J ) 14.3, 7.0 Hz, 1H),
5.49 (dq, J ) 14.3, 6.6 Hz, 1H), 5.65-5.88 (stack, 2H), 5.98-6.22
(stack, 2H), 7.29-7.45 (stack, 6H), 7.53-7.70 (stack, 4H); δC (75
MHz) 18.0 (CH3), 26.9 (CH3), 29.7 (C), 52.3 (CH), 71.6 (CH2),
83.8 (CH), 86.6 (CH), 117.4 (CH2), 127.566 (CH), 127.574 (CH),
127.6 (CH), 129.2 (CH), 129.72 (CH), 129.75 (CH), 131.2 (CH),
131.7 (CH), 132.3 (CH), 132.6 (CH), 133.5 (C), 133.6 (C), 136.08
(CH), 136.11 (CH), 136.3 (CH); m/z (TOF ES+) 467.2 ([M + Na]+,
100%); HRMS calcd for C29H36NaO2Si [M + Na]+ 467.2382, found
467.2388; and then minor diene (Z)-35 as a colorless oil (14 mg,
28%): Rf 0.25 (70% CH2Cl2 in hexane); [R]23 -27.6 (c 1.00,
D
CHCl3); νmax (film)/cm-1 1654 w (CdC), 1590 w (CdC); δH (300
MHz) 1.04 (s, 9H), 1.69 (d, J ) 5.5 Hz, 3H), 2.68-2.82 (m, 1H),
3.67 (A of ABX, JA-B ) 8.5 Hz, JA-X ) 4.8 Hz, 1H), 3.81-3.90
(m, 1H), 4.06 (B of ABX, JB-A ) 8.5 Hz, JB-X ) 6.6 Hz, 1H), 4.75
(dd, J ) 8.8, 4.4 Hz, 1H), 4.98-5.31 (stack, 4H), 5.44 (dd, J )
15.1, 7.0 Hz, 1H), 5.57 (d, J ) 15.5, 10.7 Hz, 1H), 5.66-5.86 (m,
1H), 6.04 (app. t, J ) 11.4 Hz, 1H), 6.73 (dt, J ) 16.9, 11.0 Hz,
1H), 7.28-7.45 (stack, 6H), 7.52-7.71 (stack, 4H); δC (75 MHz)
18.0 (CH3), 19.1 (C), 26.9 (CH3), 52.1 (CH), 71.5 (CH2), 82.1 (CH),
84.4 (CH), 119.3 (CH2), 127.44 (CH), 127.47 (CH), 127.54 (CH),
128.3 (CH), 129.1 (CH), 129.5 (CH), 129.67 (CH), 129.69 (CH),
129.73 (CH), 131.1 (CH), 132.0 (CH), 132.1 (CH), 132.7 (CH),
133.2 (C), 133.7 (C), 136.0 (CH), 136.1 (CH); m/z (TOF ES+)
467.3 ([M + Na]+, 100%); HRMS calcd for C29H36NaO2Si [M +
Na]+ 467.2382, found 467.2378.
(1′E,1′′E,3′′E,2S,3R,4S)-2-Buta-1′,3′-dienyl-3-hydroxy-4-penta-
1′′,3′′-dienyl-tetrahydrofuran ((-)-Aureonitol; (E)-1). TBAF (140
µL of a 1.0 M solution in THF, 0.14 mmol) was added dropwise
over 1 min to a cooled (0 °C) solution of silyl ether (E)-35 (30
mg, 0.067 mmol) in THF (1 mL). The reaction mixture was warmed
to rt, stirred for 1 h, and then diluted with EtOAc (9 mL). H2O (10
mL) was added and the phases were separated. The aqueous phase
was extracted with EtOAc (2 × 10 mL) and the combined organic
extracts were washed with brine (10 mL), dried (MgSO4), filtered,
and concentrated under reduced pressure to afford a residue that
J. Org. Chem. Vol. 73, No. 19, 2008 7623

Jervis and Cox
was purified by flash column chromatography (25% EtOAc in
(1′E,1′′E,3′′E,2S,3S,4S)-2-Buta-1′,3′-dienyl-3-hydroxy-4-penta-
1′′,3′′-dienyltetrahydrofuran (2). Dess-Martin periodinane (10 mg,
0.024 mmol) was added to a solution of alcohol (E)-1 (2.5 mg,
0.012 mmol) in CH2Cl2 (1 mL) at rt. The reaction mixture was
stirred for 30 min and then diluted with CH2Cl2 (5 mL) and
quenched with NaHCO3 solution (3 mL) and Na2S2O3 solution (3
mL) and stirred for a further 30 min. The phases were separated
and the aqueous phase was extracted with CH2Cl2 (2 × 6 mL).
The combined organic extracts were washed with H2O (3 mL) and
brine (6 mL) and dried over MgSO4. Filtration and concentration
under reduced pressure produced a residue, which was dissolved
in THF (1 mL). After cooling to -78 °C, L-Selectride (12 µL of
a 1.0 M solution in THF, 0.012 mmol) was added dropwise over
5 min. The reaction mixture was stirred at -78 °C for 1 h and
then diluted with Et2O (5 mL) before being quenched with
hydrochloric acid (2 M, 6 mL). After stirring for 30 min, the phases
were separated and the aqueous phase was extracted with Et2O (2
× 6 mL). The combined organic extracts were washed with H2O
(6 mL) and brine (6 mL) and dried over MgSO4. Concentration
under reduced pressure produced a mixture of alcohols (>10:1
2:(E)-1), which was purified by flash column chromatography (25%
EtOAc in hexane) to afford major alcohol 2 as a colorless semisolid
hexane) to afford alcohol (E)-1 as a white solid (13 mg, 91%): mp
64-65 °C (lit.7 mp 65 °C); Rf 0.22 (25% EtOAc in hexane); [R]23
D
-6.9 (c 1.00, CHCl3) (lit.7 -7.8 (c 1.00, CHCl3)); νmax (film)/cm-1
3405 s br (OH), 1605 w (CdC); δH (500 MHz) 1.75 (d with
unresolved fine coupling, J ) 6.6 Hz, 3H, 5′′-H), 1.84 (s (br), 1H,
OH), 2.85 (app. pentet, J ) 8.1 Hz, 1H, 4-H), 3.72 (app. t, J ) 8.4
Hz, 1H, 5-Ha), 3.76 (app. t, J ) 7.2 Hz, 1H, 3-H), 4.11 (app. t, J
) 8.4 Hz, 1H, 5-Hb), 4.13 (app. t, J ) 7.2 Hz, 1H, 2-H), 5.12 (d
with unresolved fine coupling, J ) 9.2 Hz, 1H, 4′-Hcis), 5.24 (d
with unresolved fine coupling, J ) 16.0 Hz, 1H, 4′-Htrans), 5.43
(dd, J ) 15.1, 8.8 Hz, 1H, 1′′-H), 5.63-5.76 (stack, 2H, 1′-H, 4′′-
H), 6.03 (dd with unresolved fine coupling, J ) 15.1, 10.4 Hz, 1H,
3′′-H), 6.15 (dd, J ) 15.1, 10.4 Hz, 1H, 2′′-H), 6.28-6.41 (stack,
2H, 2′-H, 3′-H); δH (500 MHz, C6D6) 1.61 (d, J ) 7.0 Hz, 3H,
5′′-H), 2.60 (app. pentet, J ) 8.1 Hz, 1H, 4-H), 3.46 (app. t, J )
6.4 Hz, 1H, 3-H), 3.62 (app. t, J ) 8.3 Hz, 1H, 5-Ha), 3.97 (app.
t, J ) 8.4 Hz, 1H, 5-Hb), 4.15 (app. t, J ) 6.4 Hz, 1H, 2-H), 4.99
(d, J ) 9.7 Hz, 1H, 4′-Hcis), 5.12 (d, J ) 17.1 Hz, 1H, 4′-Htrans),
5.26 (dd, J ) 14.5, 8.8 Hz, 1H, 1′′-H), 5.51 (dq, J ) 14.2, 6.8 Hz,
1H, 4′′-H), 5.73 (dd, J ) 15.2, 6.4 Hz, 1H, 1′-H), 5.94-6.06 (stack,
2H, 3′′-H, 2′′-H), 6.31 (dt, J ) 16.9, 10.3 Hz, 1H, 3′-H), 6.41 (dd,
J ) 14.9, 10.6 Hz, 1H, 2′-H); δH (500 MHz, CD3OD) 1.73 (d, J )
6.2 Hz, 3H, 5′′-H), 2.80 (app. pentet, J ) 7.7 Hz, 1H, 4-H),
3.65-3.74 (stack, 2H, 3-H, 5-Ha), 4.02-4.10 (stack, 2H, 2-H, 5-Hb),
5.10 (d, J ) 9.6 Hz, 1H, 4′-Hcis), 5.23 (d, J 16.0, 1H, 4′-Htrans),
5.46 (dd, J ) 14.9, 8.4 Hz, 1H, 1′′-H), 5.66 (dq, J ) 14.9, 6.8 Hz,
1H, 4′′-H), 5.73 (dd, J ) 14.9, 6.9 Hz, 1H, 1′-H), 5.98-6.18 (stack,
2H, 3′′-H, 2′′-H), 6.29-6.42 (stack, 2H, 2′-H, 3′-H); δC (125 MHz)
18.0 (CH3, C-5′′), 51.5 (CH, C-4), 71.0 (CH2, C-5), 81.5 (CH, C-3),
84.7 (CH, C-2), 118.2 (CH2, C-4′), 128.2 (CH, C-1′′), 129.3 (CH,
C-4′′), 130.8 (CH, C-3′′), 131.5 (CH, C-1′), 133.2 (CH, C-2′′), 133.3
(CH, C-2′), 136.1 (CH, C-3′); m/z (TOF ES-) 205.1 ([M - H]-,
100%); HRMS calcd for C13H17O2 [M - H]- 205.1229, found
205.1236.
(2.4 mg, 91%): Rf 0.24 (25% EtOAc in hexane); [R]23 -11.2 (c
D
1.00, CHCl3); νmax (film)/cm-1 3408 s br (OH), 1605 w (CdC);
δH (300 MHz) 1.72 (d, J ) 6.6 Hz, 3H), 2.95-3.14 (m, 1H), 3.85
(app. q, J ) 8.7 Hz, 1H), 3.99 (app. q, J ) 8.3 Hz, 1H), 4.04-4.17
(m, 1H), 4.44-4.54 (m, 1H), 5.11 (d, J ) 7.7 Hz, 1H), 5.23 (d, J
) 15.8 Hz, 1H), 5.55-5.83 (stack, 3H), 5.98-6.20 (stack, 2H),
6.30-6.60 (stack, 2H); δC (75 MHz) 18.0 (CH3), 48.9 (CH), 70.5
(CH2), 75.7 (CH), 83.7 (CH), 118.2 (CH2), 125.1 (CH), 128.6 (CH),
129.3 (CH), 131.1 (CH), 134.0 (CH), 134.2 (CH), 136.1 (CH); m/z
(TOF ES-) 205.2 ([M - H]-, 100%); HRMS calcd for C13H17O2
[M - H]- 205.1229, found 205.1223.
Acknowledgment. We thank the Engineering and Physical
Sciences Research Council and the University of Birmingham
for a studentship (to P.J.J.), Astra Zeneca for an unrestricted
award (to L.R.C), Dr. David Lindsay (University of Reading,
United Kingdom) for the generous gift of metathesis catalysts
20 and 21, and Professor Majekodunmi Fatope (Sultan Qaboos
University, Oman) for providing NMR spectra of the tetrahy-
drofuran metabolite isolated from Chaetomium sp.
(1′Z,1′′E,3′′E,2S,3R,4S)-2-Buta-1′,3′-dienyl-3-hydroxy-4-penta-
1′′,3′′-dienyltetrahydrofuran ((Z)-1). TBAF (70 µL of a 1.0 M
solution in THF, 0.70 mmol) was added dropwise over 1 min to a
cooled (0 °C) solution of silyl ether (Z)-35 (14 mg, 0.032 mmol)
in THF (1 mL). The reaction mixture was warmed to rt. After 1 h,
EtOAc (9 mL) and H2O (10 mL) were added. The phases were
separated and the aqueous phase was extracted with EtOAc (2 ×
10 mL). The combined organic extracts were washed with brine
(10 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure to afford a residue, which was filtered through a short
plug of silica (washing with 25% EtOAc in hexane). Concentration
under reduced pressure afforded alcohol (Z)-1 as a colorless oil,
which was immediately dissolved in CHCl3 (1 mL). I2 (0.76 mg,
0.003 mmol) was added and the reaction mixture was stirred at
reflux for 1 h. After cooling to rt, the reaction mixture was washed
with Na2S2O3 solution (2 × 2 mL) and brine (2 mL) and then dried
(MgSO4). Filtration and concentration under reduced pressure
afforded a 6:1 mixture of (E)-1 (aureonitol) and (Z)-1. Purification
by flash column chromatography (25% EtOAc in hexane) afforded
(E)-1 as a white solid (5 mg, 75%).
Supporting Information Available: Chiral HPLC analysis
of tetrahydrofuran 18, attempted dienylation of aldehyde 10 with
phosphorus olefination methods, general experimental details,
experimental procedures and compound characterization data
1
for 12, 27, 31, 32, and 34, scanned H NMR spectra and 13C
NMR spectra for all new compounds, and tables and scanned
spectra comparing the NMR data of synthetic aureonitol with
those reported by Bohlmann, Abraham, Teuscher, Fatope, and
Seto. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801338T
7624 J. Org. Chem. Vol. 73, No. 19, 2008