Total synthesis of (+)-mycotrienol and (+)-mycotrienin I: Application of assymetric crotylsilane bond constructions

Article abstract of DOI:10.1021/ja9743194

A highly convergent asymmetric synthesis of the ansamycin antibiotics (+)-myotrienin I (1c) and (+)-mycotrienol (1d) has been achieved through the synthesis and coupling of the C9-C16 subunit 3b and the aromatic subunit 4b, respectively. This article describes the complete details of that work as it illustrates the utility of our developing chiral (E)-crotylsilane bond construction methodology in total synthesis. All four sterogenic centers were introduced using chiral allylsilane bond construction methodology. In the synthesis of subunit 3b, the C12 and C13 stereocenters were installed using an asymmetric crotylsilylation reaction to α-keto dibenzyl acetal 5. The C11 stereocenter was subsequently installed via a chelate-controlled addition of allyltrimethylsilane to establish the anti-1,3-diol system. The C14-C15 trisubstituted double bond was then installed via a reductive opening of α,β-unsaturated lactone 10b. Aromatic subunit 4b was chosen on the basis of its synthon equivalency to the amidobenzoquinone system of (+)-1c and (+)- 1d. Subunit 4b was constructed in a concise six-step sequence which corporates the C3 stereogenic center of the C1-C5 side chain. The C3 sterogenic center was established using a Weinreb amidation of aniline 18 with lactone (+)-16, whose absolute stereochemistry was derived using the crotylsilane methodology. The union of subunit 3b with aromatic subunit 4b was accomplished using a sulfone-based coupling strategy. Coupling product 21 was transformed through a sequence of steps to triene 24. Divergence from this advance intermediate allows access to both natural products. The successful completion of the synthesis included the incorporation of the (E, E, E)-triene unit with simultaneous macrocyclization through a palladium (0)- catalyzed (Stille-type) coupling macrocyclization.

Full text of DOI:10.1021/ja9743194

J. Am. Chem. Soc. 1998, 120, 4123-4134
4123
Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I:
Application of Asymmetric Crotylsilane Bond Constructions
Craig E. Masse, Michael Yang, Jason Solomon, and James S. Panek*
Contribution from the Department of Chemistry, Metcalf Center for Science and Engineering, Boston
UniVersity, Boston, Massachusetts 02215
ReceiVed December 19, 1997
Abstract: A highly convergent asymmetric synthesis of the ansamycin antibiotics (+)-mycotrienin I (1c) and
(+)-mycotrienol (1d) has been achieved through the synthesis and coupling of the C9-C16 subunit 3b and
the aromatic subunit 4b, respectively. This article describes the complete details of that work as it illustrates
the utility of our developing chiral (E)-crotylsilane bond construction methodology in total synthesis. All
four stereogenic centers were introduced using chiral allylsilane bond construction methodology. In the synthesis
of subunit 3b, the C12 and C13 stereocenters were installed using an asymmetric crotylsilylation reaction to
R-keto dibenzyl acetal 5. The C11 stereocenter was subsequently installed via a chelate-controlled addition
of allyltrimethylsilane to establish the anti-1,3-diol system. The C14-C15 trisubstituted double bond was
then installed via a reductive opening of R,â-unsaturated lactone 10b. Aromatic subunit 4b was chosen on
the basis of its synthon equivalency to the amidobenzoquinone system of (+)-1c and (+)-1d. Subunit 4b was
constructed in a concise six-step sequence which incorporates the C3 stereogenic center of the C1-C5 side
chain. The C3 stereogenic center was established using a Weinreb amidation of aniline 18 with lactone (+)-
16, whose absolute stereochemistry was derived using the crotylsilane methodology. The union of subunit 3b
with aromatic subunit 4b was accomplished using a sulfone-based coupling strategy. Coupling product 21
was transformed through a sequence of steps to triene 24. Divergence from this advanced intermediate allows
access to both natural products. The successful completion of the synthesis included the incorporation of the
(E,E,E)-triene unit with simultaneous macrocyclization through a palladium (0)-catalyzed (Stille-type) coupling
macrocyclization.
Introduction
A little more than a decade ago, Umezawa and co-workers
reported the isolation of five novel ansamycin antibiotics,
trienomycins A-E, from the culture broth of Streptomyces sp.
No. 83-16.1 These molecules exhibited strong cytotoxicity in
vitro against HeLa S3 cells.2 The most potent molecule, (+)-
trienomycin A (1a, Figure 1), along with (+)-mycotrienin I (1c)
and II (1e) and the mycotrienols II (1d,f) have previously been
isolated from the fermentation broth of the Streptomyces
rishirensis. Their relative and absolute stereochemistries have
been determined by Smith and co-workers through careful
degradative and spectroscopic methods.3 A stereoview of a
minimized (+)-mycotrienin I (1c) illustrating its various struc-
tural elements is shown in Figure 2.4 The (+)-mycotrienins I
and II have displayed potent antifungal activity.5 The structural
similarities between trienomycin A, (+)-mycotrienins I and II,
(1) (a) Funyama, S.; Okada, K.; Komiyama, K.; Umezawa, I. J. Antibiot.
1985, 38, 1107-1109. (b) Funyama, S.; Okada, K.; Iwasaki, K.; Komiyama,
K.; Umezawa, I. J. Antibiot. 1985, 38, 1677-1683. (c) Katasumata, S.;
Takahashi, K.; Funayama, S.; Komiyama, K.; Umezawa, I.; Omura, S. J.
Antibiot. 1989, 24, 479-481.
(2) Umezawa, I.; Funayama, S.; Okada, K.; Iwasaki. K.; Satoh, J.;
Masuda, K.; Komiyama, K. J. Antibiot. 1985, 38, 699-705.
(3) () Smith, A. B.; Wood, J. L.; Wong, W.; Gould, A. E.; Rizzo, C. J.
J. Am. Chem. Soc. 1990, 112, 7425-7426.
(4) Three-dimensional modeling was carried out with Chem 3-D Pro
using MM2 minimization techniques.
(5) (a) Sugita, M.; Natori, Y.; Sasaki, T.; Furihata, K.; Shimazu, A.; Seto,
H.; Otake, N. J. Antibiot. 1982, 35, 1460-1466. (b) Sugita, M.; Sasaki, T.;
Furihata, K.; Shimazu, A.; Seto, H.; Otake, N. J. Antibiot. 1982, 35, 1467-
1473. For (+)-mycotrienol see: (c) Sugita, M.; Natori, Y.; Sueda, N.; Kazuo,
F.; Seto, H.; Otake, N. J. Antibiot. 1982, 35, 1474-1479.
Figure 1.
and the mycotrienols provide circumstantial evidence for a
common absolute stereochemistry. This prediction has been
confirmed by stereochemical correlation studies where the
trienomycin stereochemistry assignments were extended to (+)-
mycotrienins I and II and, therefore, to the mycotrienols.6 An
intriguing aspect of the correlation studies is illustrated by the
dramatic differences in biological activity of the trienomycins
(antitumor activity) and mycotrienins (antifungal) derived from
modification of the aromatic portion. Those structure deter-
mination-stereochemical correlation studies have laid the
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4124 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Masse et al.
section (2a) serving as our initial synthetic target. A phosphorus-
based intermolecular Horner-Emmons olefination reaction
appeared attractive in the C8-C9 bond construction due to the
relatively mild conditions and the literature precedence for an
(E)-selective olefination. The final macrolactamization step to
form the N21-C1 bond may be achieved with bis(2-oxo-3-
oxazolidinyl)phosphinic chloride (BOP-Cl) which is also based
on literature precedent.8 In the interest of convergency, the C9-
N21 synthon was further simplified. The decision was made
to section this portion of the molecule at the C16-C17 bond
which corresponds to the addition of a benzylic anion to an
allylic halide. Collectively, these transformations provided a
convergent approach utilizing the three illustrated subunits. It
is important to emphasize that this synthetic planning was
intended to illustrate the utility of chiral (E)-crotylsilanes9 for
the synthesis of complex molecules. As a result of close
structural similarities, the synthetic analyses presented are readily
applicable to other members of this class of molecules.
Synthesis of the C9-C16 Fragment. It was anticipated that
the relative and absolute stereochemical relationships in this
subunit might be controlled through the use of chiral (E)-
crotylsilane bond construction methodology to establish the C12
and C13 centers of (+)-mycotrienin I. From these stereogenic
centers, the adjacent center at C11 would be constructed through
chelate-controlled addition of allyltrimethylsilane (Hosomi-
Sakurai reaction).10 Earlier reports by Reetz11 and Keck12 had
established precedence for the stereochemical outcome of such
a Lewis acid-promoted allylation reaction. With that in mind,
the construction of the C9-C16 subunit 3a was initiated by an
asymmetric crotylation between the R-keto dibenzyl acetal 5
and silane reagent (S)-6 to establish the C12-C13 centers
(Scheme 2). This first addition proceeds through an antiperipla-
nar transition state where the observed syn stereochemistry is
consistent with an anti-SE′ mode of addition (see Scheme 2).
Two carbon homologation of the homoallylic ether 7 by
treatment with the ester enolate of benzyl acetate gave a
â-tertiary alcohol which was immediately converted to the
tertiary acetate under standard DMAP-catalyzed acetylation
conditions. Oxidative cleavage of the (E)-olefin by ozonolysis
furnished the R-methyl aldehyde 8. This was followed by the
chelation-controlled asymmetric allylsilane addition reaction to
install the C11 hydroxyl stereocenter (diastereoselection ) 28:1
anti/syn). The 1,3-anti relationship is believed to arise from
nucleophilic addition to a titanium chelate between the C13
benzyloxy group and the aldehyde carbonyl. Elaboration of
the C14-C15 (Z)-double bond was initiated by cleavage of the
terminal olefin to give the â-silyloxy aldehyde which was
masked as the ethylene acetal 9a. Cleavage of the benzyl groups
via hydrogenation and simultaneous cyclization of the derived
hydroxy acid gives the lactone which upon elimination of the
tertiary â-acetoxy group with DBU gave the R,â-unsaturated
lactone 10a. Subsequently, the lactone was reductively opened
using LiAlH4 to give the (Z)-olefinic diol. NOE measurements
on this compound supported the assignment of the olefin
configuration as the (Z)-isomer (Scheme 3). Reduction of
lactone 10a to the corresponding diol presented a series of
Figure 2. (+)-Mycotrienin I (3-D minimized view).
groundwork for future synthetic and biological studies. To date,
Smith and co-workers have reported the only total syntheses of
this class of compounds, specifically the synthesis of trieno-
mycins Α-F.7 These structurally related molecules belong to
an emerging class of ansa-bridged macrocyclic lactams that
possess potent biological activity ranging from antitumor to
antifungal activity. Thus, they are of particular interest because
of the fact that seemingly simple modifications of the aromatic
portion produces dramatic changes in the biological activity.
The facts that these natural products have useful antitumor
activity and are not readily available from natural sources make
them excellent targets for synthesis. Biological evaluation has
been limited by the lack of availability of these agents, and only
modifications of the aromatic portion of the macrocyclic lactams
have been addressed.
In addition, it was found that (+)-mycotrienol (1d) is eight
times less potent than (+)-mycotrienin I (1c), which bears the
cyclohexylcarbonyl-δ-alanine unit, indicating that this func-
tionalized amino acid moiety is crucial for the biological activity
of these agents. (+)-Mycotrienin I is a unique entry into this
class of ansamycin antibiotics, consisting of a quinone-centered
21-membered macrocyclic lactam ring bearing a cyclohexyl-
carbonyl-δ-alanine ester functionality. Its four resident stereo-
genic centers and the (Z)-trisubstituted C14-C15 double bond
render (+) mycotrienin I a difficult challenge as a target for
synthesis.
Analysis of the Synthetic Plan. The synthetic plans
developed for (+)-mycotrienin I were guided by the structural
constraints of the molecule as well as by our intention to employ
asymmetric allylsilane-based bond constructions for the instal-
lation of each of the stereogenic centers. For completeness,
two retrosynthetic analyses are described in Scheme 1. The
original retrosynthetic analysis of the (+)-mycotrienol skeleton
is shown on the left side of Scheme 1, and the final analysis is
shown on the right side. The reasoning behind the modified
analysis will be discussed in the following sections. With
respect to the order of fragment coupling, we intended to design
flexibility into the synthetic pathways for the assemblage of
the individual components of the molecule. In this regard,
disconnection of the C8-C9 and N21-C1 bonds affords two
fragments of complexity comparable with that of the C9-N21
(6) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.; Rizzo, C.
J.; Barbosa, J.; Komiyama, K.; Omura, S. J. Am. Chem. Soc. 1996, 118,
8308-8315. For other synthetic approaches to the trienomycins and related
mycotrienins, see: (a) Yadav, J. S.; Praveen Kumar, T. K.; Maniyan, P. P.
Tetrahedron Lett. 1993, 34, 2965-2968. (b) Fu¨rstner, A.; Baumgartner, J.
Tetrahedron 1993, 49, 8541-8560. For preliminary work conducted in our
laboratories, see: Panek, J. S.; Yang, M. Y.; Solomon, J. Tetrahedron Lett.
1995, 36, 1003-1006.
(8) Evans, A. D.; Miller, S. J.; Ennis, M. D.; Ornstein, P. L. J. Org.
Chem. 1992, 57, 1067-1069.
(9) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain, N. F.; Panek, J. S.
Org. Synth. 1997, 75, 78-88.
(10) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295-1298.
(11) For a discussion of chelation-controlled carbonyl addition, see:
Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468.
(12) (a) Keck, G. E.; Murry, A. J. J. Org. Chem. 1991, 56, 6606-6611.
(b) Keck, G. E.; Abbot, D. E.; Boden, E. P. J. Org. Chem. 1986, 51, 5478-
5480.
(7) Smith, A. B.; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem.
Soc. 1996, 118, 8316-8328.

Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4125
Scheme 1
Scheme 2
Scheme 3
conditions were surveyed. A summary of these experiments is
given in Table 1. After an extensive screening of reaction
variables, a LiAlH4/TMEDA combination provided the highest
yield (70%) of 11a with minimal amounts of furan 10d
produced. Table 1 summarizes the lactone opening experiments.
Finally, protection of the primary and secondary hydroxyl
groups of 11a as their TBS ethers, selective deprotection of the
primary TBS ether with HF‚pyridine, and conversion to the
allylic iodide completes the construction of 3a containing the
cyclic ethylene acetal.
In view of our need to confirm the stereochemical assignment
of the newly generated C11 stereocenter, triol 11b was converted
to the diastereomerically pure acetonide 11d in 65% yield
(Scheme 4). At this juncture, the stereochemistry of the
allylsilane-aldehyde condensation reaction was determined. The
problems with the different reducing agents that were employed.
Attempts to open the lactone using both DIBAL-H and LiAlH4/
AlCl3 repeatedly gave mixtures of unidentifiable products
including desilylated materials at a variety of temperatures (-78
°C f room temperature (rt)). Lithium trialkoxyaluminum
hydrides provided only starting lactone even with gentle
warming. Reduction with LiAlH4/TMEDA proved to be the
most successful at providing 11a as the major product. Two
side products have been isolated from this reaction and fully
characterized. They have been identified as triol 11b and furan
10d as shown in Scheme 3. We tentatively conclude that the
oxocarbenium ion 10c is one of the intermediates leading to
furan formation. In an effort to optimize the reaction conditions
for the LiAlH4 reduction of 10a, four different sets of reaction

4126 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Masse et al.
Table 1. Lithium Aluminum Hydride Reduction of the Lactone
Scheme 5
10aa
temp % yieldb % yieldb % yieldb
entry
solvent
Et2O
Et2O/5 equiv of
(°C)
of 11a
of 11b
of 10d
1
2
-15
10
50
10
15
45
30
0
TMEDA
Et2O/20 equiV of
TMEDA
3
4
0
70
20
10
Et2O
24
15
35
40
a Two equivalents of LiAlH4 were used for all reactions. b All yields
are based on pure materials isolated by chromatography on SiO2.
Scheme 4
Scheme 6
13C NMR method for the stereochemical identification of 1,3-
diols relies on the conformational properties of the derived 1,3-
diol acetonides and has been developed and utilized by
matic substitution pattern was chosen for its synthon equivalency
and ease of conversion to the amido-benzoquinone system of
mycotrienol. On the basis of literature precedent,17 we chose
to employ the six-membered cyclic dithioacetal 4a as the
precursor nucleophile. The three-step synthesis of 4a (Scheme
5) begins with the boron trifluoride etherate (BF3‚OEt2)-
promoted thioacetal formation with 1,3-propanedithiol from the
known 2,5-dimethoxy-3-nitrobenzaldehyde16 to give the cyclic
1,3-dithiane 13 in good yield. The coupling reaction with allylic
iodide 3a would require the use of a strong base and precludes
the presence of the nitro functionality, which was therefore
reduced to the corresponding amine 14 via SnCl2‚2H2O in
EtOAc at 70 °C.18 The final step in the construction of this
synthon was the protection of the arylamine as a 2,5-dimeth-
ylpyrrole,19 which was accomplished by refluxing 14 with excess
2,4-hexadione and a catalytic amount of acetic acid in toluene.
This sequence provided the functionalized aromatic subunit 4a
in 68% overall yield.
Initial Coupling Strategy for the C9-C16 and Aromatic
Fragments. With the allylic iodide 3a and aromatic synthon
4a available, the two subunits were assembled according to the
alkylation procedure outlined in Scheme 6.20 The coupling
procedure consisted of low-temperature deprotonation of the
dithioacetal 4a with nBuLi to form the lithiodithiane anion which
was alkylated with allylic iodide 3a. The coupling reaction
proceeded cleanly at -78 °C in 1.5 h to give the desired
dithioketal in 80% yield. The dithioketal was then cleaved by
treatment with a 50% slurry of W-7 Raney nickel in ethanol
under a hydrogen atmosphere, giving rise to the coupling product
Rychnovsky and Evans research groups.13 The C(2)-acetal 13
C
chemical shift of compound 11d was 101.1 ppm, and the
chemical shifts of the two acetonide methyl groups were
observed to be 24.6 and 24.0 ppm, in excellent agreement with
the values commonly observed for an anti-1,3-diol acetonide.
No resonances were observed in the regions expected for a syn-
1,3-diol acetonide. The stereochemical correlation is only
reliable where the syn- and anti-1,3-diol acetonides adopt
different conformations. Virtually any syn acetonide will adopt
a chair conformation,14 but the anti acetonide will only adopt
the twist-boat conformation when the chair conformation is
strongly destabilized. When R1 and R2 are large (e.g., R1, R2
) CH2R) the 1,3-diaxial interaction with the appropriate C(2)-
methyl destabilizes both of the possible chair conformations and
forces the acetonide to adopt a twist-boat conformation.15
Synthesis of the Aromatic Core. The design of the aromatic
core was centered around generating an intermediate that would
couple with the C9-C16 fragment while maintaining adequate
functionalization for its conversion to the amido-quinone. To
implement this idea, the primary allylic iodide of C9-C16
synthon was installed with the intention of displacing it with a
strong nucleophile, thus effecting a useful one-step alkylation
procedure. The aromatic core was constructed from 2,5-
dimethoxy-3-nitrobenzaldehyde (12)16 (Scheme 5). This aro-
(13) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945-948.
(14) Anteunis, M. J. O.; Tavernier, D.; Borremans, F. Heterocycles 1976,
4, 2931-2971.
(17) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231-237.
(18) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-842.
(19) Bruekelman, S. P.; Leach, S. E.; Mealkins, G. D.; Tirel, M. D. J.
Chem. Soc., Perkins Trans. 1 1984, 2801-2805.
(15) Pihlaja, K.; Nurmi, T. Isr. J. Chem. 1980, 20, 160-167.
(16) For the preparation of 12 as well as its conversion to the quinone
core, see: Panek, J. S.; Xu, F. J. Am. Chem. Soc. 1995, 117, 10587-10588.
(20) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231-237.

Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4127
Scheme 7
Scheme 9
Scheme 8
Table 2. Unsuccessful Coupling Attempts with 1,3-Dithiane 17
deprotection
conditions
entry
solvent system
electrophile
3a
3a
resulta
15. The desulfurization proceeded cleanly with no apparent
reduction of the (Z)-olefin.
1
2
3
4
5
6
nBuLi/-78 °C THF
NR
NR
NR
NR
NR
NR
tBuLi/-78 °C THF
The next stage in the synthesis required the deprotection of
the dimethylpyrrole to expose the masked arylamine functional-
ity for further elaboration. This deprotection was attempted
using NH2OH‚HCl/KOH in aqueous ethanol according to
literature precedent.21 However, all attempts at this deprotection
provided only low yields (<10%) of the desired product. The
major side product involved deprotection and subsequent
elimination of the C11 TIPS silyl ether. At this point, it was
decided to elaborate the C1-C5 side chain at an earlier stage
by attaching this subunit to the aromatic core prior to coupling
with the C9-C16 fragment. A precedent for this type of bond
construction had been reported by Smith and co-workers relative
to the synthesis of the trienomycins A and F.22 The procedure
involved a Weinreb amidation of the precursor aniline aromatic
core with a γ-lactone containing the C3 stereogenic center. Thus,
aniline 14 was subjected to a Weinreb-type amidation23 with
lactone 16 and the resulting amido-alcohol protected as its TBS
ether (Scheme 7). Lactone (+)-16 was also readily prepared
using the crotylsilane methodology. Lactone (+)-16 has also
been prepared from D-malic acid in four steps;22 however, we
decided to outline a more concise and cost-effective scheme
where its absolute chirality is derived from the (E)-crotylsilane
reagents. Therefore, ozonolysis of silane (R)-6 and in situ
reduction of the derived silyl aldehyde afforded the â-silyl
lactone which was subjected to silyl to hydroxyl interconver-
sion24 and methylation25 to afford lactone (+)-16 (Scheme 8).
This Lewis acid-promoted lactone opening installed the C1-
C5 side chain bearing the C3 stereogenic center of the aromatic
core and eliminates the need for arylamine N-protection at any
stage of the synthesis.
nBuLi/-78 °C THF/10% HMPA 3a
nBuLi/-78 °C THF/10% DMPU 3a
nBuLi/-78 °C THF
nBuLi/-78 °C THF
allyl bromide
benzyl bromide
a NR ) starting materials recovered.
Scheme 10
of 17 in THF (-78 °C), followed by slow addition of 3a failed
to provide the required coupling product. Attempts to effect
t
the coupling with BuLi, additives such as 10% (v/v) HMPA/
DMPU, or other electrophiles (e.g., allylbromide, benzyl
bromide) provided none of the desired coupling product
(Scheme 9, Table 2).
At this point, we elected to investigate a more reactive and
reliable dianion precursor for the coupling procedure. This
involved replacement of the dithiane functionality with a phenyl
sulfone. The prior work of Smith and co-workers had estab-
lished that such benzylic sulfones could successfully alkylate
allylic halides.22
We next turned our attention to the critical union of the C9-
C16 iodide 3a with the newly elaborated aromatic core 17.
Unfortunately, slow addition of 2.2 equiv of nBuLi to a solution
Construction and Coupling of the Sulfone Aromatic Core.
The construction of the new aromatic core also originates from
2,5-dimethoxy-3-nitrobenzaldehyde (12) (Scheme 10). This
aromatic substitution pattern was chosen for its synthon
equivalency and ease of conversion to the amido-benzoquinone
system of (+)-mycotrienol. Borane reduction of the aldehyde,
conversion to the benzylic bromide, displacement with sodium
benzenesulfinate, and reduction of the nitro group furnished the
benzylic sulfone 18. Completion of subunit 4b was achieved
(21) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47-
65.
(22) Smith, A. B., III, Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem.
Soc. 1995, 117, 10777-10778.
(23) Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth. 1988, 6, 492-
495.
(24) (a) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. Chem. Soc., Perkin Trans. 1 1995, 317-321. (b) For a review, see:
Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1-64.
(25) Lardon, A.; Reichstein, T. HelV. Chim. Acta 1949, 32, 2003-2005.

4128 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Masse et al.
Scheme 11
Scheme 12
group. In fact, our expectation that the dimethyl acetal would
hydrolyze more readily was supported by a recent work from
the Danishefsky group.28 This protecting group change requires
only a minor modification in the synthesis of the C9-C16
subunit. In this modified scheme, aldehyde 8 is elaborated
through a similar sequence in which the aldehyde derived from
ozonolysis of the terminal olefin is treated with catalytic p-TsOH
in anhydrous methanol to furnish dimethyl acetal 9b (Scheme
12). In a sequence analogous to Scheme 3, cleavage of the
benzyl groups via hydrogenation and simultaneous cyclization
of the derived hydroxy acid gives the lactone which upon
elimination of the tertiary â-acetoxy group with DBU gave the
R,â-unsaturated lactone 10b. As described earlier, the lactone
was reductively opened using LiAlH4 to give the (Z)-olefinic
diol. Differentiation of the primary and secondary hydroxyl
groups as their TBS ethers and conversion to the allylic iodide
completed the construction of allylic iodide 3b.
Coupling of Allylic Iodide 3b and Aromatic Sulfone 4b:
Completion of the Total Synthesis of (+)-Mycotrienol.
Coupling of the final subunits was accomplished by deproto-
nation of sulfone 4b with LHMDS to generate a stable lithium
dianion which was efficiently alkylated at the benzylic position
by allylic iodide 3b (Scheme 13); reductive desulfonylation gave
adduct 21. At this stage, we chose to explore a “stitching
cyclization” to elaborate the (E,E,E)-triene of (+)-mycotrienin
I via a Stille-type protocol of a bis(vinyl iodide) and an
enedistannane. This type of macrocyclization technique had
been successfully utilized in the synthesis of both rapamycin29
and dynemicin.30 With the coupling product in hand, we
initiated construction of the key bis[(E,E)-vinyl iodide] (2b) for
macrocyclization. Selective deprotection of the primary TBS
ether was followed by a Parikh-Doering oxidation27 of the
derived primary alcohol to give the N-acyl hemiaminal.
Gratifyingly, the dimethyl acetal was readily hydrolyzed with
PPTS and wet acetone31 to give the aminal-aldehyde. Ho-
mologation of the resulting aldehyde using the Takai protocol32
furnished the bis[(E,E)-vinyl iodide] 22 as the key cyclization
substrate. An (E,E) ratio of >10:1 was established in this Takai
homologation on the basis of 1H NMR analysis of 22. This set
the stage for the crucial Stille-type “stitching” macrocyclization
of 22 with the missing two-carbon enedistannane 2333 (C6-
C7) to give the (E,E,E)-triene and completing the synthesis of
the fully functionalized macrolide of (+)-mycotrienol. Subse-
Table 3. Deprotection Attempts of Acetal 20
deprotection conditions
resulta
1. FeCl3‚SiO2, acetone/H2O (10:1)
2. cat. p-TsOH, THF/H2O (50:1)
3. LiBF4/2% wet CH3CN
4. PPTS wet acetone, reflux
5. H5IO6, dioxane/H2O (10:1)
6. DMSO/H2O, 145 °C
NRb
2° TIPS deprotection
NRb
NRb
silyl deprotection (1° and 2°)
decomposition of substrate
NRb
7. Dowex-X8, THF/H2O (1:1)
a Based on materials isolated from SiO2 chromatography. b Recovered
starting material.
by Weinreb-type amidation26 of the derived aniline with the
chiral lactone 16 and protection of the primary hydroxyl as its
TBS ether.
We then redirected our attention to the coupling of the C9-
C16 iodide 3a, with the sulfone aromatic core 4b. Deproto-
nation of the latter with LHMDS (2.2 equiv) at -78 °C
generated the stable lithium dianion which was efficiently
alkylated at the benzylic position by the allylic iodide 3a (1
equiv); reductive desulfonylation gave adduct 19 (Scheme 11).
Selective deprotection of the primary TBS ether of 19 with HF‚-
pyridine was followed by a Parikh-Doering oxidation27 of the
derived primary alcohol to give the N-acyl hemiaminal 20. We
next began to explore the hydrolysis of the ethylene acetal to
set the stage for the construction of the (E,E,E)-diene system.
However, numerous attempts to deprotect the ethylene acetal
under a variety of conditions (see Table 3) failed to provide
any of the requisite aldehyde as competing desilylation of the
secondary hydroxyl groups at C11 and C13 complicated the
acetal deprotection step. Due to the difficulties associated with
the selective deprotection of the ethylene acetal, we felt the need
to tune the reactivity of the acetal protecting group. We opted
to change the ethylene acetal to a more labile dimethyl acetal
in an effort to effect a more facile cleavage of the this protecting
(28) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D.-S.;
Sorensen, E. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1996, 35,
2801-2803.
(29) Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.;
Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419-4420.
(30) Shair, M. D.; Yoon, T.; Danishefsky, S. J. J. Org. Chem. 1994, 59,
3755-3757.
(31) Sterzycki, R. Synthesis 1979, 724-725.
(26) Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth. 1988, 6, 492-
(32) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
495.
(27) Parikh, J. P.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
(33) For the preparation of enedistannane 23, see: Corey, E. J.;
Wollenberg, R. H. J. Am. Chem. Soc. 1974, 96, 5581-5583.

Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4129
Scheme 13
Scheme 14
class of compounds as well as other potentially biologically
active analogues via one centralized intermediate.
Experimental Section
quent oxidation of the aromatic core with ceric ammonium
nitrate (CAN) and removal of the silicon protecting groups with
aqueous HF furnished synthetic (+)-mycotrienol (1d).
Pyruvate Aldehyde Dibenzyl Acetal (5). To a flask containing
pyruvate aldehyde dimethyl acetal (10 g, 84.7 mmol) were added benzyl
alcohol (20.1 g, 186 mmol, 2.2 equiv) and p-toluenesulfonic acid (380
mg, 4.2 mmol, 0.05 equiv) without solvent. The mixture was heated
to 80 °C with stirring in an open flask. Over a 20-h period, the
methanol generated was allowed to evaporate into the fume hood. After
the reaction was complete, the flask was cooled and the crude oil subject
to purification on SiO2 (2.5 f 5% EtOAc/PE) to afford 5 as a light
yellow oil (12.6 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.35-7.30
(m, 10H), 4.72 (s, 1H), 4.68 and 4.63 (ABq, 4H, JAB ) 11.8 Hz), 2.24
(s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 136.8, 128.4, 127.9, 100.8,
69.1, 24.9; IR (neat) νmax 3400, 3000, 2850, 1760, 1450, 1350; CIHRMS
Total Synthesis of (+)-Mycotrienin I. The completion of
(+)-mycotrienin would ideally involve selective deprotection
of the C11 TIPS group of 24 followed by acylation of the C11
hydroxy with the cyclohexylcarbonyl-δ-alanine ester functional-
ity. During the course of the selective deprotection studies for
ethylene acetal 20, we had discovered that the use of cat.
p-TsOH in methanol cleanly afforded selective deprotection of
the secondary TIPS group on C11 without deprotection of the
C13 secondary TBS group (entry 2, Table 2). Gratifyingly,
exposure of the (E,E,E)-triene to these conditions effected
selective deprotection of the C11 TIPS group as expected.
Installation of the amino acid side chain according to literature
precedent34 and desilylation gave (+)-mycotrienin I (1c)
(Scheme 14). Both 1c,d were identical in all respects with the
corresponding natural products (1H and 13C NMR, IR, HRMS,
optical rotation, and TLC in two solvent systems).5
+
M + NH4 (calcd for C17H22NO) 288.1600, found 288.1600.
(3E,5R,6R)-Methyl-6-(benzyloxy)-5-methyl-7-oxo-3-octenoate (7).
A solution of 5 (6.00 g, 22.9 mmol) in 23 mL of CH2Cl2 (1.0 M) was
cooled to -78 °C and treated with TMSOTf (1.30 mL, 6.87 mmol,
0.30 equiv). The light yellow solution was stirred for 5 min and then
treated with a solution of (S)-6 (6.20 g, 22.9 mmol) in CH2Cl2 (1.0
M). The temperature of the reaction mixture was increased from -78
to -35 °C over a 3-h period. The reaction was then stirred for an
additional 20 h at -35 °C and subsequently diluted with saturated
NaHCO3 and warmed to rt with stirring. The reaction mixture was
extracted with CH2Cl2 (2 × 25 mL), dried (MgSO4), and concentrated
in vacuo. Purification on SiO2 (10% EtOAc/PE) afforded 7 as a light
yellow oil (80%, 5.3 g): 1H NMR (400 MHz, CDCl3) δ 7.75-7.26
(m, 5H), 5.57-5.53 (m, 1H), 5.43 (dd, 1H, J ) 7.6, 11.7 Hz), 4.55
and 4.37 (ABq, 2H, JAB ) 11.7 Hz), 3.64 (s, 3H), 3.54 (d, 1H, J ) 6.7
Hz), 2.99 (d, 2H, J ) 6.8 Hz), 2.58-2.55 (m, 1H), 2.12 (s, 3H), 1.02
(d, 3H, J ) 6.9 Hz); 13C NMR (67.5 MHz, CDCl3) δ 172.1, 137.3,
134.8, 128.4, 127.9, 127.8, 88.8, 72.9, 51.8, 39.7, 37.8, 37.7, 26.2, 15.9;
Conclusion
The asymmetric synthesis of (+)-mycotrienol has been
achieved in 32 steps with an overall yield of 3%. The synthesis
of (+)-mycotrienin I was achieved in 35 steps with an overall
yield of 1.5%. The synthesis plan is noteworthy in that all four
resident stereogenic centers were established through the
crotylsilane-based bond constructions whereas previous efforts
have relied on enolate-based methods and the chiral pool.
Additionally, the final macrocyclization was achieved through
a tandem Stille coupling procedure affording the macrocycle
with a configurationally pure (E,E,E)-triene. The synthetic plan
presented here allows access to the remaining members of this
+
IR (neat) νmax 2900, 1730, 1500, 1450, 1300, 900; CIHRMS M + NH4
(calcd for C17H26NO4) 308.1900, found 308.1900; [R]23D ) +21.4° (c
0.90, CH2Cl2).
(5R,4R,5S,6E)-Benzyl 3-Acetoxy-4-(benzyloxy)-3,5-dimethyl-8-
(methoxycarbonyl)-6-nonenoate. To a solution of HMDS (9.4 mL,
48.48 mmol, 1.2 equiv) in 80 mL of dry THF (0.5 M) at 0 °C was
added dropwise a solution of nBuLi (2.5 M in hexanes, 19.4 mL, 48.48
(34) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.; Omura,
S.; Komiyama, K. Tetrahedron Lett. 1991, 32, 1627-1630.

4130 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Masse et al.
mmol, 1.2 equiv). The reaction was stirred for 30 min at 0 °C then
cooled to -78 °C. To the reaction mixture at -78 °C was added benzyl
acetate (46.4 mL, 44.44 mmol, 1.1 equiv), and the reaction mixture
was stirred for 30 min at -78 °C, after which time a solution of 7 in
THF (12 mL, 1.0 M) was added. The reaction mixture was stirred for
1.0 h at -78 °C and subsequently diluted with saturated NH4Cl and
stirred to rt. The reaction mixture was extracted with Et2O (3 × 25
mL), dried (MgSO4), and concentrated in vacuo, leaving the crude
alcohol which was immediately dissolved in 40 mL of dry CH2Cl2 (1.0
M). In a separate flask, catalytic DMAP (2.5 g, 20.2 mmol, 0.5 equiv)
was dissolved in 40 mL of dry CH2Cl2 and cooled to 0 °C. To the
cooled DMAP solution was added triethylamine (45.3 mL, 0.32 mol,
8.0 equiv) and Ac2O (22.9 mL, 0.24 mol, 6.0 equiv), and the bright
yellow reaction mixture was stirred for 5 min, after which time the
solution of the crude alcohol was added via syringe over an 1-h period.
The reaction mixture was stirred for 48 h at 0 °C and subsequently
diluted with NaHCO3 and warmed to rt with stirring. The reaction
mixture was extracted with CH2Cl2 (3 × 25 mL), and the organic
extracts were washed with 5% HCl. The organic layer was dried
(MgSO4) and concentrated in vacuo to afford the crude acetate.
Purification on SiO2 (7.5% EtOAc/PE) afforded the tertiary acetate as
a light yellow oil (80%, two steps, 15.5 g): 1H NMR (400 MHz, CDCl3)
δ 7.33-7.26 (m, 10H), 5.56-5.51 (m, 2H), 5.04 (d, 2H, J ) 2.4 Hz),
4.57 (d, 2H, J ) 4.0 Hz), 3.91 (d, 1H, J ) 5.3 Hz), 3.66 (s, 3H), 3.21
and 3.09 (ABq, 2H, JAB ) 5.9 Hz), 3.01 (d, 2H, J ) 6.3 Hz), 2.62-
(3R,4R,5R,6S)-Benzyl 3-Acetoxy-4-(benzyloxy)-3,5-dimethyl-6-
(triisopropylsiloxy)-8-oxooctanoate. A dilute solution of the above
silyl ether (11.1 g, 18.1 mmol) in a 1:1 mixture of methanol/methylene
chloride (180 mL, 0.1 M) was treated with 5 drops of pyridine to reduce
acidity. The solution was then cooled to -78 °C. Ozone was bubbled
through the homogeneous solution until a blue color persisted. The
solution was then purged with argon to remove any excess ozone. The
ozonide was reduced with methyl sulfide (13.3 mL, 181 mmol, 10.0
equiv) and gradually warmed to rt over a 12-h period. The reaction
mixture was concentrated in vacuo to afford the crude aldehyde.
Purification on SiO2 (10% EtOAc/PE) afforded the aldehyde as a
colorless oil (100%, 11.1 g): 1H NMR (400 MHz, CDCl3) δ 9.76 (s,
1H), 7.34-7.24 (m, 10H), 5.07 and 5.03 (ABq, 2H, JAB ) 12.2 Hz),
4.67 and 4.57 (ABq, 2H, JAB ) 11.6 Hz), 4.44 (m, 1H), 3.84 (d, 1H,
J ) 3.3 Hz), 3.28 and 3.05 (ABq, 2H, JAB ) 14.8 Hz), 2.66-2.61 (m,
2H) 2.19-2.18 (m, 1H), 1.82 (s, 3H), 1.53 (s, 3H), 1.10 (d, 3H, J )
6.4 Hz), 1.06 (s, 18H), 1.03-0.98 (m, 3H); 13C NMR (67.5 MHz,
CDCl3) δ 201.5, 170.2, 170.1, 138.4, 128.5 (2), 128.3, 128.2, 127.3,
127.0, 84.2, 79.6, 73.9, 70.9, 66.2, 48.1, 39.6, 39.2, 22.1, 19.9, 18.2,
18.1, 12.7, 11.3; IR (neat) νmax 2900, 2780, 1750, 1480, 1380; CIHRMS
M + NH4+ (calcd for C35H55NSiO7) 629.3790, found 629.3800; [R]23
D
) -8.90° (c 0.55, CH2Cl2).
(3R,4R,5R,6S)-3-Acetoxy-4-(benzyloxy)-3,5-dimethyl-6-(triisopro-
pylsiloxy)-8-(dimethoxy)-octan-4-olide. A dilute solution of 9b (11.0
g, 17.5 mmol) in anhydrous EtOH (350 mL, 0.05 M) was treated with
10% Pd-C (2.3 g, 20 wt %) and catalytic trifluoroacetic acid (3 drops).
The suspension was stirred under 1 atm of hydrogen for 24 h. The
resulting suspension was filtered through Celite, washed with EtOH,
and concentrated in vacuo. Purification on SiO2 (20 f 30% EtOAc/
PE) afforded the lactone as a colorless oil (98%, 8.6 g): 1H NMR (400
MHz, CDCl3) δ 4.62 (dd, 1H, J ) 3.2, 3.6 Hz), 4.53 (d, 1H, J ) 3.6
Hz), 4.09-4.05 (m, 1H), 3.30 (s, 3H), 3.29 (s, 3H), 2.91 and 2.81 (ABq,
2H, JAB ) 17.6 Hz), 2.19 (m, 1H), 2.02 (s, 3H), 1.86-1.61 (m, 2H),
1.60 (s, 3H), 1.07 (s, 18H), 1.06-1.03 (m, 3H), 0.96 (d, 3H, J ) 6.8
Hz); 13C NMR (67.5 MHz, CDCl3) δ 173.5, 170.0, 102.0, 86.4, 83.6,
71.5, 53.0, 52.2, 42.7, 39.4, 35.6, 21.6, 18.9, 18.2, 12.9, 8.20; IR (neat)
νmax 2945, 2894, 2868, 1792, 1744, 1464; CIHRMS M + H+ (calcd
2.60 (m, 1H), 1.82 (s, 3H), 1.51 (s, 3H), 1.29 (d, 3H, J ) 3.9 Hz); 13
C
NMR (67.5 MHz, CDCl3) δ 172.1, 170.3, 170.1, 139.0, 135.8, 128.4,
128.3, 128.2, 128.1, 127.5, 127.4, 120.1, 83.7, 74.7, 66.1, 51.7, 39.9,
38.0, 37.8, 37.7, 22.0, 16.5; IR (neat) νmax 2900, 1720, 1440, 1360,
+
1250, 1140, 1100; CIHRMS M + NH4 (calcd for C28H37NO7)
499.2600, found 499.2590; [R]23 ) -8.80° (c 0.95, CH2Cl2).
D
(3R,4R,5S)-Benzyl 3-Acetoxy-4-(benzyloxy)-3,5-dimethyl-6-oxo-
hexanoate (8). A dilute solution of the tertiary acetate (11.09 g, 23.0
mmol) in a 1:1 mixture of methanol/methylene chloride (0.1 M, 230
mL) was treated with 5 drops of pyridine to reduce acidity. The solution
was then cooled to -78 °C. Ozone was bubbled through the
homogeneous solution until a blue color persisted. The solution was
then purged with argon to remove any excess ozone. The ozonide
was reduced with methyl sulfide (17 mL, 230 mmol, 10.0 equiv) and
gradually warmed to rt over a 12-h period. The reaction mixture was
concentrated in vacuo to afford the crude aldehyde. Purification on
SiO2 (15% EtOAc/PE) afforded 8 as a colorless oil (88%, 8.3 g): 1H
NMR (400 MHz, CDCl3) δ 9.51 (d, 1H, J ) 2.76 Hz), 7.33-7.23 (m,
10H), 5.12 and 5.06 (ABq, 2H, JAB ) 3.6 Hz), 4.58 and 4.56 (ABq,
2H, J ) 3.6 Hz), 4.29 (d, 1H, J ) 6.1 Hz), 3.31 and 3.04 (ABq, 2H,
JAB ) 14.7 Hz), 2.72-2.65 (m, 1H), 1.79 (s, 3H), 1.51 (s, 3H), 1.20
(d, 3H, J ) 7.12 Hz); 13C NMR (67.5 MHz, CDCl3) δ 202.0, 169.7,
169.6, 137.5, 135.6, 128.5, 128.4, 128.3(2), 127.8, 127.4, 82.6, 78.6,
74.4, 48.8, 34.7, 21.8, 20.1, 10.4; IR (neat) νmax 3400, 1710, 1450,
1370, 1240, 1150, 1090; CIHRMS M+ (calcd for C24H29O6): 413.1980,
for C23H45SiO7) 461.2935, found 461.2952; [R]23 ) +2.81° (c 0.89,
D
CHCl3).
(2Z,4R,5R,6S)-3,5-Dimethyl-6-(triisopropylsiloxy)-8-(ethylene-
oxy)octen-4-olide (10a). The procedure is the same as that for 10b
below and afforded 10a as a colorless oil (94%, 1.7 g): 1H NMR (400
MHz, CDCl3) δ 5.78 (s, 1H), 5.12 (s, 1H), 5.077 (t, 1H, J ) 5.3 Hz),
4.09-4.06 (m, 1H), 3.92-3.78 (m, 5H), 2.07-2.01 (m, 2H), 1.97 (s,
3H), 1.88-1.83 (m, 1H), 1.04 (s, 18H), 1.04-0.99 (m, 3H), 0.62 (d,
3H, J ) 7.0 Hz); 13C NMR (67.5 MHz, CDCl3) δ 173.5, 168.3, 117.4,
101.7, 84.5, 71.6, 64.9, 64.2, 40.1, 38.1, 18.1, 18.0, 13.8, 12.8, 6.60;
IR (neat) νmax 2950, 2870, 1760, 1470, 1380; CIHRMS M+ (calcd for
C37H59NSiO8) 399.2500, found 399.2524; [R]23D ) +14.3° (c 0.40, CH2-
Cl2).
(2Z,4R,5R,6S)-3,5-Dimethyl-6-(triisopropylsiloxy)-8,8-dimethoxy-
octen-4-olide (10b). A solution of the above lactone (4.8 g, 9.60 mmol)
in 96 mL of THF (0.1 M) was cooled to -78 °C and treated with
DBU (1.32 mL, 9.60 mmol, 1.0 equiv). The resulting solution was
stirred at 0 °C for 30 min and subsequently diluted with H2O (100
mL). The reaction mixture was extracted with Et2O (3 × 25 mL),
dried (MgSO4) and concentrated in vacuo. Purification on SiO2 (20%
EtOAc/PE) afforded 10b as a colorless oil (95%, 4.1 g): 1H NMR (400
MHz, CDCl3) δ 5.82 (s, 1H), 5.07 (s, 1H), 4.67 (t, 1H, J ) 4.8 Hz),
4.08-4.06 (m, 1H), 3.30 (s, 3H), 3.28 (s, 3H), 2.07-2.02 (m, 1H),
2.00 (s, 3H), 1.83-1.78 (m, 2H), 1.08 (s, 18H), 1.06-0.99 (m, 3H),
0.65 (d, 3H, J ) 7.2 Hz); 13C NMR (67.5 MHz, CDCl3) δ 173.5, 167.9,
117.6, 101.5, 84.8, 72.1, 52.7, 51.9, 40.5, 36.7, 18.2, 13.8, 13.0, 12.9,
found: 413.2000; [R]23 ) +1.50° (c 0.65, CH2Cl2).
D
(3R,4R,5S,6S)-Benzyl 3-Acetoxy-4-(benzyloxy)-3,5-dimethyl-6-
hydroxy-8-nonenoate. To a stirred solution of 8 (8.3 g, 20.2 mmol)
in 100 mL of CH2Cl2 (0.2 M) at -78 °C was added dropwise freshly
distilled TiCl4 (2.7 mL, 24.24 mol, 1.2 equiv). The reaction mixture
was stirred for 5 min at -78 °C followed by addition of allyltrimeth-
ylsilane (4.2 mL, 26.2 mmol, 1.3 equiv) in one portion. The reaction
was stirred for 16 h at -78 °C before dilution with H2O (100 mL) and
warmed to rt with stirring. The reaction mixture was extracted with
CH2Cl2 (3 × 25 mL), dried (MgSO4), and concentrated in vacuo.
Purification on SiO2 (15 f 20% EtOAc/PE) afforded the homoallylic
alcohol as a colorless oil (90%, 8.2 g): 1H NMR (400 MHz, CDCl3)
δ 7.32-7.28 (m, 10H), 5.83-5.79 (m, 1H), 5.19-5.05 (m, 2H), 5.04
(s, 2H), 4.72 and 4.59 (ABq, 2H, JAB ) 11.4 Hz), 4.26 (s, 1H), 3.46-
3.40 (m, 1H), 3.18 (s, 2H), 2.39-2.16 (m, 1H) 2.16-2.10 (m, 1H),
1.92 (t, 1H, J ) 6.8 Hz), 1.87 (s, 3H), 1.54 (s, 3H), 1.03 (d, 3H, J )
6.1 Hz); 13C NMR (67.5 MHz, CDCl3) δ 170.3, 170.1, 138.7, 135.7,
134.8, 128.4, 128.3, 128.2, 128.1, 127.4, 127.3, 118.3, 84.1, 79.0, 74.0,
73.7, 66.1, 39.6, 39.5, 38.7, 22.1, 20.2, 12.4; IR (neat) νmax 3400, 2800,
6.17; IR (neat) νmax 2944, 2868, 1763, 1646, 1385; CIHRMS M +
NH4 (calcd for C21H44NSiO5) 418.2990, found 418.3020; [R]23
+9.60° (c 1.34, CHCl3).
)
+
D
(3S,4R,5R,6Z)-4,6-Dimethyl-5,8-dihydroxy-3-(triisopropylsiloxy)-
6-octenal 1,2-Ethanediol Acetal (11a). Lithium aluminum hydride
(0.14 g, 3.77 mmol, 2.5 equiv) was added to a stirred solution of
N,N,N′,N′-tetramethylethylenediamine (TMEDA; 4.6 mL, 30.2 mmol,
20 equiv) in anhydrous Et2O (8 mL, 0.2 M) at 0 °C. This solution
+
1700, 1450, 1380, 1200; CIHRMS M + NH4 (calcd for C27H37NO6)
471.2600, found 471.2490; [R]23 ) -4.30° (c 1.50, CH2Cl2).
D

Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4131
was stirred for 3 min followed by the addition of a solution of 10a
(0.67 g, 1.51 mmol) in Et2O (3 mL, 0.5 M). The mixture was stirred
for 1 h at 0 °C and subsequently quenched with a quantitative amount
of H2O (0.14 mL), 15% NaOH (0.14 mL), and additional H2O (0.42
mL). The resulting suspension was filtered through Celite and
concentrated in vacuo. Purification on SiO2 (40% EtOAc/PE) afforded
11a as a colorless oil (50%, 0.34 g): 1H NMR (400 MHz, CDCl3) δ
5.60 (t, 1H, J ) 7.4 Hz), 4.86 (dd, 1H, J1 ) 3.8 Hz, J2 ) 6.2 Hz), 4.81
(t, 1H, J ) 4.9 Hz), 4.57 (d, 1H, J ) 5.4 Hz), 4.28-4.08 (m, 3H),
3.99-3.61 (m, 5H), 2.59-1.76 (m, 3H), 1.70 (s, 3H), 1.05 (s, 18H),
0.98 (d, 3H, J ) 6.7 Hz), 1.04-0.96 (m, 3H); 13C NMR (67.5 MHz,
CDCl3) δ 139.2, 127.4, 102.2, 73.1, 72.7, 64.7, 58.2, 38.2, 20.2, 18.1,
12.7, 11.1; IR (neat) νmax 3450, 2950, 2880, 1800, 1500, 1420; CIHRMS
3(R)-(Dimethylphenylsilyl)butanolide. A solution of (R)-6 (0.5 g,
1.91 mmol) in MeOH (19 mL, 0.1 M) was cooled to -78 °C. Ozone
was bubbled through the homogeneous solution until a blue color
persisted. The solution was then purged with argon to remove any
excess ozone. The reaction was treated with NaBH4 (0.072 g, 1.91
mmol, 1.0 equiv) and gradually warmed to rt over a 12-h period. The
reaction mixture was concentrated in vacuo to afford the crude â-silyl
lactone. Purification on SiO2 (20% EtOAc/PE) afforded the â-silyl
lactone as a colorless oil (100%, 0.42 g): 1H NMR (400 MHz, CDCl3)
δ 7.46-7.36 (m, 5H), 4.40 (t, 1H, J ) 9.2 Hz), 4.09 (dd, 1H, J ) 9.2
Hz), 2.49 (dd, 1H, J ) 8.8, 8.4 Hz), 2.27 (dd, 1H, J ) 12.8 Hz), 2.09-
2.00 (m, 1H), 0.35 (s, 3H), 0.34 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
δ 178.0, 135.1, 133.6, 129.9, 128.2, 70.8, 30.3, 23.8, -4.85, -5.13;
+
M
+ (calcd for C21H43SiO5) 403.2800, found 403.2820; [r]23D ) -9.8°
IR (neat) νmax 3022, 2957, 2900, 1773, 1646; CIHRMS M + NH4
(c 0.50, CH2Cl2).
(calcd for C12H20NSiO2) 238.1263, found 238.1295; [R]23 ) +5.65°
D
(c 1.77, CHCl3).
(3S,4R,5R,6Z)-4,6-Dimethyl-5,8-dihydroxy-3-(triisopropylsiloxy)-
6-octenal Dimethyl Acetal. Lithium aluminum hydride (0.75 g, 19.83
mmol, 2.5 equiv) was added to a stirred solution of N,N,N′,N′-
tetramethylethylenediamine (TMEDA; 24 mL, 158.6 mmol, 20 equiv)
in anhydrous Et2O (40 mL, 0.2 M) at 0 °C. This solution was stirred
for 3 min followed by the addition of a solution of 10b (3.5 g, 7.93
mmol) in Et2O (20 mL, 0.5 M). The mixture was stirred for 1 h at 0
°C and subsequently quenched with a quantitative amount of H2O (0.75
mL), 15% NaOH (0.75 mL), and additional H2O (2.25 mL). The
resulting suspension was filtered through Celite and concentrated in
vacuo. Purification on SiO2 (40% EtOAc/PE) afforded the diol as a
colorless oil (70%, 2.5 g): 1H NMR (400 MHz, CDCl3) δ 5.60 (t, 1H,
J ) 7.2 Hz), 4.48-4.45 (m, 2H), 3.99-3.96 (m, 3H), 3.64 (s, br, 1H),
3.30 (s, 3H), 3.29 (s, 3H), 3.28 (s, br, 1H), 1.92-1.73 (m, 3H), 1.71
(s, 3H), 1.06 (s, 18H), 1.05-1.00 (m, 3H), 0.99 (d, 3H, J ) 6.4 Hz);
13C NMR (67.5 MHz, CDCl3) δ 138.8, 127.7, 102.6, 74.8, 72.5, 58.1,
54.1, 52.4, 40.6, 37.3, 19.8, 18.2, 12.8, 10.9; IR (neat) νmax 3416, 2972,
2869, 2076, 1653; CIHRMS M+ (calcd for C21H44SiO5) 404.2958, found
3(R)-Hydroxybutanolide. A solution of the â-silyl lactone in acetic
acid (1.0 mL, 2 M) was treated with mercuric acetate (0.91 g, 2.87
mmol, 1.5 equiv) followed by a catalytic amount of concentrated
sulfuric acid (1 drop). The resulting white suspension was warmed to
rt with stirring for 24 h and subsequently concentrated in vacuo. The
crude solid is then diluted with Et2O, stirred for 1 h, and filtered, and
the filtrate is concentrated in vacuo. Purification on SiO2 (30 f 50%
EtOAc/PE) afforded the â-hydroxy lactone as a colorless oil (50%,
0.10 g): 1H NMR (400 MHz, CDCl3) δ 4.66 (m, br, 1H), 4.39 (dd,
1H, J ) 4.8, 4.4 Hz), 4.27 (d, 1H, J ) 11.6 Hz), 2.92 (s, br, 1H), 2.72
(dd, 1H, J ) 6.0 Hz), 2.51 (d, 1H, J ) 18.8 Hz); 13C NMR (67.5
MHz, CDCl3) δ 176.5, 76.1, 67.5, 37.8; IR (neat) νmax 3412, 2934,
1773, 1653; CIHRMS M + H+ (calcd for C4H7NO3) 103.0425, found
103.0417; [R]23D ) +86.0° (c 2.0, EtOH); [R]23D (lit.35 +85.9° (c 2.2,
EtOH)
3(R)-Methoxybutanolide (16). A solution of the â-hydroxy lactone
(1.75 g, 17.16 mmol) was dissolved in MeI (30 mL, 0.5 M) and treated
with silver(I) oxide (3.98 g, 17.16 mmol, 1.0 equiv). The resulting
suspension was refluxed in the dark for 12 h and subsequently
concentrated in vacuo. The crude mixture was diluted with Et2O,
filtered through Celite, and concentrated in vacuo to afford a colorless
oil. Purification on SiO2 (20% EtOAc/PE) afforded 11 as a colorless
oil (70%, 1.4 g): 1H NMR (400 MHz, CDCl3) δ 4.32 (d, 2H, J ) 3.6
Hz), 4.14 (m, 1H), 3.30 (s, 3H), 2.66 (dd, 1H, J ) 6.0 Hz), 2.53 (dd,
1H, J ) 2.4 Hz); 13C NMR (67.5 MHz, CDCl3) δ 175.4, 75.9, 72.7,
56.5, 34.5; IR (neat) νmax 2937, 2833, 1779; CIHRMS M+H+ (calcd
404.2953; [R]23 ) -16.5° (c 1.76, CHCl3).
D
(3S,4R,5R,6Z)-4,6-Dimethyl-8-iodo-5-(tert-butyldimethylsiloxy)-
3-(triisopropylsiloxy)-6-octenal 1,2-Ethanediol Acetal (3a). The
intermediate allylic alcohol (0.040 g, 0.08 mmol) was dissolved in
anhydrous DMF (0.25 mL, 0.3 M) and cooled to 0 °C. The solution
was treated with methyltriphenoxyphosphonium iodide (0.053 g, 0.12
mmol, 1.5 equiv). The ice bath was removed, and the reaction was
allowed to warm to rt for 30 min and subsequently diluted with excess
H2O (5 mL). The reaction mixture was extracted with Et2O (3 × 10
mL), dried (MgSO4), and concentrated in vacuo. Purification on SiO2
(PE f 2% EtOAc/PE) afforded 3a as a colorless oil (82%, 0.040 g):
1H NMR (400 MHz, CDCl3) δ 5.59 (dd, 1H, J ) 6.8, 11.2 Hz), 4.92
(d, 1H, J ) 8.3 Hz), 4.03-3.74 (m, 7H), 1.92-1.75 (m, 2H), 1.35
(dd, 1H, J ) 8.3, 13.2 Hz), 1.05-1.02 (m, 3H), 1.02 (s, 18H), 0.96 (d,
3H, J ) 6.8 Hz), 0.87 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR
(67.5 MHz, CDCl3) δ 140.7, 124.8, 102.7, 69.2, 64.7, 37.3, 25.9, 18.2,
18.0, 12.8, 10.4, -4.40, -5.00; IR (neat) νmax 2940, 2900, 1850, 1500;
for C5H9O3) 117.0552, found 117.0570; [R]23 ) +34.2° (c 0.92,
D
CHCl3).
(3S,4R,5R,6Z)-9-[2,3-Dimethoxy-4-(2, 5-dimethylpyrrole)benzene]-
4,6-dimethyl-5-(tert-butyldimethylsiloxy)-3-(triisopropylsiloxy)-6-
nonenal 1,2-Ethanediol Acetal (15). A solution of 4a (0.060 g, 0.1
mmol) in THF (1 mL, 0.1 M) was cooled to -78 °C and treated with
nBuLi (60 µL, 0.1 mmol, 1.25 equiv) and stirred for 30 min to afford
a bright yellow colored solution. To the solution of the lithio anion at
-78 °C was added a solution of 3a (0.042 g, 0.08 mmol) in THF (1
mL, 0.08 M) in one portion. The yellow color disappeared immediately
and the reaction allowed to stir at -78 °C for 30 min and subsequently
diluted with a saturated NH4Cl solution (5 mL). The reaction mixture
was extracted with EtOAc (3 × 5 mL), dried (MgSO4), and concentrated
in vacuo to give the crude dithiane. The crude dithiane was immediately
dissolved in dry EtOH (4 mL, 0.01 M) and treated with W-7 Raney
nickel (3 mL of a 50% suspension in EtOH). The reaction was stirred
under a hydrogen atmosphere for 10 min and subsequently filtered
through SiO2 and the filtrate concentrated in vacuo. Purification on
SiO2 (5% EtOAc/PE) afforded 15 as a colorless oil (78%, secondeps,
0.030 g): 1H NMR (400 MHz, CDCl3) δ 6.77 (d, 1H, J ) 3.1 Hz),
6.53 (d, 1H, J ) 3.1 Hz), 5.89 (s, 2H),5.25-5.22 (m, 1H), 4.95 (d,
1H, J ) 8.1 Hz), 4.10-4.08 (m, 1H), 3.95-3.66 (m, 4H), 3.74 (s,
3H), 3.17 (s, 3H), 2.68-2.64 (m, 1H), 2.35-2.29 (m, 1H), 2.02 (s,
6H), 1.98-1.82 (m, 2H), 1.68 (s, 3H), 1.54-1.38 (m, 1H), 1.18-0.98
(m, 3H), 1.02 (s, 18H), 0.95 (d, 3H, J ) 6.7 Hz), 0.86 (s, 9H), 0.02 (s,
3H), -0.05 (s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 154.9, 148.4,
CIHRMS M+ (calcd for C27H46ISi2O4) 617.1900, found 617.1907; [R]23
) +62.0 (c 0.35, CH2Cl2).
D
(3S,4R,5R,6Z)-4,6-Dimethyl-8-iodo-5-(tert-butyldimethylsiloxy)-
3-(triisopropylsiloxy)-6-octenal Dimethyl Acetal (3b). A solution of
the primary allylic alcohol (0.13 g, 0.25 mmol) in anhydrous DMF
(0.3 mL, 1.0 M) was cooled to 0 °C and treated with methyltriph-
enoxyphosphonium iodide (0.70 g, 0.38 mmol, 1.5 equiv). The ice
bath was removed, and the reaction was allowed to warm to rt for 30
min and subsequently diluted with excess H2O (10 mL). The reaction
mixture was extracted with Et2O (3 × 15 mL), dried (MgSO4), and
concentrated in vacuo. Purification on SiO2 (PE f 2% EtOAc/PE)
afforded 3b as a colorless oil (82%, 0.13 g): 1H NMR (400 MHz,
CDCl3) δ 5.57 (dd, 1H, J ) 5.6, 4.4 Hz), 4.47 (dd, 1H, J ) 2.0 Hz),
4.00 (t, 1H, J ) 11.2 Hz), 3.74 (d, 1H, J ) 9.6 Hz), 3.30 (s, 3H), 3.29
(s, 3H), 1.90 (m, 2H), 1.70 (s, 3H), 1.67-1.44 (m, 3H), 1.19-1.00
(m, 3H), 1.02 (s, 18H), 0.96 (d, 3H, J ) 6.8 Hz), 0.87 (s, 9H), 0.05 (s,
3H), 0.04 (s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 140.7, 124.8, 103.3,
69.1, 54.5, 52.7, 36.7, 30.3, 29.7, 26.2, 25.9, 25.8, 18.1, 12.9, 12.6,
10.5, -4.34, -5.00; IR (neat) νmax 2945, 2866, 1729, 1649; CIHRMS
M+ (calcd for C27H57ISi2O4) 628.2840, found 628.2790; [R]23D ) +63.5
(c 0.95, CHCl3).
(35) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu,
S.; Moriwake, T. Chem. Lett. 1984, 1389-1391.

4132 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Masse et al.
137.0, 136.3, 131.4, 129.0, 128.8, 126.9, 115.6, 112.2, 105.7, 102.9,
76.5, 71.9, 71.8, 71.7, 69.2, 64.5, 64.4, 59.7, 59.6, 55.5, 43.9, 36.8,
30.4, 29.7, 29.2, 25.9, 25.8, 18.2, 18.1, 12.9, 12.7, 10.6, -4.70, -4.90;
IR (neat) νmax 2900, 2890, 1550., 1480; CIHRMS M+ (calcd for C42H74-
Si2NO6) 744.5100, found 744.5120; [R]23D ) -8.0° (c 0.15, CH2Cl2).
2,5-Dimethoxy-3-(3′(R)-methoxy-4-hydroxybutyramido)benzylphe-
nyl sulfone. A sealed flask was purged with argon and charged with
benzene (5 mL, 0.5 M) and Me3Al (1.4 mL, 2.80 mmol, 1.2 equiv) at
rt. To this mixture was added a solution of 18 (0.79 g, 2.56 mmol, 1.1
equiv) in benzene (5 mL, 0.5 M) and the reaction stirred at rt for 45
min at which point a solution of 16 (0.27 g, 2.33 mmol) in benzene (4
mL, 0.5 M) was added dropwise under stirring. The reaction was stirred
at rt for 2 h and subsequently diluted with 5% HCl. The reaction
mixture was extracted with EtOAc (2 × 25 mL), dried (MgSO4), and
concentrated in vacuo. Purification on SiO2 (50 f 100% EtOAc/PE)
afforded the hydroxy amide as a white solid (70%, 0.70 g): 1H NMR
(400 MHz, CDCl3) δ 8.25 (s, br, 1H), 7.85 (d, 1H, J ) 3.2 Hz), 7.65-
7.36 (m, 5H), 6.24 (d, 1H, J ) 3.2 Hz), 4.26 (s, 2H), 3.73-3.61 (m,
2H), 3.56 (s, 3H), 3.52-3.49 (m, 1H), 3.50 (s, 3H), 3.34 (s, 3H), 2.56-
2.53 (m, 2H), 2.20 (s, br, 1H); 13C NMR (67.5 MHz, CDCl3) δ 169.3,
155.8, 142.0, 138.4, 133.8, 132.3, 129.0, 128.6, 121.4, 111.2, 107.6,
78.3, 62.7, 61.8, 57.4, 56.5, 55.5, 39.8; IR (neat) νmax 3441, 2961, 1650,
1543, 1467; CIHRMS M + H+ (calcd for C20H26NSO7) 424.1430, found
(diastereomers, d, J ) 3.2, 2.8 Hz, 1H), 5.00, 4.91 (diastereomers,
apparent t, 1H), 4.55, 4.40 (diastereomers, dd, J ) 1.6 Hz, dd, J )
10.0 Hz, 1H), 3.85, 3.80, 3.76, 3.72 (diastereomers, s, s, s, s, 6H), 3.71-
3.57 (diastereomers, m, 4 H), 3.55 (s, 3H), 3.53 (s, 3H), 3.44, 3.43,
3.39, 3.38 (diastereomers, s, s, s, s, 6H), 2.65-2.49 (m, 4H), 1.86 (m,
2H), 1.55, 1.53 (diastereomers s, s, 3H), 1.11-1.08 (m, 3H), 1.03, 0.99
(diastereomers, s, s, 18H), 0.87 (d, 3H, J ) 1.6 Hz), 0.87, 0.86
(diastereomers, s, s, 9H), 0.81, 0.79 (diastereomers, s, s, 9H), 0.046,
0.039, 0.033, 0.020 (diastereomers, s, s, s, s, 6H), -0.060, -0.078,
-0.091, -0.010 (diastereomers, s, s, s, s, 6H) 13C NMR (67.5 MHz,
CDCl3) δ 169.8, 169.6, 169.5, 156.3, 156.1, 142.6, 142.1, 139.8, 139.7,
138.1, 138.0, 137.9, 137.6, 133.4, 133.3, 132.3, 132.2, 129.4, 128.3,
129.0, 128.8, 128.5, 126.4, 125.1, 122.0, 121.8, 120.9, 113.3, 108.7,
107.0, 106.8, 102.8, 102.7, 69.2, 68.8, 63.8, 62.6, 61.5, 61.4, 57.9, 57.7,
55.5, 54.5, 51.8, 44.1, 40.3, 40.2, 29.7, 27.3, 25.8, 25.7, 18.6, 18.5,
18.2, 18.1, 13.6, 13.4, 12.9, 12.8, 10.6, 10.5, -4.93; IR (neat) νmax
2955, 2865, 1614, 1465, 1423; CIHRMS M + H+ (calcd for C53H96-
NO11Si3S) 1038.6012, found 1038.6000; [R]23 ) -2.60° (c 1.13,
D
CHCl3).
Desulfonylated Arene (21). A mixture of sulfones (0.16 g, 0.15
mmol), Na2HPO4 (88 mg, 0.62 mmol, 4.1 equiv), and anhydrous MeOH
(3 mL, 0.05 M) was cooled to - 20 °C. Excess Na(Hg) (0.72 g, 4.5
wt equiv) was added to the mixture and the suspension stirred until
the starting material was consumed as indicated by TLC analysis (30
min). The crude reaction mixture was filtered through a short plug of
silica gel with EtOAc as the eluant, and the filtrate was concentrated
in vacuo. The residue was redissolved in EtOAc (25 mL), washed
with water and brine (2 × 25 mL each), dried (MgSO4), and
concentrated in vacuo. Purification on SiO2 (20% EtOAc/PE) afforded
14 as a single isomer: colorless oil (98%, 0.13 g); 1H NMR (400 MHz,
CDCl3) δ 8.64 (s, br, 1H), 7.80 (d, 1H, J ) 3.2 Hz), 6.38 (d, 1H, J )
2.8 Hz), 5.10 (t, 1H), 4.42 (dd, 1H, J ) 2.0 Hz), 4.00 (m, 1H), 3.72 (d,
1H, J ) 10.4 Hz), 3.66 (s, 3H), 3.65-3.57 (m, 4H), 3.58 (s, 3H), 3.42
(s, 3H), 3.13 (s, 3H), 3.10 (s, 3H), 2.57-2.48 (m, 5H) 2.27-2.25 (m,
2H), 1.57 (s, 3H), 1.54-1.51 (m, 1H), 0.93 (s, 18H), 0.95-0.88 (m,
3H), 0.86 (d, 3H, J ) 6.4 Hz), 0.79 (s, 9H), 0.76 (s, 9H), -0.039 (s,
3H), -0.044 (s, 3H), -0.084 (s, 3H), -0.093 (s, 3H); 13C NMR (67.5
MHz, CDCl3) δ 169.5, 156.0, 140.8, 136.6, 135.0, 132.2, 126.9, 110.3,
103.2, 102.9, 78.9, 71.7, 69.1, 63.8, 61.0, 57.7, 55.5, 53.8, 52.1, 44.1,
40.3, 35.9, 29.9, 29.6, 28.6, 25.8, 18.8, 18.4, 18.2, 13.4, 12.9, 10.7,
-4.76, -4.85, -4.98, -5.44; IR (neat) νmax 2930, 2865, 1691, 1531,
1464; CIHRMS M+ (calcd for C47H91NSi3O9) 897.6002, found 897.6009;
424.1511; [R]23 ) +6.0° (c 0.34, CHCl3).
D
Desulfonylated Arene (19). A solution of 4b (0.16 g, 0.30 mmol,
1.5 equiv) in THF (2.0 mL, 0.1 M) at -78 °C was treated dropwise
with lithium bis(trimethylsilyl) amide (0.5 M in THF, 1.3 mL, 0.66
mmol), and the resultant yellow solution was stirred for 20 min at -78
°C. A solution of iodide 3a (0.11 g, 0.20 mmol) in THF (1 mL, 0.2
M) was then added. The reaction mixture was stirred for 1 h at -78
°C and subsequently poured onto a 1:1 mixutre of Et2O/pH 7 buffer at
0 °C and warmed to rt with stirring. The reaction mixture was extracted
with Et2O (3 × 25 mL), dried (MgSO4), and concentrated in vacuo.
The crude 1:1 mixture of sulfones was used without further purification.
The mixture of sulfones (0.065 g, 0.07 mmol), Na2HPO4 (0.040 g, 0.28
mmol, 4.1 equiv), and anhydrous MeOH (1.5 mL, 0.05 M) was cooled
to - 20 °C. Excess Na(Hg) (0.29 g, 4.5 wt equiv) was added to the
mixture and the suspension stirred until the starting material was
consumed as indicated by TLC analysis (20 min). The crude reaction
mixture was filtered through a short plug of silica gel with EtOAc as
the eluant, and the filtrate was concentrated in vacuo. The residue
was redissolved in EtOAc (25 mL), washed with water and brine (2 ×
25 mL each), dried (MgSO4), and concentrated in vacuo. Purification
on SiO2 (20% EtOAc/PE) afforded 19 as a single isomer: colorless
oil (78%, two steps, 0.056 g): 1H NMR (400 MHz, CDCl3) δ 8.64 (s,
br, 1H), 7.85 (d, 1H, J ) 3.2 Hz), 6.42 (d, 1H, J ) 2.8 Hz), 5.20 (t,
1H), 4.92 (dd, 1H, J ) 2.0 Hz), 4.10 (m, 1H), 3.90 (d, 1H, J ) 10.4
Hz), 3.75 (s, 3H), 3.74-3.62 (m, 8H), 3.63 (s, 3H), 3.50 (s, 3H), 2.65-
2.55 (m, 5H) 2.38-2.22 (m, 2H), 1.68 (s, 3H), 1.40-1.30 (m, 1H),
1.00 (s, 18H), 0.95-0.88 (m, 3H), 0.92 (d, 3H, J ) 6.4 Hz), 0.90 (s,
9H), 0.82 (s, 9H), 0.050 (s, 3H), -0.004 (s, 3H), -0.084 (s, 3H),
-0.093 (s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 169.5, 156.0, 140.8,
136.6, 135.0, 132.2, 126.9, 110.3, 103.2, 102.9, 78.9, 71.7, 69.1, 65.0,
64.5, 63.8, 61.0, 57.7, 55.5, 53.8, 52.1, 44.1, 29.9, 29.6, 28.6, 25.8,
18.8, 18.4, 18.2, 13.4, 12.9, 10.7, -4.76, -4.85, -4.98, -5.44; IR
(neat) νmax 2930, 2865, 1691, 1531, 1464; CIHRMS M+ (calcd for
[R]23 ) -12.9° (c 2.28, CHCl3).
D
Hydroxy Arene. A solution of 21 (0.13 g, 0.15 mmol) in anhydrous
THF (1.5 mL, 0.1 M) at 0 °C was treated with a stock solution of
HF‚pyridine (4:1; 0.9 mL, 6.0 equiv). The reaction was stirred at rt
over a period of 3 h, at which time the reaction was diluted dropwise
with NaHCO3 and warmed to rt with stirring. The reaction mixture
was extracted with Et2O (3 × 25 mL), dried (MgSO4), and concentrated
in vacuo. Purification on SiO2 (50% EtOAc/PE) afforded the hydroxy
1
arene as a colorless oil (95%, 0.11 g): H NMR (400 MHz, CDCl3) δ
8.43 (s, br, 1H), 7.86 (d, 1H, J ) 3.2 Hz), 6.49 (d, 1H, J ) 2.4 Hz),
5.21 (t, 1H, J ) 16.8 Hz), 4.50 (d, 1H, J ) 6.8 Hz), 4.05 (m, 1H),
3.70 (d, 1H, J ) 10.4 Hz), 3.93-3.57 (m, 4H), 3.75 (s, 3H), 3.68 (s,
3H), 3.49 (s, 3H), 3.24 (s, 3H), 3.20 (s, 3H), 2.71-2.60 (m, 5H) 2.35
(d, 2H, J ) 6.4 Hz), 1.94 (s, br, 1H), 1.67 (s, 3H), 1.63-1.59 (m, 1H),
1.19-1.03 (m, 3H), 1.03 (s, 18H), 0.94 (d, 3H, J ) 6.8 Hz), 0.85 (s,
9H), 0.009 (s, 3H), -0.057 (s, 3H); 13C NMR (67.5 MHz, CDCl3) δ
169.1, 156.0, 140.8, 136.6, 135.1, 131.9, 126.9, 110.5, 103.3, 103.1,
78.4, 69.1, 62.9, 61.2, 57.5, 55.5, 53.8, 52.3, 39.8, 36.0, 29.6, 28.6,
25.9, 25.8, 18.4, 18.2, 18.1, 13.4, 12.9, 10.7, -4.75, -4.96; IR (neat)
νmax 3450, 2920, 2860, 1690, 1530, 1460; CIHRMS M+ (calculated
for C41H77NSi2O9) 783.5137, found 783.5130; [R]23D ) -22.5° (c 0.20,
CHCl3).
Lactam Aminal. A solution of the hydroxy arene (0.11 g, 0.14
mmol) in DMSO (3.0 mL, 0.05 M) was treated with triethylamine (1.0
mL, 7.19 mmol, 50.5 equiv) followed by pyridine‚SO3 (0.33 g, 2.10
mmol, 15 equiv). The resulting mixture was stirred for 45 min at rt
and subsequently diluted with excess H2O (20 mL) and brine (10 mL).
The reaction mixture was extracted with EtOAc (3 × 25 mL), dried
(MgSO4), and concentrated in vacuo. Purification on SiO2 (50 f 75%
C47H89NSi3O9) 895.5845, found 895.5840; [R]23 ) +2.81° (c 0.89,
D
CHCl3).
Coupled Sulfone. A solution of 4b (0.16 g, 0.29 mmol, 1.5 equiv)
in THF (2.0 mL, 0.1 M) at -78 °C was treated dropwise with lithium
bis(trimethylsilyl) amide (0.5 M in THF, 1.3 mL, 0.63 mmol) and the
resultant yellow solution was stirred for 20 min at -78 °C. A solution
of iodide 3b (0.12 g, 0.19 mmol) in THF (1 mL, 0.2 M) was then
added. The reaction mixture was stirred for 1 h at -78 °C and
subsequently poured onto a 1:1 mixutre of Et2O/pH 7 buffer at 0 °C
and warmed to rt with stirring. The reaction mixture was extracted
with Et2O (3 × 25 mL), dried (MgSO4), and concentrated in vacuo.
Purification on SiO2 (30% EtOAc/PE) afforded the coupled sulfone as
1
a 1:1 diastereomeric mixture: colorless oil (80%, 0.16 g); H NMR
(400 MHz, CDCl3) δ 8.54 (s, br, 1H), 8.02, 7.93 (diastereomers, d, J
) 3.2 Hz, 1H), 7.69 (d, 2H), 7.62-7.35 (complex m, 3H), 6.70, 6.62

Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4133
EtOAc/PE) afforded the lactam aminal as a light yellow oil (82%, 90
mg): 1H NMR (400 MHz, CDCl3) δ 6.71, 6.70 (diastereomers, d, J )
3.2 Hz, 1H), 6.63, 6.62 (diastereomers, d, J ) 2.8 Hz, 1 H), 5.38, 5.31
(diastereomers, d, J ) 2.0 Hz, 1H), 5.20 (t, 1H, J ) 6.4 Hz), 4.49 (dd,
1H, J ) 2.0 Hz), 4.38 (s, br, 1H), 3.87 (d, 1H, J ) 2.0 Hz), 3.80 (d,
1H, J ) 10.8 Hz), 3.74 (s, 3H), 3.65, 3.62 (diastereomers, s, s, 3H),
3.49, 3.43 (diastereomers, s, s, 3H), 3.26, 3.25 (diastereomers, s, s, 3
H), 3.24, 3.20 (diastereomers, s, s, 3H), 2.99 (dd, 1H, J ) 6.4, 6.0
Hz), 2.66-2.61 (m, 2H), 2.49 (d, 1H, J ) 17.2 Hz), 2.33 (s, br, 1H),
1.67, 1.64 (diastereomers, s, s, 3H), 1.42 (dd, 1H, J ) 8.8 Hz), 1.31-
1.26 (m, 4H), 1.04-0.95 (m, 3H), 1.03 (s, 18H), 0.93 (d, 3H, J ) 6.8
Hz), 0.86, 0.85 (diastereomers, s, s, 9H), 0.041, 0.007 (diastereomers,
s, s, 3H), -0.014, -0.053 (diastereomers, s, s, 3H); 13C NMR (67.5
MHz, CDCl3) δ 173.7, 156.3, 147.5, 137.3, 130.3, 126.7, 116.2, 112.1,
103.4, 89.0, 80.0, 69.0, 61.9, 56.9, 55.6, 52.9, 44.1, 36.1, 36.0, 29.9,
29.7, 29.0, 25.9, 25.8, 18.2, 14.1, 13.4, 12.9, 10.7, -4.73, -4.94; IR
(neat) νmax 3550, 2980, 2820, 1690, 1530, 1460; CIHRMS M+ (calcd
for C41H75NSi2O9) 781.4980, found 781.5000; [R]23D ) -20.0° (c 0.15,
CHCl3).
Aminal-Aldehyde. A solution of the lactam-aminal (90 mg, 0.11
mmol) in wet acetone (1.1 mL, 0.1 M) was treated with PPTS (14 mg,
0.06 mmol, 0.5 equiv). The reaction mixture was refluxed for 1 h
then cooled to rt and the mixture concentrated in vacuo. The residue
was redissolved in Et2O (25 mL), washed with NaHCO3 and brine (2
× 25 mL each), dried (MgSO4), and concentrated in vacuo. Purification
on SiO2 (40% EtOAc/PE) afforded the aldehyde as a colorless oil (90%,
73 mg): 1H NMR (400 MHz, CDCl3) δ 9.86 (m, 1H), 6.71, 6.70
(diastereomers, d, J ) 3.2 Hz, 1H), 6.62, 6.61 (diastereomers, d, J )
2.9 Hz, 1 H), 5.38, 5.31 (diastereomers, d, J ) 1.9 Hz, 1H), 5.21 (t,
1H, J ) 6.4 Hz), 4.49 (dd, 1H, J ) 2.0 Hz), 4.38 (s, 1H), 3.87 (d, 1H,
J ) 1.9 Hz), 3.80 (d, 1H, J ) 10.0 Hz), 3.74 (s, 3H), 3.65, 3.62
(diastereomers, s, s, 3H), 3.50, 3.43 (diastereomers, s, s, 3H), 2.99 (dd,
1H, J ) 6.4, 6.2 Hz), 2.66-2.60 (m, 2H), 2.50 (d, 1H, J ) 17.0 Hz),
2.33 (s, br, 1H), 1.67, 1.63 (diastereomers, s, s, 3H), 1.41 (dd, 1H, J )
8.6 Hz), 1.31-1.26 (m, 4H), 1.04-0.95 (m, 3H), 1.02 (s, 18H), 0.94
(d, 3H, J ) 6.8 Hz), 0.86, 0.85 (diastereomers, s, s, 9H), 0.041, 0.007
(diastereomers, s, s, 3H), -0.014, -0.052 (diastereomers, s, s, 3H);
13C NMR (67.5 MHz, CDCl3) δ 201.5, 173.8, 147.5, 137.3, 130.2,
126.8, 116.4, 112.0, 103.4, 89.0, 80.0, 69.1, 62.0, 52.9, 44.1, 36.1, 36.0,
29.9, 29.7, 29.0, 26.0, 25.8, 18.2, 14.1, 13.4, 12.9, 10.7, -4.70, -4.95;
IR (neat) νmax 3550, 2980, 2800, 1750, 1690, 1460; CIHRMS M+ (calcd
for C39H69NSi2O8) 735.4562, found 735.4560; [R]23D ) -33.0° (c 0.10,
CHCl3).
mL) and diisopropylethylamine (18 µL, 0.105 mmol, 1.5 equiv). The
reaction mixture was stirred for 24 h at rt and subsequently diluted
with 10% NH4OH (6 mL) and stirred for an additional 5 min. The
reaction mixture was extracted with Et2O (3 × 25 mL), dried (MgSO4),
and concentrated in vacuo to afford the crude triene. The crude triene
was immediately dissolved in a mixture of THF/H2O (10:1, 20 mL,
0.003 M), cooled to 0 °C, and treated with CAN (1 M in H2O, 0.35
mL, 5.0 equiv). The bright yellow solution was stirred for 30 min at
0 °C and subsequently poured onto H2O (20 mL). The reaction mixture
was extracted with Et2O (2 × 25 mL) and CH2Cl2 (2 × 15 mL), dried
(MgSO4), and concentrated in vacuo to afford the crude quinone as a
bright yellow oil. The crude quinone was dissolved in acetonitrile (1.4
mL, 0.05 M) and treated with 40% aqueous HF (10% v/v, 0.14 mL).
The reaction mixture was stirred at rt for 48 h and subsequently diluted
slowly with NaHCO3. The reaction mixture was extracted with EtOAc
(3 × 25 mL), dried (MgSO4), and concentrated in vacuo. Purification
on SiO2 (25% acetone/benzene) afforded (+)-1d as a yellow solid (54%,
1
3 steps, 17 mg): H NMR (400 MHz, CDCl3) δ 9.23 (s, br, 1H), 7.50
(s, 1H), 6.47 (s, 1H), 6.18 (d, 1H, J ) 10.5 Hz), 6.10-5.95 (complex
m, 4H), 5.59 (m, 2H), 5.05 (apparent t, 1H, J ) 6.8 Hz), 4.78 (br d,
1H, J ) 4.1 Hz), 4.02 (s, br, 1H), 3.74 (m, 1H), 3.35 (s, 3H), 2.71 (dd,
1H, J ) 13.8, 4.0 Hz), 2.62-2.44 (complex m, 4H), 2.29 (m, 3H),
2.02 (m, 1H), 1.78 (s, 3H), 1.75 (m, 1H), 0.98 (d, 3H, J ) 6.0 Hz); 13
C
NMR (67.5 MHz, CDCl3) δ 188.3, 182.3, 169.2, 145.4, 138.9, 137.7,
134.0, 133.8, 133.4 (2), 131.8, 130.6, 128.7, 123.4, 114.4, 78.5, 72.4,
69.1, 56.4, 44.6, 40.6, 36.2, 29.7, 25.8, 20.3, 10.7; IR (neat) νmax 3340,
1650, 1503, 1005; CIHRMS M + H+ (calcd for C26H34NO6) 456.2386,
found 456.2388; [R]23D ) +4.7° (c 0.15, MeOH); [R]23D (lit.5c) ) +4.3°
(c 1.0, MeOH) Rf (CHCl3/EtOH, 15:1) ) 0.20; Rf (benzene/CHCl3/
MeOH, 3:7:3) ) 0.50.
Arene (25). A solution of the silyl triene (50 mg, 0.066 mmol) in
methanol (6.0 mL, 0.01 M) was treated with catalytic p-toluenesulfonic
acid (3.0 mg, 0.033 mmol, 0.5 equiv). The reaction mixture was stirred
at rt for 30 min and subsequently diluted with NaHCO3 and H2O (20
mL). The reaction mixture was extracted with EtOAc (3 × 25 mL),
dried (MgSO4), and concentrated in vacuo. Purification on SiO2 (20
f 30% EtOAc/PE) afforded 25 as a colorless oil (90%, 36 mg): 1H
NMR (400 MHz, CDCl3) δ 9.21 (s, br, 1H), 7.84 (d, 1H, J ) 3.2 Hz),
6.43 (d, 1H, J ) 2.8 Hz), 6.10-5.90 (complex m, 4H), 5.90 (d, 1H, J
) 9.5 Hz), 5.59 (m, 2H), 5.05 (apparent t, 1H, J ) 6.8 Hz), 4.95 (m,
1H), 4.80 (br d, 1H, J ) 4.0 Hz), 4.40 (m, 1H), 4.02 (s, br, 1H), 3.72
(s, 3H), 3.68 (s, 3H), 3.35 (s, 3H), 2.71 (dd, 1H, J ) 13.8, 4.0 Hz),
2.50 (m, 4H), 2.00 (m, 2H), 1.78 (s, 3H), 1.75 (m, 1H), 0.98 (d, 3H,
J ) 6.0 Hz), 0.82 (s, 9H), -0.033 (s, 3H), -0.044 (s, 3H); 13C NMR
(67.5 MHz, CDCl3) δ 169.1, 151.0, 141.0, 138.9, 134.0, 133.8, 133.4,
131.8, 131.0, 130.6, 128.7, 128.0, 123.4, 115.5, 107.6, 78.5, 72.4, 69.1,
60.5, 56.4, 56.0, 44.6, 40.6, 36.2, 29.7, 25.8, 25.0, 20.3, 18.3, 10.7,
-5.00, -5.50; IR (neat) νmax 3400, 1650, 1500; CIHRMS M + H+
Bis[(E,E)-Vinyl Iodide] (22). Anhydrous CrCl2 (0.12 g, 1.0 mmol,
10.0 equiv) was suspended in THF (1 mL, 0.1 M). A solution of the
aminal-aldehyde (73 mg, 0.10 mmol) and iodoform (0.2 g, 0.5 mmol,
5.0 equiv) in THF (1 mL, 0.1 M) was cannulated into the CrCl2
suspension at 0 °C. The mixture was stirred to rt over a 10-h period
and subsequently poured into H2O (10 mL). The reaction mixture was
extracted with EtOAc (3 × 25 mL), dried (MgSO4), and concentrated
in vacuo. Purification on SiO2 (30% EtOAc/PE) afforded 15 as a light
yellow oil (70%, 69 mg): 1H NMR (400 MHz, CDCl3) δ 8.00 (s, br,
1H), 6.74, (d, 2H, J ) 3.2 Hz), 6.62, (d, 2H, J ) 2.9 Hz), 5.40 (d, 1H,
J ) 1.9 Hz), 5.21 (t, 1H, J ) 6.4 Hz), 4.49 (dd, 1H, J ) 2.0 Hz), 4.38
(s, 1H), 3.87 (d, 1H, J ) 1.9 Hz), 3.80 (d, 1H, J ) 10.0 Hz), 3.74 (s,
3H), 3.63 (s, 3H), 3.42 (s, 3H), 2.99 (dd, 1H, J ) 6.4, 6.2 Hz), 2.66-
2.60 (m, 2H), 2.50 (d, 1H, J ) 17.0 Hz), 1.63 (s, 3H), 1.41 (dd, 1H,
J ) 8.6 Hz), 1.31-1.26 (m, 4H), 1.04-0.95 (m, 3H), 1.02 (s, 18H),
0.93 (d, 3H, J ) 6.8 Hz), 0.85 (s, 9H), 0.007 (s, 3H), -0.014, (s, 3H);
13C NMR (67.5 MHz, CDCl3) δ 169.2, 156.0, 150.0, 140.8, 136.8,
135.1, 131.9, 127.0, 120.0, 119.4, 110.5, 103.3, 103.0, 78.4, 69.1, 62.8,
53.8, 52.0, 39.8, 36.0, 29.8, 28.6, 25.9, 25.8, 18.4, 18.2, 18.1, 13.4,
13.0, 10.7, -4.75, -4.96; IR (neat) νmax 2980, 2850, 1700, 1690, 1400;
CIHRMS M + H+ (calcd for C41H72I2NSi2O6) 984.2988, found
(calcd for C34H54NSiO6) 600.3720, found 600.3755; [R]23 ) +71.0°
D
(c 0.10, CHCl3).
Cyclohexylcarbonyl-δ-alanine Arene (26). The symmetrical an-
hydride of Fmoc-D-alanine was prepared in CH2Cl2 (0.1 M) prior to
use by the addition of DCC (82 mg, 0.396 mmol) to a solution of Fmoc-
D-alanine (250 mg, 0.792 mmol) in CH2Cl2. The reaction mixture was
cooled to 0 °C and stirred for 30 min, then warmed to rt for 30 min.
The reaction mixture was then filtered into a flask and diluted with
CH2Cl2 to a final volume of 12 mL. A solution of the arene 25 (36
mg, 0.060 mmol) and DMAP (2 mg, 0.0132 mmol, 0.2 equiv) in CH2-
Cl2 (2.6 mL, 0.025 M) was cooled to -78 °C, then treated with the
solution of Fmoc-D-alanine anhydride. The suspension was stirred at
-78 °C for 1 h, subsequently diluted with pH 7 buffer (10 mL), and
allowed to warm to rt. The reaction mixture was extracted with CH2-
Cl2 (3 × 25 mL), dried (MgSO4), and concentrated in vacuo. The
crude Fmoc derivative was redissolved in CH2Cl2 (1 mL, 0.06 M) and
treated with diethylamine (1 mL). The reaction mixture was stirred at
rt for 30 min and subsequently concentrated in vacuo. The crude
residue was dissolved in CH2Cl2 (10 mL, 0.003 M), and BOP (0.18 g,
0.396 mmol, 6.6 equiv), triethylamine (3.0 mL), and cyclohexanecar-
boxylic acid (0.1 mL, 0.60 mmol, 10.0 equiv) were added successively.
The reaction mixture was stirred at rt for 15 min and subsequently
diluted with pH 7 buffer (20 mL). The reaction mixture was extracted
984.3003; [R]23 ) +21.8° (c 0.35, CHCl3).
D
(+)-Mycotrienol (1d). To a flame-dried flask purged with argon
was added bis(acetonitrile)palladium(II) dichloride (4.0 mg, 0.014
mmol, 20 mol %) followed by a degassed mixture of 1:1 DMF/THF
(0.5 mL). To this mixture was added via cannula a solution of 22 (69
mg, 0.07 mmol) in DMF/THF (1 mL) followed by a solution of the
enedistannane 23 (51 mg, 0.084 mmol, 1.2 equiv) in DMF/THF (1

4134 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Masse et al.
with EtOAc (3 × 15 mL), dried (MgSO4), and concentrated in vacuo.
Purification on SiO2 (30% EtOAc/PE) afforded 26 as a colorless oil
(32 mg, 70%, three steps): 1H NMR (400 MHz, CDCl3) δ 9.21 (s, br,
1H), 7.84 (d, 1H, J ) 3.2 Hz), 6.43 (d, 1H, J ) 2.8 Hz), 6.10-5.90
(complex m, 4H), 5.90 (d, 1H, J ) 9.5 Hz), 5.59 (m, 2H), 5.05 (apparent
t, 1H, J ) 6.8 Hz), 4.95 (m, 1H), 4.40 (m, 1H), 4.02 (s, br, 1H), 3.72
(s, 3H), 3.68 (s, 3H), 3.35 (s, 3H), 2.71 (dd, 1H, J ) 13.8, 4.0 Hz),
2.52 (m, 3H), 2.41-1.51 (complex m, 16H), 1.78 (s, 3H), 1.75 (m,
1H), 1.39 (d, 3H, J ) 5.8 Hz), 0.98 (d, 3H, J ) 6.0 Hz), 0.80 (s, 9H),
-0.030 (s, 3H), -0.045 (s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 176.6,
173.0, 169.5, 152.0, 142.0, 140.0, 138.2 (2), 133.2, 133.0, 131.2, 129.5,
127.8, 122.2, 116.5, 108.0, 79.1, 75.3, 68.0, 60.5, 56.7, 56.0, 48.5, 45.0,
44.8, 40.0, 33.0, 29.4, 29.2 (2), 26.5, 25.7 (2), 25.6 (2), 20.5, 18.2,
17.2, 9.8, -5.00, -5.80; IR (neat) νmax 1730, 1650, 1530, 1210;
CIHRMS M + H+ (calcd for C44H69N2SiO8) 781.4823, found 781.4861;
1H), 6.45 (s, 1H), 6.10-5.90 (complex m, 4H), 5.90 (d, 1H, J ) 9.5
Hz), 5.59 (m, 2H), 5.05 (apparent t, 1H, J ) 6.8 Hz), 4.95 (m, 1H),
4.80 (br d, 1H, J ) 4.0 Hz), 4.40 (m, 1H), 4.02 (s, br, 1H), 3.35 (s,
3H), 2.71 (dd, 1H, J ) 13.8, 4.0 Hz), 2.52 (m, 3H), 2.41-1.51 (complex
m, 16H), 1.78 (s, 3H), 1.75 (m, 1H), 1.39 (d, 3H, J ) 5.8 Hz), 0.98 (d,
3H, J ) 6.0 Hz); 13C NMR (67.5 MHz, CDCl3) δ 188.1, 182.4, 176.6,
173.0, 169.5, 145.2, 140.0, 137.9, 138.2 (2), 133.2, 133.0, 131.2, 129.5,
122.2, 114.3, 79.1, 75.3, 68.0, 56.7, 48.5, 45.0, 44.8, 40.0, 33.0, 29.4,
29.2 (2), 25.7 (2), 25.6 (2), 20.5, 17.2, 9.8; IR (neat) νmax 3340, 1720,
1650, 1530, 1200, 1004; CIHRMS M + NH4+ (calcd for C36H52N3O8)
654.3754, found 654.3758; [R]23 ) +91.0° (c 0.16, MeOH); [R]23
D
D
(lit.5a) ) +92° (c 1.0, MeOH); Rf (CHCl3/EtOH, 15:1) ) 0.60; Rf
(benzene/CHCl3/MeOH, 3:7:3) ) 0.74.
[R]23 ) +72.7° (c 0.11, CHCl3).
Acknowledgment. Financial support was obtained from
NIH/NCI (RO1 CA56304). C.E.M. is the recipient of a Graduate
Fellowship from the Organic Chemistry Division of the
American Chemical Society 1996-1997, sponsored by Organic
Syntheses, Inc.
D
(+)-Mycotrienin I (1c). A solution of 18 (32 mg, 0.039 mmol) in
a mixture of THF/H2O (10:1, 10 mL, 0.003 M) was cooled to 0 °C
and treated with CAN (1 M in H2O, 0.20 mL, 5.0 equiv). The bright
yellow solution was stirred for 30 min at 0 °C and subsequently poured
onto H2O (20 mL). The reaction mixture was extracted with Et2O (2
× 25 mL) and CH2Cl2 (2 × 15 mL), dried (MgSO4), and concentrated
in vacuo to afford the crude quinone as a bright yellow viscous oil.
The crude quinone was dissolved in acetonitrile (1.0 mL, 0.05 M) and
treated with 40% aqueous HF (10% v/v, 0.10 mL). The reaction
mixture was stirred at rt for 24 h and subsequently diluted slowly with
NaHCO3. The reaction mixture was extracted with EtOAc (3 × 25
mL), dried (MgSO4), and concentrated in vacuo. Purification on SiO2
(2.5% MeOH/CH2Cl2) afforded (+)-1c as a yellow solid (40%, two
steps, 10 mg): 1H NMR (400 MHz, CDCl3) δ 9.21 (s, br, 1H), 7.48 (s,
Supporting Information Available: 1H NMR and 13C NMR
spectral data for all intermediates and final products as well as
full spectral data for all intermediates not listed in the
Experimental Section (109 pages, print/PDF). See any current
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JA9743194