Total synthesis of sordaricin

Article abstract of DOI:10.1021/jo048199b

(Chemical Equation Presented) An enantioconvergent total synthesis of sordaricin (3), the diterpene aglycon of an important class of antifungal compounds, is described. Two approaches were explored, the first of which utilized a possible biogenetic intram

Full text of DOI:10.1021/jo048199b

Total Synthesis of Sordaricin
Lewis N. Mander* and Regan J. Thomson
Research School of Chemistry, The Australian National University, Canberra, ACT 0200, Australia
mander@rsc.anu.edu.au
Received October 12, 2004
An enantioconvergent total synthesis of sordaricin (3), the diterpene aglycon of an important class
of antifungal compounds, is described. Two approaches were explored, the first of which utilized a
possible biogenetic intramolecular [4 + 2] cycloaddition to form the complete carbon skeleton of
the target molecule as a single regioisomer 30. A second approach employed a tandem cycloreversion/
intramolecular [4 + 2] cycloaddition process to afford not only the desired product 30 but also
significant quantities of the undesired regioisomer iso-30. An investigation into the reasons for
the difference in regioselectivity between these two reactions revealed the intervention of a
cycloreversion/cycloaddition pathway at elevated temperatures leading to the formation of iso-30.
Experimental evidence supports the hypothesis that iso-30 is the more thermodynamically stable
of the two regioisomers.
Introduction
The sordarins are an emerging class of potent anti-
fungal compounds, of which sordarin (4),1 isolated in 1971
from the ascomycete Sordaria araneosa Cain, is the
structural prototype. The sordarins exhibit remarkable
in vitro activity against a wide range of fungal pathogens
such as Candida albicans,2 the causative agent of the
common thrush infection. Additionally, sordarins show
encouraging in vivo activity against several pathogenic
fungi, including Pneumocystis carnii,2 the major cause
of lethal pneumonia among immunocompromised pa-
tients. Unlike the other major antifungals, which are
targeted against fungal ergosterol biosynthesis, the sor-
darins are selective inhibitors of fungal protein synthesis
through a specific interaction with Elongation Factor 2
(EF2),3 a remarkable feat considering the high degree of
EF2 homology (85%) between fungi and higher order
Eukaryotes. The combination of potent biological activity
and a novel mode of action have made the sordarins lead
compounds for the development of new antifungal agents.
We were interested in the sordarins not only because
of their potent biological activity but also because of their
unusual structures4 and possible biosynthesis (Figure 1).5
Borschberg demonstrated that sordaricin (3), the diter-
pene aglycon common to all sordarins, was biosyntheti-
cally derived from cycloaraneosene (1), a member of the
FIGURE 1. Proposed biosynthesis of the sordarins from
cycloaraneosene 1.
fusicoccin class of diterpenes. It is tempting to speculate
that the conversion of 1 to 3 might proceed by means of
(4) Sordarin: Vasella, A. T. Ph.D. Dissertation, Eidgenossischen
Technischen Hochschule, Zurich, 1972. Zofimarin: Ogita, T.; Hiyashi,
A.; Sato, S.; Furutani, W. JP Patent 6240292, 1987; Chem. Abstr. 1987,
107, 5745. GR135402: (a) Kinsman, O. S.; Chalk, P. A.; Jackson, H.
C.; Middleton, R. F.; Shuttleworth, A.; Rudd, B. A. M.; Jones, C. A.;
Noble, H. M.; Wildman, H. G.; Dawson, M. J.; Stylli, C.; Sidebottom,
P. J.; Lamont, B.; Lynn, S.; Hayes, M. V. J. Antibiot. 1998, 51, 41. (b)
Kennedy, T. C.; Webb, G.; Cannell, R. J. P.; Kinsman, O. S.; Middleton,
R. F.; Sidebottom, P. J.; Taylor, N. L.; Dawson, M. J.; Buss, A. D. J.
Antibiot. 1998, 51, 1012. Hypoxysordarin: Daferner, M.; Mensch, S.;
Anke, T.; Sterner, O. Z. Naturforsch. 1999, 54c, 474. Neosordarin and
Hydroxysordarin: Davoli, P.; Engel, G.; Werle, A.; Sterner, O.; Anke,
T. J. Antibiot. 2002, 55, 377.SCH57404/Xylarin: (c) Coval, S. J.; Puar,
M. S.; Phife, D. W.; Terracciano, J. S.; Patel, M. J. Antibiot. 1995, 48,
1171. (d) Schneider, G.; Anke, H.; Sterner, O. Nat. Prod. Lett. 1995, 7,
309. BE-31405: Okada, H.; Kamiya, S.; Shiina, Y.; Suwa, H.; Na-
gashima, M.; Nakajima, S.; Shimokawa, H.; Sugiyama, E.; Kondo, H.;
Kojiri, K.; Suda, H. J. Antibiot. 1998, 51, 1081.
(1) Hauser, D.; Sigg, H. P. Helv. Chim. Acta 1971, 54, 1178.
(2) For a review of sordarin biological activity, see: Gargollo-Viola,
D. Curr. Opin. Anti-Infect. Invest. Drugs 1999, 1, 297.
(3) Justice, M. C.; Hsu, M. J.; Tse, B.; Ku, T.; Balkovec, J.; Schmatz,
D.; Neilsen, J. J. Biol. Chem. 1998, 273, 3148.
10.1021/jo048199b CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/25/2005
1654
J. Org. Chem. 2005, 70, 1654-1670

Total Synthesis of Sordaricin
SCHEME 1
this enolate was deemed essential. In the model study
previously published from our group,6a a norbornene ester
served as an operational equivalent of 5, but this ap-
proach did not lead to a successful synthesis due to
problematic late-stage transformations.10 The revised
strategy (Scheme 1) we chose to employ for the synthesis
of sordaricin (3) involved alkylation of aldehyde 7 with
iodide 6, which could be expected to give 8 after some
simple manipulations. We hoped that aldehyde 8 would
undergo a tandem cycloreversion/intramolecular [4 + 2]
cycloaddition11 to form the sordaricin carbon skeleton in
a single operation. Demethylation of the resultant ester
would then afford the natural product 3. As the coupling
of racemic 6 and 7 would be expected to give a mixture
of diastereomers, we planned to prepare 6 and 7 in
enantiopure form. With ready access to both enantiomers
of enone 10,12 we envisaged sequences that might allow
iodide 6 and aldehyde 7 to be prepared from the (-)- and
(+)-enantiomers of 10, respectively (cf. Schemes 2-4).
Synthesis of the Aldehyde 7. Because the alkylation
of aldehyde 7 with iodide 6 was expected to be nontrivial
we focused our attention on developing a straightforward
synthesis of rac-7, with a view to carrying out a simple
model alkylation with isobutyl iodide as a surrogate for
6. Our initial approach to aldehyde 7, outlined in Scheme
2, involved the cerium trichloride mediated 1,2-addition
of isopropylmagnesium chloride to enone rac-10,12 fol-
lowed by oxidative transposition with Jones’ reagent to
afford 11 in good yield (70%, two steps). The use of cerium
trichloride13 is essential as exposure of 10 to the Grignard
FIGURE 2. Previous cycloadditions related to sordaricin.
an intramolecular [4 + 2] cycloaddition, such as that
shown by the conversion of 2 to 3. Contemporaneously,
Mander and Kato independently demonstrated the fea-
sibility of such a transformation on simplified model
systems,6 both of which reported formation of the desired
product as a single regioisomer. Shortly thereafter, Kato7
disclosed the first total synthesis of sordaricin methyl
ester based upon this transformation (Figure 2).
Recently, we communicated our efforts in this area,
which culminated in an enantioconvergent total synthesis
of sordaricin (3).8 Two successful approaches utilizing
intramolecular [4 + 2] cycloadditions were detailed: one
that provided sordaricin methyl ester as a single regio-
isomer and a second that afforded a mixture of regioiso-
meric cycloadducts. Narasaka has since disclosed a total
synthesis of racemic sordaricin based upon an intra-
molecular Tsuju-Trost reaction to form the norbornene
system.9
This paper provides a full account of our research and
also describes the results of a study into the interesting
outcomes of previously mentioned cycloadditions.
Results and Discussion
Synthetic Strategy. Regardless of biosynthetic con-
siderations, retrosynthetic analysis of sordaricin (3)
guided by the Diels-Alder transform leads to a strategy
based upon a formal alkylation of cyclopentadienyl eno-
late 5 with iodide 6. Because both regio- and diastereo-
facial selectivity were expected to be poor for the alky-
lation of enolate 5, use of an operational equivalent of
(10) Mander, L. N.; Robinson, R. P. J. Org. Chem. 1991, 56, 5718.
(11) For a recent review on retro-Diels-Alder reactions, see: Rick-
born, B. Org. React. 1998, 52, 1. For examples of tandem processes in
synthesis, see: Ho, T.-L. Tandem organic reactions; Wiley: New York,
1992; and references therein.
(12) This initial approach was carried out on racemic 10. All
subsequent work utilized enantiopure substrates; see: (a) Takano, S.;
Inomata, K.; Takahashi, M.; Ogasawara, K. Synlett 1991, 636. (b)
Takano, S.; Moriya, M.; Tanaka, K.; Ogasawara, K. Synthesis 1994,
687.
(13) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392.
(5) Borschberg, H. J. Ph.D. Dissertation, Eidgenossischen Technis-
chen Hochschule, Zurich, 1975.
(6) (a) Mander, L. N.; Robinson, R. P. J. Org. Chem. 1991, 56, 3595.
(b) Kato, N.; Wu, X.; Takeshita, H. Chem. Express 1991, 6, 687.
(7) Kato, N.; Kusakabe, S.; Wu, X.; Kamitamari, M.; Takeshita, H.
J. Chem. Soc., Chem. Commun. 1993, 1002.
(8) Mander, L. N.; Thomson, R. J. Org. Lett. 2003, 5, 1321.
(9) Kitamura, M.; Chiba, S.; Narasaka, K. Chem. Lett. 2004, 33, 942.
J. Org. Chem, Vol. 70, No. 5, 2005 1655

Mander and Thomson
SCHEME 2
SCHEME 4
SCHEME 3
II if equilibrating conditions were used during enolate
generation.15 Also, formation of II would result in a high
degree of torsional strain, thereby lowering the intrinsic
acidity of the R proton. After significant experimentation,
we found that treatment of enone 11 with NaHMDS (1.5
equiv) in THF (-78 °C f rt, 3 h), followed by the addition
of methyl cyanoformate (1.5 equiv, -78 °C) gave a 54%
isolated yield of the desired ester 12. Our next intention
was to form aldehyde 7 by homologation of the ketone
functionality within 12. Unfortunately, a variety of
methods, including Wittig and Horner-Wittig homolo-
gations, failed to give rise to useful amounts of the
desired product, and we therefore sought an alternative
route to 7.
Our second, and ultimately successful, route to alde-
hyde 7, this time working with enantiopure material, is
shown in Scheme 3. 1,4-Addition of the cuprate derived
from MOMOCH2Li16 to enone (-)-10 in the presence of
TMSCl gave the expected silyl enol ether 13, which was
then treated with MeLi followed by methyl cyanoformate
to afford â-keto ester 14 (71% over two steps from (-)-
10) as a mixture of enol and keto tautomers (6:1,
respectively). The expected exo addition of the cuprate
was proven by NOE experiments carried out on 13
(reciprocal interactions between H-3 and H-5). Next,
installation of the isopropyl group was achieved by
converting 14 into the corresponding triflate followed by
addition of the higher order mixed cuprate derived from
reagent alone leads to quantitative 1,4-addition. Next,
we hoped to install the carboxyl group by acylation of
the linear dienolate derived from 11. The C-selective
acylation of cross-conjugated enolates using methyl cy-
anoformate is well established,14 but to the best of our
knowledge the acylation of a linear dienolate has not yet
been reported. On the grounds of thermodynamic stabil-
ity we expected enolate I to form in preference to enolate
(15) For relevant examples of C-selective acylation of enolates
generated under equilibrating conditions, see: (a) Ziegler, F. E.; Klein,
S. I.; Pati, U. K.; Wang, T.-F.; J. Am. Chem. Soc. 1985, 107, 2730. (b)
Schuda, P. F.; Phillips, J. L.; Morgan, T. M. J. Am. Chem. Soc. 1986,
51, 2742
(16) Linderman, R. J.; Godfrey, A.; Horne, K. Tetrahedron 1989, 45,
495.
(14) (a) Mander, L. N.; Sethi, S. P.; Tetrahedron Lett. 1983, 24, 5425.
(b) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1991, 70,
256.
1656 J. Org. Chem., Vol. 70, No. 5, 2005

Total Synthesis of Sordaricin
SCHEME 5
isopropylmagnesium chloride and 2-Th(Cu)CNLi (56%
yield of 15 over two steps).17 Removal of the MOM group
using MgBr2‚Et2O and butanethiol,18 and subsequent
oxidation with Dess-Martin periodinane,19 afforded the
desired aldehyde 7 (60% over two steps). Alkylation of 7
with isobutyl iodide was carried out using t-BuOK to
afford 16 as a single stereoisomer in moderate yield
(50%), the exo selectivity of the alkylation being proven
by the presence of an NOE correlation between the
aldehyde CH and norbornene olefinic proton.
Synthesis of the Iodide 6. Having developed a
synthesis of aldehyde 7 and demonstrated a successful
model alkylation, we focused our efforts on iodide 6. As
shown in Scheme 4, the synthesis of iodide 6 commenced
with the 1,4-addition of the cuprate derived from
MOMOCH2Li16 to enone (+)-10 in the presence of TMSCl
to give the expected silyl enol ether, which was then
treated with MeLi followed by methyl iodide, to afford
the syn-substituted tricycle 17 (60% over two steps, 95:5
dr). The selectivity of the alkylation was assumed at this
stage but was later proven by comparison to a known
compound (vide infra). Heating 17 at reflux in 1,2-
dichlorobenzene under a stream of dry nitrogen effected
smooth cycloreversion to cyclopentenone 18 (85%).20 The
next task in the synthesis was to conduct a 1,4-addition
of a nucleophile that would correspond to the allylic ether
substituent present in the target fragment. Initially, it
was hoped that this conversion might be achieved by the
direct addition of the dianion derived from 2-bromo-prop-
2-en-1-ol,21 but this was unsuccessful, as were attempts
to add protected versions of this nucleophile. After
investigating several other possible nucleophiles, the
copper-promoted 1,4-addition of isopropenylmagnesium
bromide was carried out with the intention of function-
alizing the alkenyl substituent at a later time. Thus, the
trisubstituted cyclopentanone 19 was obtained in good
yield (70%) as a single diastereomer. Addition of the
cuprate was assumed to have occurred on the less
hindered R-face of the enone, placing the isopropenyl
group anti to the existing substituents. So as to avoid
epimerization of the methyl substituent in 19, carbonyl
deletion was carried out over three steps by borohydride
reduction followed by the Barton-McCombie reaction22
to give the key cyclopentane 20 in good overall yield
(88%). We had hoped to install the required allylic
hydroxyl group via an epoxide, which could be opened
by treatment with a lithium alkylamide base. Unfortu-
nately, and surprisingly, epoxidation of the alkene bond
present in 20 was invariably followed by a facile [1,2]
hydride shift to form aldehyde 21, even under the neutral
conditions allowed by employing dimethyl dioxirane
(DMDO). However, conversion of the MOM ether 20 to
the corresponding TBS ether and subsequent treatment
with m-CPBA gave an excellent yield of the desired
epoxide (formed as an inseparable mixture of diastere-
omers). The mixture of epoxides was subsequently con-
verted to allylic alcohol 22 (49% from 20) upon exposure
to lithium cyclohexyl isopropyl amide (LCIA). This se-
quence also served to confirm the stereochemistry of our
earlier alkylations, because the alcohol formed by depro-
tection of 20 was identical with the one which had been
prepared previously from carvone.23 Protection of the
hydroxy group in 22 as a MOM ether, followed by TBS
ether removal with TBAF, gave the parent alcohol which
was readily converted into the target iodide 6 (84% over
three steps) using iodine/Ph3P/imidazole.24
Attempted Alkylation of Aldehyde 7. Having al-
ready established a procedure for the alkylation of 7 with
isobutyl iodide, these conditions were the first choice for
the initial attempt using iodide 6. Although consumption
1
of aldehyde 7 was observable, H NMR spectra of the
reaction mixture showed only unchanged iodide 6 and
no signals corresponding to the desired product. Further
experimentation did not improve this situation.
Revised Synthetic Strategy. The failure of 7 to yield
any alkylated product led us to consider the use of nitrile
23 as the substrate for the alkylation step (Scheme 5).
In this case, we felt that the simplified structure and
more reactive nitrile anion25 would allow for an efficient
coupling with 6 to afford 24. Although this revised
strategy was less convergent than that outlined in
Scheme 1, it provided a more flexible approach to the
natural product. Thus, nitrile 24 could be converted into
the originally targeted aldehyde 8, which should then
undergo the tandem cycloreversion/intramolecular cy-
cloaddition process. Of additional interest, however,
would be the conversion of ketone 25 into aldehyde 9 in
(17) Lipshultz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett.
1987, 28, 945.
(18) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett 1991, 183.
(19) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(20) For a review pertaining to similar cycloreversions, see: Klunder,
A. J. H.; Zhu, J.; Zwanenburg, B. Chem. Rev. 1999, 99, 1163.
(21) (a) Corey, E. J.; Widiger, G. N. J. Org. Chem. 1975, 40, 2975.
(b) Fevig, J. M.; Marquis, R. W., Jr.; Overman, L. E. J. Am. Chem.
Soc. 1991, 113, 5085.
(23) Robinson, R. Unpublished work.
(24) Corey, E. J.; Pyne, S. G.; Su, W. Tetrahedron Lett. 1983, 24,
4883.
(22) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(25) For a review on the reaction of nitrile stabilized carbanions,
see: Arseniyadis, S.; Kyler, K. S. Org. React. 1984, 31, 1.
J. Org. Chem, Vol. 70, No. 5, 2005 1657

Mander and Thomson
SCHEME 6
SCHEME 7
a controlled stepwise manner, which would allow for
further study of the cycloaddition process.
Alkylation of Nitrile 23 and Conversion to Ketone
25. First, nitrile 23 was synthesized by 1,4-addition of
cyanide anion to enone 10,26 followed by protection of the
ketone function as the corresponding ketal (72% over two
steps, Scheme 6). Examination of the required alkylation
could now be addressed. After extensive experimentation,
a set of reliable conditions was found, whereby the
desired product 24 could be obtained, as a single di-
astereomer, in yields between 55% and 67%, based on
iodide consumption. In this transformation, 2 equiv of
the nitrile 23 were utilized in order to effect complete
consumption of the iodide 6. Unchanged nitrile 23 could
be readily recovered during product purification by flash
column chromatography. The nitrile group in 24 was then
reduced over two steps to afford the corresponding alcohol
which was protected as the MOM ether and then con-
verted into ketone 25 following ketal hydrolysis (90% over
four steps). The presence of an NOE correlation within
25 between the alkoxymethyl protons and the norbornene
olefinic proton confirmed that alkylation had occurred on
the less hindered exo face of nitrile 23.
Total Syntheses of Sordaricin. With the ketone 25
now in hand we chose first to explore the route to
sordaricin via aldehyde 9 (Scheme 7) before attempting
the proposed cycloreversion/cycloaddition sequence. To
this end, ketone 25 underwent smooth cycloreversion to
afford cyclopentenone 26 (96%) upon heating under reflux
in 1,2-dichlorobenzene. The next step in the synthesis
required the introduction of a carboxyl group by selective
C-acylation of the enolate derived from 26. Methyl
cyanoformate is highly regioselective for C vs O acylation
in most systems, but O-acylation may predominate with
enolates that are sterically hindered as in the present
situation. If diethyl ether is used as the solvent instead
of the more commonly used THF, however, then C-
acylation is usually ensured.14b In view of these consid-
erations, acylation of enone 26 was carried out using
LiHMDS/hexanes in diethyl ether, followed by the addi-
tion of MeO2CCN to afford the desired â-keto ester in
excellent yield (97%, 1:1 ratio of enol 27 and ketone 28).
Installation of the isopropyl substituent was achieved by
converting 27/28 into the corresponding enol triflate and
subsequent addition of the higher order mixed cuprate
derived from isopropylmagnesium chloride and 2-Th(Cu)-
CNLi (58% over two steps).17 Concomitant removal of
both MOM protecting groups with MgBr2‚Et2O)/n-bu-
tanethiol,18 followed by selective allylic oxidation with
MnO2,27 afforded the target aldehyde 9 in excellent yield
(86% over 2 steps). Aldehyde 9 cyclized over 3 days at 40
°C to give 30 as a single regioisomer in quantitative yield,
which could be demethylated with propanethiolate to give
sordaricin (3), mp 189-191 °C, [R]D -55 (c 0.2, MeOH);
authentic sample [R]D -58 (c 0.2, MeOH) [lit.12 mp 190s
191 °C, [R]D -62 (c 0.2, MeOH)] (79% yield); spectroscopic
data (1H and 13C NMR, MS, IR) were identical to those
of natural material.
Investigation into the possible tandem cycloreversion/
intramolecular [4 + 2] cycloaddition approach to sorda-
ricin (3) began with the previously described ketone, 25
(Scheme 8). Installation of the requisite carboxyl and
isopropyl groups was achieved in a manner similar to
that detailed for the synthesis of 29 from 25 (see Scheme
7). In this case, however, acylation of 25 did not proceed
(26) Bugel, J. P.; Ducos, P.; Gringore, O.; Rouessac, F. Bull. Soc.
Chim. Fr. 1972, 4371.
(27) Babler, J. H.; Martin, M. J. J. Org. Chem. 1977, 42, 1799.
1658 J. Org. Chem., Vol. 70, No. 5, 2005

Total Synthesis of Sordaricin
SCHEME 8
FIGURE 4. Regioselective cycloadditions of diols 32 and 34.
with the high levels of C-selectivity observed for 26.
Under optimized conditions, a mixture of C- to O-acylated
products was obtained in a ratio of 6:1. Typically, the
unpurified reaction mixture was exposed to K2CO3/
MeOH, converting the unwanted enol carbonate back into
ketone 25, and in this manner an 86% yield of 31 was
obtained on the basis of recovered starting material.
Transformation of 31 into 8 then proceeded in good
overall yield (74% over four steps) using the chemistry
developed previously.
Heating 8 in 1,2-dichlorobenzene at 180 °C for 1 h gave
a 4:1 mixture of the desired product 30 and a second
compound identified as the regioisomer iso-30 (76%
combined yield). Further experimentation did not lead
to any improvement in the product ratio. Demethylation
of the mixture and subsequent separation by preparative
HPLC afforded 3 (38%) and iso-3 (25%). Structural
assignment of iso-3 was made on the basis of the NOE
data, the key correlations of which are shown in Figure
3, and by the appearance of an isolated AB spin system
due to the protons on C5 (2.49 and 2.84 ppm, J ) 12.7
Hz).
FIGURE 5. Thermal interconversion of 30 and iso-30.
prepared en route to 3, proceeded to afford 33 as a single
regioisomer, but in order to achieve a significant rate of
reaction, heating at 100 °C was necessary, and even then,
a period of 3 days was required for complete conversion.
In sharp contrast to aldehyde 8, the cycloreversion/
intramolecular [4 + 2] cycloaddition of diol 34 rendered
33 as a single regioisomer (64%).
Given that the formation of ester 30 from aldehyde 9
was completely regioselective at 40 °C, we considered the
possibility that iso-30 was being formed from 30 by a
retro-Diels-Alder process that occurs at the elevated
temperatures necessary to induce the initial cyclorever-
sion. To validate this hypothesis, isomerically pure 30
was heated in 1,2-dichlorobenzene at 180 °C for 2.5 h to
afford a 2:1 mixture of iso-30 and 30, respectively (Figure
5). The excess of iso-30 indicated that it is probably more
thermodynamically stable than 30.
To establish the energy difference experimentally
between the two isomers and to obtain some information
regarding the activation energy necessary to induce the
isomerization, a series of experiments were performed,
the results of which are summarized in Table 1.
Clearly, the activation energy corresponds to a tem-
perature somewhere between 120 and 150 °C. The exact
position of the equilibrium was difficult to establish as
prolonged heating led to significant decomposition. After
heating 30 for 72 h a 3:1 ratio of iso-30 to 30 was
obtained. Conversely, heating pure iso-30 at 150 °C for
24 h gave a 4:1 ratio of isomers. These results indicate
an equilibrium ratio of 3-4:1 providing a ∆G of ap-
proximately 1 kcal/mol at 150 °C. The stability of iso-30
relative to 30 is clearly the result of an alleviation of the
nonbonding interactions of the aldehyde substituent with
both the carboxyl and isopropyl groups. Minimizing these
Cycloaddition Studies. Formation of this alternative
regioisomer was totally unexpected, given our observa-
tions for the cyclization of 9, and on the previous studies
of both Kato and Mander.6,7 This result prompted us to
explore the cyclizations of diol intermediates 33 and 34
in order to gain a better understanding of the cycload-
dition process (Figure 4). Cyclization of the diol 32,
1
FIGURE 3. Key H NMR signals for iso-3.
J. Org. Chem, Vol. 70, No. 5, 2005 1659

Mander and Thomson
TABLE 1. Isomerization of 30 into iso-30 over Time
the equivalent reaction involving propene and sorbic acid.
Therefore, from these models it would be predicted that
9 should cyclize at a lower temperature than diol 32, as
observed experimentally.
The observed regioselectivity for the low-temperature
cyclizations is in line with what would be expected based
on FMO analysis for Diels-Alder reactions between such
reacting partners.
T (°C)
time (h)
iso-30/30
120
150
150
150
150
6
5
20
46
72
0:100
25:75
50:50
66:34
72:28
Summary and Conclusions
An enantioconvergent total synthesis of sordaricin (3)
has been achieved in 26 steps (longest linear sequence)
from (+)-10 in 3% overall yield, using (-)-10 and (+)-10
as starting materials. Alkylation of nitrile 23 with iodide
6 afforded, after elaboration, 25, which served as a
common intermediate for the alternative syntheses. The
first of these syntheses involved the construction of
aldehyde 9, which underwent regioselective cycloaddition
to generate 30 and, following demethylation, sordaricin
(3). Given the ease with which this cycloaddition occurs,
the question of it’s role in the biosynthesis of 3 or 4
remains moot. Enzymatic catalysis could be involved as
was recently shown by Sterner and co-workers for the
biosynthesis of galiellalactone,29 but would not appear
to be necessary. The second synthesis made use of the
tandem cycloreversion/intramolecular cycloaddition of 8,
which afforded the desired compound 30 as well as the
alternative regioisomer, iso-30. Subsequent studies re-
vealed that formation of iso-30 is the result of a thermo-
dynamically driven cycloreversion/cycloaddition process
which 30 undergoes at temperatures over 150 °C.
TABLE 2. Frontier Orbital Energies for Model
Dienophiles and Diene
a Values taken from: Smith, M. B. Organic Synthesis; McGraw-
Hill Book Co.: Singapore, 1994.
interactions results in an overall lowering of energy
despite the fact that the B-ring is then forced to adopt a
boatlike conformation.
Experimental Section
NMR spectra were recorded in CDCl3 at 300 MHz (1H),
unless stated otherwise.
Modeling predicted that iso-33 should also be more
stable than 33, and hence it should be possible to induce
isomerization at elevated temperatures. Given that the
isomeric structure was not observed during the sequen-
tial cycloreversion/cycloaddition process for diol 32 at 180
°C, the diol was heated at 200 °C, but unfortunately, this
led only to decomposition and no data could be obtained.
Rationalizing the Kinetic Outcomes of the Cy-
cloadditions. The dramatic difference in the rates of
cyclization for aldehyde 9 and diol 32 may not have been
easy to predict at the outset of this study. However, the
reactivity of both aldehyde 9 and diol 32 may be rational-
ized in terms of frontier molecular orbital (FMO) analy-
sis28 using simple model compounds whereby sorbic acid
represents the diene portion of both substrates, and the
dienophile portion of 9 and 32 is represented by acrolein
and propene, respectively.
Inspection of Table 2 reveals that the favored orbital
interactions for both aldehyde 9 and diol 32 will be the
HOMO of the diene and the LUMO of the dienophile
(-11.21 eV for HOMO(sorbic acid)-LUMO(propene), and -10.01
eV for HOMO(sorbic acid)-LUMO(acrolein), compared with
-12.27 eV and -12.88 eV, respectively, for the alterna-
tive arrangement.). From these data it is clear that the
reaction of acrolein and sorbic acid is more favorable, due
to a smaller energy gap between the participating orbit-
als, and hence would proceed at a lower temperature than
(1RS,3aRS,4SR,7RS,7aSR)-1-Isopropyl-3a,4,7,7a-tet-
rahydro-1H-4,7-methanoinden-1-ol. CeCl3‚7H2O (7.0 g, 18.7
mmol) was heated at 130 °C under vacuum for 2 h, cooled to
room temperature, and crushed into a fine powder. The powder
was then heated with stirring at 130 °C under vacuum for 2
days, after which time the flask was charged with nitrogen
gas and cooled to room temperature. THF (130 mL) was added
in a single volume and the suspension stirred for 5 h.
Isopropylmagnesium chloride/THF (2.0 M, 9.4 mL, 18.7 mmol)
was added dropwise to the stirred suspension at 0 °C and
stirring continued for 1.5 h before a solution of ketone (()-10
(2.5 g, 17.0 mmol) in THF (20 mL) was added. A 2.0 M aqueous
acetic acid solution (25 mL) was added after 30 min and the
reaction mixture stirred for 10 min. When all of the solid had
dissolved, the solution was extracted three times with diethyl
ether (100 mL). The combined organic extracts were washed
with a saturated aqueous NaHCO3 solution (100 mL) and brine
(100 mL) and dried (MgSO4). Concentration in vacuo, followed
by flash chromatography on a column of silica gel using 25%
ethyl acetate in petroleum spirits as the eluant, afforded the
alcohol (2.7 g, 83%) as a colorless oil. IR (film) ν: 3480, 3044,
2962, 2874, 1468, 1370, 1341, 1166, 1075, 1024, 774 cm-1. 1H
NMR δ: 0.88 (d, 3 H, J ) 6.8 Hz, CHMe), 0.93 (d, 3 H, J ) 6.7
Hz, CHMe), 1.36 (s, 1 H, OH), 1.46 (d, 1 H, J ) 8.1 Hz), 1.58
(dt, 1 H, J ) 7.7, 1.6 Hz), 1.74 (sep, 1 H, J ) 6.9 Hz, CHMe2),
2.65 (dd, 1 H, J ) 7.8, 3.0 Hz), 2.86 (m, 2 H, H4 + H7), 3.19
(29) Johansson, M.; Ko¨pcke, B.; Anke, H.; Sterner, O. Angew. Chem.,
Int. Ed. 2002, 41, 2158. For other examples of enzyme-catalyzed Diels-
Alder reactions, see: (a) Oikawa, H.; Kobayashi, T.; Katayama, K.;
Suzuki, Y.; Ichihara, A. J. Org. Chem. 1998, 63, 8748. (b) Katayama,
K.; Kobayashi, T.; Oikawa, H.; Honma, M.; Ichihara, A, A. Biochim.
Biophys. Acta 1998, 1384, 387. (c) Auclair, K.; Sutherland, A.; Kennedy,
J.; Witter, D. J.; Van denHeever, J. P.; Hutchinson, C. R.; Vederas, J.
C. J. Am. Chem. Soc. 2000, 122, 11519. (d) Witter, D. J.; Vederas, J.
C. J. Org. Chem. 1996, 61, 2613.
(28) Houk, K. N. J. Am. Chem. Soc. 1973, 95, 4092. See also:
Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley-
Interscience: Chicester, 1996.
1660 J. Org. Chem., Vol. 70, No. 5, 2005

Total Synthesis of Sordaricin
(m, 1 H), 5.43 (dd, 1 H, J ) 5.8, 1.7 Hz, H3), 5.55 (dd, 1 H, J
) 5.7, 2.0 Hz, H2), 5.86 (dd, 1 H, J ) 5.6, 3.2 Hz), 6.18 (dd, 1
H, J ) 5.6, 2.8 Hz). 13C NMR δ: 16.5 (Me), 17.1 (Me), 37.5
(CH), 45.4 (CH), 46.3 (CH), 49.5 (CH), 52.4 (CH2), 53.7 (CH),
86.3 (C), 133.2, 134.4, 134.5, 136.8 (4 × dCH). MS m/z: 190
(M+‚, 14), 172 (32), 157 (37), 147 (52), 129 (38), 124 (45), 119
(24), 109 (100), 91 (40), 81 (46). HRMS: calcd for C13H18O1
190.1358, found 190.1355.
with saturated aqueous ammonium chloride solution (10 mL)
and allowed to warm to room temperature. Following dilution
with water (100 mL) and 10% aqueous ammonia solution (5
mL), the mixture was extracted twice with diethyl ether (150
mL), and the combined organic extracts were washed with
brine (100 mL) and dried (MgSO4). Concentration in vacuo,
followed by flash chromatography on a column of silica gel
using petroleum spirits, then 5% ethyl acetate in petroleum
spirits as the eluant, afforded the unstable silyl enol ether 13
(2.23 g, 73%) which was used immediately in the next reaction.
(3aRS,4SR,7RS,7aSR)-3-Isopropyl-3a,4,7,7a-tetrahydro-
4,7-methanoinden-1-one (11). Jones’ reagent was added
dropwise to a stirred solution of the alcohol (1.4 g, 7.2 mmol)
in acetone (70 mL) at 0 °C, until no starting material remained
by TLC. Propan-2-ol (5 mL) was added, and the resulting blue-
green solution diluted with water (100 mL) and extracted twice
with ethyl acetate (100 mL). The combined organic extracts
were washed with brine (100 mL) and dried (MgSO4), and the
solvent was removed in vacuo. Flash chromatography on a
column of silica gel using 50% ethyl acetate in petroleum
spirits as the eluant afforded the enone 11 (940 mg, 70%) as
a colorless oil. IR (film) ν: 2966, 2872, 1694, 1601, 1466, 1337,
(1R,3aR,4S,7R,7aR)-Methyl-3-hydroxy-1-methoxymeth-
oxymethyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-2-
carboxylate (14). MeLi/diethyl ether (1.0 M, 6.2 mL, 8.8
mmol) was added dropwise to a solution of silyl enol ether 13
(2.23 g, 8.0 mmol) in THF (70 mL) at -20 °C under a nitrogen
atmosphere. Stirring was continued at -20 °C for 30 min, and
then after cooling to -78 °C methyl cyanoformate (1.3 mL,
16.0 mmol) was added. After 20 min, water (10 mL) was
carefully added and the solution allowed to warm to room
temperature. The mixture was further diluted with water (100
mL) and extracted twice with diethyl ether (100 mL). The
combined organic extracts were washed with brine (100 mL)
and dried (MgSO4), and the solvent was removed in vacuo. The
residue was subjected to flash chromatography on a column
of silica gel using 10%, increasing to 20% ethyl acetate in
petroleum spirits as the eluant, to afford 14 (1.6 g, 71%) as an
inseparable mixture of enol:keto (6:1) tautomers. [R]20D: -131.0
(c 0.78 CHCl3). IR (film) ν: 2952, 1756, 1731, 1661, 1619, 1445,
1358, 1342, 1243, 1217, 1150, 1111, 1041, 917 cm-1. 1H NMR
(key signals for keto) δ: 1.47 (d, 1 H), 1.62 (d, 1 H), 6.16 (m,
2 H, H5 + H6); (key signals for 14) δ: 1.30 (d, 1 H, J ) 8.2
Hz), 1.52 (d, 1 H, J ) 8.2 Hz), 2.37 (m, 1 H), 2.55 (m, 1 H),
3.00 (br s, 1 H), 3.08 (br s, 1 H), 3.29 (t, 1 H, J ) 8.2 Hz, H3),
3.34 (s, 3 H, OMe), 3.69 (m, 5 H, CO2Me + CH2OMOM), 4.60
(AB d, 2 H, J ) 6.6 Hz, OCH2OMe), 5.97 (m, 1 H), 6.02 (m, 1
H), 10.40 (br s, 1 H, OH). 13C NMR (key signals for keto) δ:
52.5 (CH2), 69.2 (CH2), 96.1 (CH2), 135.2, 136.4 (2 × dCH),
168.0 (C, CO2Me), 209.7 (C, CO); (key signals for 14) δ: 50.0
(CH2), 70.8 (CH2), 96.3 (CH2), 101.1 (C), 133.5, 134.5 (2 × d
CH), 169.6 (C), 177.6 (C, CO2Me). MS m/z 280 (M+‚, 6), 243
(13), 215 (14), 205 (47), 183 (52), 173 (12), 154 (71), 139 (70),
122 (46), 107 (66), 66 (100). HRMS: calcd for C15H20O5
280.1311, found 280.1311.
(1R,3aR,4S,7R,7aR)-Methyl-1-methoxymethoxymethyl-
3-trifluoromethanesulfonyloxy-3a,4,7,7a-tetrahydro-1H-
4,7-methanoindene-2-carboxylate. NaH (60% w/w in oil,
214 mg, 5.4 mmol) and N-phenyltrifluoromethanesulfonimide
(1.4 g, 4.0 mmol) were carefully added to a stirred solution of
14 (1.0 g, 3.6 mmol) in THF (36 mL) at 0 °C under a nitrogen
atmosphere. The reaction mixture was allowed to warm to
room temperature and stirred for 4 h after which time water
(5 mL) was carefully added at 0 °C. The resulting mixture was
further diluted with water (80 mL) and extracted twice with
diethyl ether (75 mL). The combined organic extracts were
washed with brine (100 mL) and dried (MgSO4), and the
solvent was removed in vacuo. The residue was subjected to
flash chromatography on a column of silica gel using 20% ethyl
acetate in petroleum spirits as the eluant, to afford the triflate
(1.14 g, 77%) as a colorless oil. [R]20D: -13.6 (c 0.96 CHCl3).
IR (film) ν: 3440, 2953, 2887, 1725, 1660, 1661, 1427, 1343,
1231, 1212, 1143, 1041, 947 cm-1. 1H NMR δ: 1.28 (d, 1 H, J
) 8.5 Hz), 1.60 (d, 1 H, J ) 8.5 Hz), 2.57 (m, 1 H), 2.67 (m, 1
H), 3.06 (br s, 2 H, H4 + H7), 3.33 (s, 3 H, OMe), 3.52 (m, 2 H,
H1 + CH2OMOM), 3.66 (dd, 1 H, J ) 5.6, 3.9 Hz, CH2OMOM′),
3.74 (s, 3 H, CO2Me), 4.59 (AB d, 2 H, J ) 6.7 Hz, OCH2OMe),
6.07 (m, 1 H), 6.11 (m, 1 H). 13C NMR δ: 42.1 (CH), 44.7 (CH),
44.7 (CH), 46.0 (CH), 49.6 (CH2), 51.6, 51.8 (CH + OMe), 55.1
(CO2Me), 69.5 (CH2), 96.4 (CH2), 118.3 (C, q, J ) 320 Hz, CF3),
123.6 (C), 134.1, 134.9 (2 × dCH), 156.2 (C), 162.2 (CO2Me).
MS m/z: 412 (M+‚, 3), 380 (3), 347 (40), 315 (67), 285 (44), 153
(24), 66 (100). HRMS: calcd for C16H19O7F3S 412.0804, found
412.0805.
1
1267, 1180, 770 cm-1. H NMR δ: 1.13 (d, 1 H, J ) 6.9 Hz,
CHMe), 1.16 (d, 1 H, J ) 7.0 Hz, CHMe), 1.58 (br d, 1 H, J )
8.4 Hz), 1.75 (dt, 1 H, J ) 8.4, 1.2 Hz), 2.45 (sep, 1 H, J ) 6.7
Hz, CHMe2), 2.85 (t, 1 H, J ) 5.2 Hz), 3.00 (m, 1 H, H4), 3.18
(m, 1 H), 3.37 (td, 1 H, J ) 4.4, 1.1 Hz), 5.69 (s, 1 H, H2), 5.75
(dd, 1 H, J ) 5.5, 3.1 Hz), 5.98 (dd, 1 H, J ) 5.5, 3.1 Hz). 13C
NMR δ: 20.3 (Me), 21,1 (Me), 30.9 (CH), 43.8 (CH), 43.9 (CH),
48.3 (CH), 51.2 (CH), 52.1 (CH2), 130.0 (CH), 131.6, 133.1 (2
× dCH), 133.1 (C), 210.0 (C, CO). MS m/z:188 (M+‚, 48), 173
(46), 160 (21), 145 (48), 123 (34), 117 (48), 105, 17), 91 (32), 77
(27), 66 (100). HRMS: calcd for C13H16O1 188.1201, found
188.1199.
(3aRS,4SR,7RS,7aSR)-Methyl-3-isopropyl-1-oxo-
3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-2-carbox-
ylate (12). NaHMDS/THF (1.0 M, 15.1 mL, 15.1 mmol) was
added dropwise to a stirred solution of enone 11 (1.9 g, 10
mmol) in THF (100 mL) at 0 °C under a nitrogen atmosphere.
The reaction mixture was stirred at 0 °C for 1.5 h and cooled
to -78 °C and methyl cyanoformate (2.4 mL, 30 mmol) added.
After 30 min, water (25 mL) was carefully added and the
reaction mixture allowed to warm to room temperature, diluted
with water (75 mL), and extracted twice with diethyl ether
(100 mL). The combined organic extracts were washed with
brine (75 mL), dried (MgSO4), and concentrated in vacuo. The
residue was subjected to flash chromatography on a column
of silica gel using 30% ethyl acetate in petroleum spirits as
the eluant to afford ester 12 (1.8 g, 73%) as an oil. IR (film) ν:
2971, 2876, 1739, 1703, 1606, 1468, 1432, 1335, 1288, 1234,
1
1187, 1125, 1028 cm-1. H NMR δ: 1.19 (d, 3 H, J ) 7.4 Hz,
CHMe), 1.22 (d, 3 H, J ) 7.4 Hz, CHMe), 1.62 (br d, 1 H, J )
8.5 Hz), 1.77 (dt, 1 H, J ) 8.5, 1.8 Hz), 2.9 (dd, 1 H, J ) 4.8,
4.8 Hz), 3.14 (m, 1 H, H4), 3.24 (m, 1 H, H7), 3.36 (sep, 1 H,
J ) 7.4 Hz, CHMe2), 3.42 (dd, 1 H, J ) 5.8, 4.1 Hz, H3a), 3.78
(s, 3 H, CO2Me), 5.78 (dd, 1 H, J ) 5.6, 2.6 Hz), 6.05 (dd, 1 H,
J ) 5.6, 3.0 Hz). 13C NMR δ: 20.9 (Me), 21.2 (Me), 30.6 (CH),
44.4 (CH), 46.0 (CH), (51.2 (CH), 51.9 (OMe), 52.8 (CH2), 132.1,
134.0 (2 × dCH), 134.6 (C), 164.1 (C, CO2Me), 190.7 (C), 204.2
(C, CO). MS m/z: 246 (M+‚, 25), 214 (26), 181 (40), 171 (26),
149 (100), 122 (21), 115 (15), 91 (26), 66 (81). HRMS: calcd
for C15H18O3 246.1256, found 246.1254.
(3S,3aR,4R,7S,7aR)-(3-Methoxymethoxymethyl-
3a,4,7,7a-tetrahydro-3H-4,7-methanoinden-1-yloxy)tri-
methylsilane (13). n-BuLi/hexanes (1.6 M, 13.7 mL, 21.8
mmol) was added dropwise to a stirred solution of n-Bu3SnCH2-
OMOM (8.0 g, 21.8 mmol) in THF (60 mL) at -78 °C under a
nitrogen atmosphere. After 5 min, the reaction mixture was
transferred via a cannula to a stirred solution of CuI (2.1 g,
10.9 mmol) and TMEDA (5.0 mL, 32.7 mmol) in THF (20 mL)
at -78 °C under a nitrogen atmosphere. The resulting mixture
was stirred for 30 min before TMSCl (4.2 mL, 32.7 mmol) and
a solution of (-)-10 (1.6 g, 10.9 mmol) in THF (20 mL) were
added consecutively. After 45 min, the reaction was quenched
J. Org. Chem, Vol. 70, No. 5, 2005 1661

Mander and Thomson
(1R,3aR,4S,7R,7aR)-Methyl-3-isopropyl-1-methoxy-
methoxymethyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-
2-carboxylate (15). n-BuLi/hexanes (1.6 M, 5.2 mL, 8.2 mmol)
was added to a stirred solution of thiophene (660 µL, 8.2 mmol)
in THF (10 mL) at 0 °C under a nitrogen atmosphere. After
20 min, the resulting solution was transferred via a cannula
to a stirred suspension of CuCN (738 mg, 8.2 mmol) in THF
(10 mL) at -78 °C. The mixture was allowed to slowly warm
to -40 °C and stirred for a further 30 min, after which time
the solution was cooled to -78 °C. Isopropylmagnesium
chloride/THF (2.0 M, 4.12 mL, 8.2 mmol) was added, followed
by the addition of a solution of the triflate (1.7 g, 4.1 mmol) in
THF (15 mL). After 1 h, aqueous ammonium chloride solution
(10 mL) was added and the mixture allowed to warm to room
temperature. The mixture was diluted with water (100 mL)
and 10% aqueous ammonia solution (5 mL) and then extracted
three times with diethyl ether (150 mL). The combined organic
extracts were washed with 1.0 M HCl (200 mL) and brine (200
mL) and dried (MgSO4). Concentration in vacuo followed by
flash chromatography on a column of silica gel using 10% ethyl
acetate in petroleum spirits as the eluant afforded 15 (919 mg,
73%) as a colorless oil. [R]20D: -110.2 (c 0.68 CHCl3). IR (film)
ν: 2949, 1707, 1618, 1465, 1434, 1337, 1231, 1150, 1111, 1041
cm-1. 1H NMR δ: 1.10 (apparent t, 6 H, 2 × CHMe), 1.29 (m,
1 H), 1.50 (dt, 1 H, J ) 8.1, 1.9 Hz), 2.52 (m, 2 H, H1 + H7a),
3.05 (m, 2 H, H4 + H7), 3.29 (d, 1 H, J ) 7.8 Hz, CH2OMOM),
3.35 (s, 3 H, OMe), 3.40 (m, 1 H, H3a), 3.54 (sep, 1 H, J ) 7.0
Hz, CHMe2), 3.64 (m, 1 H, CH2OMOM′), 3.66 (s, 3 H, CO2Me),
4.60 (AB d, 2 H, J ) 6.6 Hz, OCH2OMe), 5.90 (dd, 1 H, J )
5.7, 2.8 Hz), 6,04 (dd, 1 H, J ) 5.7, 2.9 Hz). 13C NMR δ: 21.3
(Me), 21.5 (Me), 27.8 (CH), 43. ((CH), 45.7 (CH), 45.7 (CH),
47.1 (CH), 48.9 (CH), 50.2 (CH2), 50.8 (CH), 54.7, 54.9 (OMe
+ CO2Me), 71.4 (CH2), 96.3 (CH2), 127.3 (C), 133.5, 135.2 (2 ×
dCH), 165.8, 166.0 (CO2Me + C3). MS m/z: 306 (M+‚, 27), 274
(13), 260 (45), 243 (33), 231 (24), 180 (100), 165 (24), 134 (28),
105 (26). 66 (15). HRMS: calcd for C18H27O4 ([M + H]+)
307.1909, found 307.1904.
(1R,3aR,4S,7R,7aR)-Methyl-1-hydroxymethyl-3-isopro-
pyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-2-car-
boxylate. A solution of MOM ether 15 (160 mg, 0.52 mmol),
MgBr2‚Et2O (1.35 g, 5.2 mmol), and 1-butanethiol (504 µL, 4.7
mmol) in diethyl ether (5 mL) was stirred at room temperature
for 24 h. The resulting solution was then diluted with 1.0 M
HCl (10 mL) and extracted three times with ethyl acetate (10
mL). The combined organic extracts were washed with brine
(20 mL) and dried (MgSO4), and the solvent was removed in
vacuo. The residue was subjected to flash chromatography on
a column of silica gel using 50% ethyl acetate in hexanes as
the eluant to afford the alcohol (113 mg, 83%) as a colorless
oil. [R]20D: -104.0 (c 0.65 CHCl3). IR (film) ν: 3401, 2963, 1697,
1615, 1434, 1338, 1231, 1100, 1035 cm-1. 1H NMR δ: 1.10 (m,
6 H, 2 × CHMe), 1.29 (d, 1 H, J ) 8.1 Hz), 1.51 (dt, 1 H, J )
8.2, 1.8 Hz), 2.39 (m, 1 H, H7a), 2.46 (m, 1 H, H1), 3.00 (br s,
2 H, H4 + H7), 3.39 (m, 1 H, H3a), 3.46 (m, 1 H, CHMe2),
3.59 (m, 2 H, CH2OMOM), 3.70 (s, 3 H, CO2Me), 5.90 (dd, 1
H, J ) 5.7, 2.9 Hz), 6.02 (dd, I H, J ) 5.9, 2.9 Hz). 13C NMR
δ: 21.5 (Me), 21.7 (Me), 28.4 (CH), 43.4 (CH), 45.6 (CH), 47.2
(CH), 50.1 (CH2), 51.2 (CH + OMe), 54.5 (OMe), 67.3 (CH2),
127.9 (C, C2), 133.6, 135.5 (2 × dCH), 167.0 (C3 + CO2Me).
MS m/z: 262 (M+‚, 4), 231 (4), 196 (40), 178 (29), 166 (100),
151 (44), 135 (19), 119 (51), 91 (36), 66 (28). HRMS: calcd for
C16H22O3 262.1569, found 262.1567.
were washed with brine (50 mL) and dried (MgSO4), and the
solvent was removed in vacuo. The residue was subjected to
flash chromatography on a column of silica gel using 15% ethyl
acetate in hexanes as the eluant to afford 7 (80 mg, 72%) as a
colorless oil. [R]20D: -18.7 (c 0.46). IR (film) ν: 2967, 1719,
1619, 1467, 1434, 1344, 1228, 1193, 1109, 1030 cm-1. 1H NMR
δ: 1.13 (m, 6 H, 2 × CHMe), 1.35 (d, 1 H, J ) 8.4 Hz), 1.57
(dt, 1 H, J ) 8.2 Hz), 2.76 (m, 1 H, H7a), 3.04 (br s, 1 H, H7),
3.07 (br s, 1 H, H4), 3.12 (d, 1 H, J ) 3.1 Hz, H1), 3.44(m, 1 H,
H3a), 3.66 (m, 1 H, CHMe2), 3.67 (s, 3 H, CO2Me), 5.96 (dd, 1
H, J ) 6.0, 2.6 Hz), 6.05 (dd, 1 H, J ) 5.7, 2.9 Hz), 9.57 (d, 1
H, J ) 2.8 Hz, CHO). 13C NMR δ: 21.4 (Me), 21,7 (Me), 28.2
(CH), 40.0 (CH), 45.5 (CH), 47.1 (CH), 50.4 (CH2), 51.3 (CH),
55.2 (CO2Me), 61.0 (CH), 124.3 (C, C2), 133.4, 135.8 (2 × d
CH), 164.8 (C, C3), 170.2 (CO2Me), 201.7 (CHO). MS m/z 260
(M+‚, 5), 233 (20), 195 (76), 166 (100), 151 (85), 133 (48), 119
(52), 107 (56), 91 (66), 77 (38), 66 (97). HRMS: calcd for
C16H20O3 260.1412, found 260.1410.
(1R,3aR,4S,7R,7aS)-Methyl-1-formyl-1-isobutyl-3-iso-
propyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-2-car-
t
boxylate (16). BuOK/THF (1.0 M, 115 µL, 115 µmol) was
added to a stirred solution of aldehyde 7 (25 mg, 96 µmol) in
THF (1.0 mL) at 0 °C under a nitrogen atmosphere. After 5
min, isobutyl iodide (33 µL, 288 µmol) was added and the
reaction mixture allowed to warm to room temperature. After
2.5 h, the mixture was diluted with water (10 mL) and
extracted twice with diethyl ether (10 mL). The combined
organic extracts were washed with brine (20 mL) and dried
(MgSO4), and the solvent was removed in vacuo. The residue
was subjected to flash chromatography on a column of silica
gel using 5% ethyl acetate in hexanes as the eluant to afford
16 (15 mg, 50%) as a single stereoisomer. [R]20D: -78.4 (c 0.26
CHCl3). IR (film) ν: 2917, 1715, 1606, 1466, 1342, 1226, 1082,
1024 cm-1. 1H NMR δ: 0.76 (d, 3 H, J ) 6.6 Hz, CHMe′), 0.94
(d, 3 H, J ) 6.7 Hz, CHMe′), 1.15 (d, 3 H, J ) 7.0 Hz, CHMe),
1.16 (d, 3 H, J ) 6.9 Hz, CHMe), 1.31 (d, 1 H, J ) 8.4 Hz),
1.41 (m, 1 H, CHMe2′), 1.58 (br d, 1 H, J ) 8.2 Hz), 1.74 (m, 2
H, CH2CHMe2), 2.59 (dd, 1 H, J ) 8.1, 4.0 Hz, H7a), 2.97 (br
s, 1 H), 3.14 (br, s, 1 H), 3.52 (dd, 1 H, J ) 8.2, 4.3 Hz, H3a),
3.66 (sep, 1 H, J ) 7.0 Hz, CHMe2), 3.68 (s, 3 H, CO2Me), 5.80,
5.88 (2 × m, 1 H, H5 + H6), 9.61 (s, 1 H, CHO). 13C NMR δ:
21.3 (Me), 21.5 (Me), 24.3 (Me), 24.5 (Me), 25.5 (CH), 28.6 (CH),
45.2 (CH), 45.7 (CH2), 47.5 (CH), 50.6 (CH), 51.5 (CH), 51.5
(CH), 51.5 (CH2), 52.6 (OMe), 63.5 (C), 129.2 (C), 134.3, 135.3
(2 × dCH), 169.4 (C3 + CO2Me), 205.9 (CHO). MS m/z: 316
(M+‚, 10), 298 (10), 260 (28), 248 (20), 222 (100), 207 (20), 179
(88), 147 (50), 119 (50), 91 (42), 66 (38). HRMS: calcd for
C20H26O3 316.2038, found 316.2037.
(2S,3S,3aS,4S,7R,7aS)-3-Methoxymethoxymethyl-2-
methyl-2,3,3a,4,7,7a-hexahydro-4,7-methanoinden-1-
one (17). MeLi/diethyl ether (1.0 M, 6.4 mL, 6.4 mmol) was
added dropwise to a solution of silyl enol ether ent-13 (1.87 g,
6.4 mmol) in THF (50 mL) at -20 °C under a nitrogen
atmosphere. Stirring was continued at -20 °C for 30 min, and
then after the mixture was cooled to -78 °C, HMPA (5.5 mL,
32 mmol) and MeI (1.98 mL, 32 mmol) were added. After 30
min, the reaction mixture was allowed to gradually warm to
-20 °C and stirred for a further 1 h before aqueous ammonium
chloride solution (10 mL) was carefully added. The mixture
was allowed to warm to room temperature, diluted with water
(100 mL), and extracted twice with diethyl ether (100 mL).
The combined organic extracts were washed with brine (75
mL) and dried (MgSO4). Concentration in vacuo, followed by
flash chromatography on a column of silica gel using 10% ethyl
acetate in petroleum spirits as the eluant, gave the ketone 17
(95:5 dr, 881 mg, 60%) as a colorless oil. [R]20D: +131.7 (c 0.67
CHCl3). IR (film) ν: 2933, 1730, 1455, 1182, 1149, 1108, 1052,
(1S,3aR,4S,7R,7aS)-Methyl-1-formyl-3-isopropyl-
3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-2-carbox-
ylate (7). Dess-Martin periodinane (366 mg, 0.86 mmol) was
added to a stirred solution of the alcohol (113 mg, 0.43 mmol)
in DCM (5 mL) at room temperature. After 1 h, the reaction
mixture was diluted with DCM (5 mL) and then treated with
1.0 M sodium thiosulfate (5 mL) and saturated aqueous sodium
bicarbonate (5 mL). After vigorous stirring for 10 min, the
reaction mixture was diluted with water (20 mL) and extracted
three times with DCM (20 mL). The combined organic extracts
1
917 cm-1. H NMR δ: 0.95 (d, 3 H, J ) 7.3 Hz, CHMe), 1.41
(dt, 1 H, J ) 8.2, 1.4 Hz), 1.53 (dt, 1 H, J ) 8.2, 1.6 Hz), 2.01
(m, 1 H, H3), 2.18 (m, 1 H, H2), 2.70 (ddd, 1 H, J ) 9.2, 4.1,
2.2 Hz, H3a), 2.91 (dd, 1 H, J ) 9.2, 4.7 Hz, H7a), 3.05 (m, 1
H, H4), 3.18 (m, 1 H, H7), 3.34 (s, 3 H, OMe), 3.45, 3.53 (AB
1662 J. Org. Chem., Vol. 70, No. 5, 2005

Total Synthesis of Sordaricin
d, 2 H, J ) 9.3 Hz, CH2OMOM), 4.55 (s, 2 H, OCH2OMe), 6.07
(dd, 1 H, J ) 5.6, 2.9 Hz, H6), 6.22 (dd, 1 H, J ) 5.6, 3.0 Hz,
H5). 13C NMR δ: 9.5 (Me), 39.7 (CH), 44.1 (CH), 46.9 (CH),
47.1 (CH), 47.3 (CH), 52.4 (CH2), 53.4 (CH), 55.3 (OMe), 69.3
(CH2), 96.5 (CH2), 134.6, 136.0 (2 × dCH), 220.8 (C, CO). MS
m/z: 236 (M+‚, 5), 191 (3), 171 (48), 139 (50), 109 (47), 91 (32),
81 (39), 66 (100). HRMS: calcd for C14H20O3 236.1412, found
236.1415.
solution of the crude alcohols in DCM (5 mL) at room
temperature under a nitrogen atmosphere. After 2 h, the
reaction mixture was diluted with a 1.0 M aqueous HCl
solution (30 mL) and extracted three times with DCM (20 mL).
The combined organic extracts were washed with aqueous
sodium bicarbonate (25 mL) and brine (25 mL) and dried
(MgSO4). Concentration in vacuo, followed by flash chroma-
tography on a column of silica gel using 10% ethyl acetate in
petroleum spirits as the eluant, afforded an inseparable 2:1
mixture of thionocarbonates (435 mg, 88%). 1H NMR δ:
(major) 5.59 (m, 1 H, CHOC(S)OPh); (minor) 5.28 (m, 1 H,
CHOC(S)OPh). n-Bu3SnH (398 µL) and AIBN (cat.) were added
to a stirred solution of thionocarbonates (435 mg, 1.2 mmol)
in benzene (5 mL) at reflux under a nitrogen atmosphere. After
30 min the reaction mixture was allowed to cool to room
temperature and the solvent removed in vacuo. The residue
was subjected to flash chromatography on a column of silica
gel using petroleum spirits and then 10% ethyl acetate in
petroleum spirits as the eluant, to afford cyclopentane 20 (258
mg, 100%) as a colorless oil. [R]20D: -42.8 (c 0.80 CHCl3). IR
(4S,5S)-4-Methoxymethoxymethyl-5-methylcyclopent-
2-enone (18). Nitrogen was bubbled through a stirred solution
of ketone 17 (800 mg, 3.4 mmol) in 1,2-dichlorobenzene (6 mL)
at reflux for 7 h. After being cooled to room temperature, the
reaction mixture was subjected to flash chromatography on a
column of silica gel using petroleum spirits, then 50% ethyl
acetate in petroleum spirits as the eluant, to give the enone
18 (507 mg, 85%) as a colorless oil. [R]20 +234.9 (c 0.48
D
CHCl3). IR (film) ν: 2883, 1709, 1588, 1458, 1383, 1354, 1187,
1
1150, 1109, 1036 cm-1. H NMR δ: 1.15 (d, 3 H, J ) 7.6 Hz,
CHMe), 2.52 (m, 1 H, H5), 3.52 (m, 1 H, H4), 3.35 (s, 3 H,
OMe), 3.55 (dd, 1 H, J ) 10.5, 7.0 Hz, CH2OMOM), 3.70 (dd,
1 H, J ) 9.6, 6.9 Hz, CH2OMOM′), 4.60 (s, 2 H, OCH2OMe),
6.24 (dd, 1 H, J ) 5.9, 2.0 Hz, H2), 7.67 (dd, 1 H, J ) 5.9, 2.6
Hz, H3). 13C NMR δ: 10.5 (Me), 42.1 (CH), 45.) (CH), 55.4
(OMe), 67.0 (CH2), 96.5 (CH2), 133.5 (CH), 164.2 (CH), 211.8
(C, CO). MS m/z: 170 (M+‚, 15), 140 (100), 125 (5), 108 (34),
95 (21), 81 (51), 75 (39), 67 (29). HRMS: calcd for C9H14O3
170.0943, found 170.0943.
(film) ν: 2950, 1642, 1454, 1377, 1213, 1147, 1110, 1048 cm-1
.
1H NMR δ: 0.93 (d, 3 H, J ) 7.2 Hz, CHMe), 1.24-1.38 (m, 1
H), 1.42-1.58 (m, 1 H), 1.70 (m, 3 H, dCMe), 1.78-1.90 (m, 2
H), 2.02-2.12 (m, 1 H, H1), 2.20-2.36 (m, 2 H), 3.37 (s, 3 H,
OMe), 3.44 (m, 2 H, CH2OMOM), 4.60 (AB d, 2 H, J ) 6.4 Hz,
OCH2OMe), 4.69 (m, 2 H, dCH2). 13C NMR δ: 15.5 (Me), 19.2
(dCMe), 29.7 (CH2), 33.4 (CH2), 35.0 (CH), 45.7 (CH), 48.2
(CH), 55.2 (OMe), 68.0 (CH2), 96.6 (CH2), 110.0 (dCH2), 147.5
(dCMe). MS m/z 198 (M+‚, 1), 167 (11), 153 (15), 136 (68), 123
(100), 107 (55), 95 (62), 81 (84), 67 (35). HRMS: calcd for
C12H22O2 198.1620, found 198.1620.
(2S,3S,4R)-4-Isopropenyl-3-methoxymethoxymethyl-2-
methylcyclopentanone (19). Isopropenylmagnesium bromide/
THF (0.5 M, 345 mL, 2.4 mmol) was added to a stirred
suspension of CuI (224 mg, 1.2 mmol) in THF (10 mL) at -78
°C under a nitrogen atmosphere. After 5 min, TMSCl (298 µL,
2.4 mmol) and a solution of enone 18 (345 mg, 2.0 mmol) in
THF (5 mL) were added dropwise. After the mixture was
stirred for 15 min, a solution of aqueous ammonium chloride
(5 mL) was added and the reaction mixture allowed to warm
to room temperature. The solution was diluted with water (50
mL) and 10% aqueous ammonia (2 mL) and then extracted
three times with ethyl acetate (30 mL). The combined organic
extracts were washed with brine (50 mL), dried (MgSO4), and
concentrated in vacuo. The residue was subjected to flash
chromatography on a column of silica gel using 20% ethyl
acetate in petroleum spirits as the eluant to afford olefin 19
(300 mg, 70%) as a single diastereoisomer. [R]20D: -19.2 (c
1.02 CHCl3). IR (film) ν: 2933, 1740, 1645, 1454, 1377, 1149,
1108, 1042 cm-1. 1H NMR δ: 1.07 (d, 3 H, J ) 7.3 Hz, CHMe),
1.78 (m, 3 H, dCMe), 2.26 (ddd, 1 H, J ) 18.8, 7.5, 1.5 Hz),
2.40-2.60 (m, 3 H, H2), 2.72 (dd, 1 H, J ) 14.4, 6.9 Hz, H4),
3.35 (s, 3 H, OMe), 3.56 (AB d, 2 H, J ) 5.6 Hz, CH2OMOM),
4.58 (s, 2 H, OCH2OMe), 4.76, 4.82 (m, 2 × 1 H, dCH2). 13C
NMR δ: 9.8 (Me), 20.2 (dCMe), 41.8 (CH2), 42.9 (CH), 43.5
(CH), 43.8 (CH), 55.3 (OMe), 67.3 (CH2), 96.5 (CH2), 110.8 (d
CH2), 145.3 (dCMe), 219.4 (CO). MS m/z 212 (M+‚, 55), 180
(40), 167 (39), 152 (41), 137 (53), 121 (56), 107 (82), 93 (74), 81
(62), 68 (92), 55 (100). HRMS: calcd for C12H20O3 212.1412,
found 212.1410.
(1R,2R,3R)-1-Isopropenyl-2-methoxymethoxymethyl-
3-methylcyclopentane (20). NaBH4 (106 mg, 2.8 mmol) was
added to a stirred solution of ketone 19 in MeOH (10 mL) at
0 °C. After 20 min, water (5 mL) was added and the mixture
stirred for a further 5 min. The reaction mixture was diluted
with water (20 mL) and extracted three times with ethyl
acetate (25 mL). The combined organic extracts were then
washed with brine (20 mL), dried (MgSO4), and concentrated
in vacuo to afford a 2:1 mixture of diastereomeric alcohols
which was used in the next reaction without further purifica-
tion. 1H NMR δ: (major) 1.04 (d, 3 H, J ) 7.2 Hz, CHMe),
1.70 (m, 3 H, dCMe), 3.39 (s, 3 H, OMe), 3.98 (m, 1 H, CHOH);
(minor) 0.94 (d, 3 H, J ) 7.2 Hz, CHMe), 1.73 (m, 3 H,
dCHCMe), 3.35 (s, 3 H, OMe), 3.87 (q, 1 H, J ) 5.7 Hz,
CHOH). Pyridine (280 µL, 3.5 mmol) and phenyl chlorothiono-
formate (211 µL, 1.5 mmol) were added successively to a stirred
(1R,2R,5R)-(2-Isopropenyl-5-methylcyclopentyl)meth-
anol. A solution of ether 20 (80 mg, 0.4 mmol) and PPTS (624
mg, 2.4 mmol) in tBuOH (8 mL) was heated at reflux for 20 h.
After cooling to room temperature, the reaction mixture was
diluted with a 1.0 M aqueous HCl solution (10 mL) and
extracted three times with ethyl acetate (15 mL). The com-
bined organic extracts were washed with brine (20 mL) and
dried (MgSO4), and the solvent was removed in vacuo. The
residue was subjected to flash chromatography on a column
of silica gel using 40% ethyl acetate in petroleum spirits as
the eluant to give the alcohol (50 mg, 80%) as a pale yellow
oil. Identical with spectra obtained from (S)-(+)-carvone.30
(1R,2R,5R)-tert-Butyl[2-isopropenyl-5-methylcyclopen-
tylmethoxy)dimethylsilane. TBSCl (3.5 g, 23.3 mmol) was
added to a stirred solution of the alcohol (3.0 g, 19.4 mmol)
and DIPEA (4.7 mL, 27.2 mmol) in DMF (50 mL) at 0 °C under
a nitrogen atmosphere. The reaction mixture was allowed to
warm to room temperature and stir for 12 h, after which time
the mixture was diluted with water (250 mL) and 1.0 M HCl
(250 mL) and then extracted three times with diethyl ether
(100 mL). The combined organic extracts were washed with
brine (200 mL) and dried (MgSO4), and the solvent was
removed in vacuo. The residue was subjected to flash chro-
matography on a column of silica gel using 10% ethyl acetate
in petroleum spirits as the eluant to give the TBS ether (5 g,
96%) as an oil. [R]20D: +10.1 (c 0.24 CHCl3). IR (film) ν: 2954,
2858, 1643, 1471, 1462, 1387, 1255, 1098 cm-1 1H NMR δ:
.
0.03 (s, 6 H, SiMe2), 0.89 (s, 9 H, SitBu), 0.94 (d, 3 H, J ) 7.0
Hz, CHMe), 1.22-1.50 (m, 2 H), 1.70 (m, 3 H, dCMe), 1.75-
1.98 (m, 3 H), 2.21 (m, 1 H, H5), 2.35 (q, 1 H, J ) 8.8 Hz, H2),
3.53 (m, 2 H, CH2OTBS), 4.67 (m, 2 H, dCH2). 13C NMR δ:
-5.3 (SiMe2), 15.5 (Me), 18.3 (SiCMe3), 19.5 (dCMe), 26.0
(SiCMe3), 30.1 (CH2), 33.7 (CH2), 35.4 (CH), 48.0 (2 × CH),
62.8 (CH2), 109.5 (dCH2), 148.2 (dCMe). MS m/z: 211 ([M -
tBu]+‚, 45), 193 (5), 181 (8), 169 (18), 135 (12), 89 (18), 75 (100).
HRMS: calcd for C12H23OSi 211.1518, found 211.1516.
(1R,2R,5R)-tert-Butyldimethyl[2-methyl-5-(2′-meth-
yloxiranyl)cyclopentylmethoxy]silane. To a stirred solu-
(30) Obtained by reduction of the parent methyl ester, which was
prepared by the method of: Wolinsky, J.; Gibson, T.; Chan, D.; Wolf,
H. Tetrahedron 1965, 21, 1247.
J. Org. Chem, Vol. 70, No. 5, 2005 1663

Mander and Thomson
tion of the olefin (7.5 g, 28.8 mmol) and NaHCO3 (25 g) in DCM
(300 mL) was added small portions of m-CPBA (57-86%) until
all the starting material was consumed, as judged by TLC. A
solution of Na2SO3 (15 g) in water (150 mL) was added and
the resulting mixture stirred vigorously for 10 min. The
reaction mixture was diluted with diethyl ether (200 mL) and
washed twice with 3% aqueous NaOH solution (500 mL). The
combined organic extracts were washed with brine (200 mL)
and dried (MgSO4), and the solvent was removed in vacuo. The
residue was subjected to flash chromatography on a column
of silica gel using 5% ethyl acetate in petroleum spirits as the
eluant, to afford an inseparable mixture of epoxides (7.6 g,
98%) as a colorless oil. IR (film) ν: 2954, 2858, 1472, 1387,
1255, 1094 cm-1. 1H NMR (key signals) δ: 0.04 (s, 6 H, SiMe2),
0.89 (s, 9 H, SitBu), 0.92 (m, 3 H, CHMe), 1.30 (s, 3 H, Me′),
1.30-1.90 (m, 6 H), 2.10 (m 1 H, H2), 2.53, 2.61 (AB d, 2 H, J
) 7.2 Hz, H1′), 3.57 (m, 2 H, CH2OTBS). MS m/z: 284
([M+H]+‚, 2), 267 (8), 227 (52), 209 (8), 197 (17), 153 (12), 135
(100), 121 915), 93 (30), 75 (70). HRMS: calcd for C12H23O2Si
227.1467, found 227.1469.
109.7 (dCH2), 148.6 (dC). MS m/z: 297 ([M - OMe]+‚, 2), 267
(20), 209 (18), 179 (20), 147 (95), 135 (30), 119 (75), 105 (70),
89 (80), 75 (100). HRMS: calcd for [M + H] C18H37O3Si
329.2512, found 329.2521.
(1R,2R,5R)-[2-(1′-Methoxymethoxymethyl-vinyl)-5-meth-
yl-cyclopentyl]-methanol. TBAF/THF (1.0 M, 45.6 mL, 45.6
mmol) was added dropwise to a stirred solution of the TBDMS
ether (5.0 g, 15 mmol) in THF (50 mL) at 0 °C under a nitrogen
atmosphere. The reaction mixture was allowed to stir at room
temperature for 16 h, then diluted with water (150 mL) and
extracted three times with diethyl ether (100 mL). The
combined organic extracts were washed with brine (100 mL),
dried (MgSO4) and the solvent removed in vacuo. The residue
was subjected to flash chromatography on a column of silica
gel using 50% ethyl acetate in petroleum spirits as the eluant,
to give the alcohol (3.1 g, 93%) as an oil. [R]20 -40.7 (c 0.70
D
CHCl3). IR (film) ν: 3435, 2950, 2874, 1649, 1456, 1399, 1214,
1150, 1050 cm-1. 1H NMR δ: 0.92 (d, 3 H, J ) 7.2 Hz, CHMe),
1.24-1.36 (m, 1 H), 1.42-1.58 (m, 1 H), 1.8-2.25 (m, 3 H),
1.85 (br s, 1 H, OH), 2.26 (sep, 1 H, J ) 6.7 Hz, H5), 2.41 (q,
1 H, J ) 8.8 Hz, H2), 3.38 (s, 3 H, OMe), 3.62 (m, 2 H, CH2-
OH), 4.04 (s, 2 H, CH2OMOM), 4.64 (s, 2 H, OCH2OMe), 5.02,
5.08 (br s, 2 × 1 H, dCH2). 13C NMR δ: 15.3 (Me), 31.2 (CH2),
33.3 (CH2), 34.9 (CH), 44.6 (CH), 49.3 (CH), 55.1 (OMe), 62.9
(CH2), 69.5 (CH2), 95.4 (CH2), 110.9 (dCH2), 148.5 (dC). MS
m/z: 183 ([M - MeOH]+‚, 3), 169 (10), 151 (49), 137 (35), 123
9100), 107 (65), 91 (38), 81 (74), 67 (45). HRMS: calcd for [M
- MeOH] C11H18O2 182.1307, found 182.1309.
(1′R,2′R,3′R)-[2′-(tert-Butyldimethylsilanyloxymethyl)-
3′-methylcyclopentyl]prop-2-en-1-ol (22). A solution of the
epoxides (2.0 g, 7.0 mmol) in diethyl ether (20 mL) was
transferred via a cannula into a stirred solution of LCIA,
prepared by addition of n-BuLi/hexane (1.6 M, 26.4 mL, 42.0
mmol) to a solution cyclohexylisopropylamine (6.9 mL, 42.0
mmol) in diethyl ether (100 mL) at 0 °C. The mixture was
stirred at room temperature for 6.5 h, cooled to 0 °C, and
quenched with saturated aqueous ammonium chloride solution
(25 mL). The resulting mixture was diluted with water (125
mL) and extracted twice with diethyl ether (100 mL). The
combined organic extracts were then washed with 1.0 M HCl
(150 mL) and brine (150 mL) and dried (MgSO4). Concentra-
tion in vacuo, followed by flash chromatography on a column
of silica gel using 20% ethyl acetate in petroleum spirits as
the eluant, afforded allylic alcohol 22 (1.28 g, 64%) as a
colorless oil. [R]20D: -30.6 (c 0.32 CHCl3). IR (film) ν: 3369,
2953, 1647, 1471, 1462, 1388, 1254, 1096, 1056 cm-1. 1H NMR
δ: 0.05 (s, 6 H, SiMe2), 0.89 (s, 9 H, SitBu), 0.90 (obscured d,
3 H, CHMe), 1.28 (m, 1 H), 1.51 (m, 1 H), 1.78-2.50 (m, 4 H),
2.47 (m, 1 H), 2.54 (br s, 1 H, OH), 3.52 (dd, 1 H, J ) 10.0, 7.2
Hz, CH2OTBS), 3.65 (dd, 1 H, J ) 9.8, 6.0 Hz, CH2OTBS′),
4.10 (apparent t, 2 H, J ) 13.6 Hz, CH2OH), 4.90, 5.00 (br s,
2 × 1 H, dCH2). 13C NMR δ: -5.5, -5.4 (SiMe2), 15.3 (Me),
18.2 (C, SiCMe3), 25.9 (SiCMe3), 31.2 (CH2), 33.5 (CH2), 35.4
(CH), 44.5 (CH), 49.0 (CH), 63.6 (CH2), 65.1 (CH2), 108.5 (d
(1R,2R,3R)-2-Iodomethyl-1-(1′-methoxymethoxymeth-
ylvinyl)-3-methylcyclopentane (6). Iodine (3.6 g, 14.0 mmol)
was added to a stirred solution of the alcohol (2.0 g, 9.3 mmol)
and triphenylphosphine (3.7 g, 14.0 mmol) in 3:1 diethyl ether:
acetonitrile (80 mL) at room temperature under a nitrogen
atmosphere. After 30 min, the mixture was diluted with
saturated aqueous sodium bicarbonate solution (100 mL) and
extracted twice with diethyl ether (100 mL). The combined
organic extracts were washed with brine (100 mL) and dried
(MgSO4), and the solvent was removed in vacuo. The resulting
residue was taken up in diethyl ether and the insoluble
triphenylphosphine oxide removed by filtration. The mother
liquor was evaporated and the residue subjected to flash
chromatography on a column of silica gel using 5% diethyl
ether in hexanes as the eluant to give 6 (2.9 g, 96%) as a
colorless oil. [R]20D: -64.7 (c 0.30 CHCl3). IR (film) ν: 2953,
1646, 1464, 1428, 1378, 1211, 1150, 1104, 1052 cm-1. 1H NMR
δ: 0.88 (d, 3 H, J ) 6.7 Hz, CHMe), 1.37 (m, 1 H), 1.60 (m, 1
H), 1.86 (m, 1 H), 2.05 (m, 1 H), 2.31 (m, 3 H), 2.93 (apparent
t, 1 H, J ) 9.8 Hz, CH2I), 3.28 (dd, 1 H, J ) 9.5, 3.5 Hz, CH2I′),
3.39 (s, 3 H, OMe), 4.01 (s, 2 H, CH2OMOM), 4.64 (s, 2 H,
OCH2OMe), 4.97, 5.13 (br s, 2 × 1 H, dCH2). 13C NMR δ: 7.3
(CH2I), 14.7 (Me), 31.5 (CH2), 31.6 (CH2), 36.0 (CH), 47.0 (CH),
50.2 (CH), 55.4 (OMe), 69.0 (CH2), 95.6 (CH2), 111.5 (dCH2),
147.2 (dC). MS m/z: 279 ([M - 45]+‚, 27), 264 (6), 235 (36),
165 (18), 147 (42), 135 (64), 121 (32), 107 (64), 95 (90), 81 (100),
67 (59). HRMS: calcd for C12H21O2I 324.0586, found 324.0590.
t
CH2), 152.1 (dC). MS m/z: 227 ([M - Bu]+‚, 22), 135 (35),
107 (46), 93 (85), 75 (100). HRMS: calcd for C12H23O2Si
227.1467, found 227.1465.
(1R,2R,5R)-tert-Butyl-[2-(1′-methoxymethoxymethylvi-
nyl)-5-methylcyclopentylmethoxy]dimethy-silane. To a
stirred solution of alcohol 22 (4.5 g, 16.0 mmol) and DMAP
(193 mg, 1.6 mmol) in DCM (150 mL) at 0 °C under a nitrogen
atmosphere were added DIPEA (6.06 mL, 35.2 mmol) and
MOMCl (2.4 mL, 32.0 mmol). The reaction mixture was
allowed to stir at room temperature for 13 h, diluted with 1.0
M HCl (100 mL), and extracted twice with diethyl ether (150
mL). The combined organic extracts were washed with brine
(150 mL) and dried (MgSO4), and the solvent was removed in
vacuo. The residue was subjected to flash chromatography on
a column of silica gel using 10% ethyl acetate in petroleum
spirits as the eluant to give the MOM ether (5.0 g, 94%) as a
colorless oil. [R]20D: -40.3 (c 0.33 CHCl3). IR (film) ν: 2953,
1647, 1471, 1463, 1388, 1255, 1151, 1100, 1055 cm-1. 1H NMR
δ: 0.03 (s, 6 H, SiMe2), 0.88 (s, 9 H, SitBu), 0.94 (d, 3 H, J )
7.0 Hz, CHMe), 1.22 (m, 1 H), 1.47 (m, 1 H), 1.75-2.04 (m, 4
H), 2.23 (sep, 1 H, J ) 7.3 Hz, H5), 2.40 (q, 1 H, J ) 8.6 Hz,
H2), 3.38 (s, 3 H, OMe), 3.55 (m, 2 H, CH2OTBS), 4.02 (s, 2 H,
CH2OMOM), 4.64 (s, 2 H, OCH2OMe), 4.94, 5.05 (br s, 2 × 1
H, dCH2). 13C NMR δ: -5.5, -5.4 (SiMe2), 15.4 (Me), 18.1 (C,
SiCMe3), 25.9 (SiCMe3), 31.1 (CH2), 33.6 (CH2), 35.3 (CH), 44.2
(CH), 48.6 (CH), 55.1 (OMe), 62.6 (CH2), 69.1 (CH2), 95.4 (CH2),
(1S,3aR,4S,7R,7aS)-3-Oxo-2,3,3a,4,7,7a-hexahydro-1H-
4,7-methanoindene-1-carbonitrile. To a stirred solution of
potassium cyanide (2.23 g, 34.2 mmol) and ammonium chloride
(1.54 g, 28.8 mmol) in water (35 mL) at 0 °C under a nitrogen
atmosphere was added a solution of enone (-)-10 (2.5 g, 17.1
mmol) in DMF (35 mL). The reaction mixture was stirred at
room temperature for 48 h, diluted with water (400 mL), and
extracted three times with ethyl acetate (200 mL). The
combined organic extracts were washed with water (300 mL)
and brine (300 mL) and dried (MgSO4). Concentration in vacuo,
followed by flash chromatography on a column of silica gel
using 60% ethyl acetate in petroleum spirits as the eluant,
afforded the nitrile (2.8 g, 95%) as a white solid. Mp: 48-50
°C (petroleum spirits, ethyl acetate). [R]20D: -149.5 (c 0.66
CHCl3). IR (film) ν: 2977, 223, 1735, 1453, 1404, 1332, 1228,
1
1186, 1133, 840 cm-1. H NMR δ: 1.52 (d, 1 H, J ) 8.6 Hz),
1.67 (dt, 1 H, J ) 8.6, 1.6 Hz), 2.42 (dd, 1 H, J ) 18.5, 10.1
1664 J. Org. Chem., Vol. 70, No. 5, 2005

Total Synthesis of Sordaricin
Hz, H2), 2.56 (ddd, 1 H, J ) 18.5, 6.9, 1.6 Hz, H4′), 2.66 (m, 1
H, H1), 3.11, 3.35 (m, 2 × 1 H, H4 +H7), 3.23, 3.35 (m, 2 × 1
H, H3a + H7a), 6.17 (dd, 1 H, J ) 5.7, 3.1 Hz), 6.23 (dd, 1 H,
J ) 5.7, 3.1 Hz). 13C NMR δ: 25.6 (CH), 44.5 (CH2), 46.2 (CH),
46.3 (CH), 46.6 (CH), 52.1 (CH2), 53.6 (CH), 121.9 (CN), 133.5,
137.5 (2 × dCH), 214.1 (CO). MS m/z: 173 (M+‚, 5), 144 (10),
130 (32), 117 (12), 103 (20), 92 (30), 91 (100), 77 (36). HRMS:
calcd for C11H11NO 173.0841, found 173.0834. Anal. Calcd for
C11H11NO: C, 76.3; H, 6.4; N, 8.1. Found: C, 76.0; H, 6.1; N,
8.0.
46.8 (CH), 47.5 (CH), 47.6 (CH2), 51.0 (CH2), 53.7 (CH), 54.3
(CH), 55.1 (OMe), 63.6 (CH2), 64.2 (CH2), 68.6 (CH2), 95.4
(CH2), 1115.5 (dCH2), 115.8 (C), 123.7 (CN), 133.4, 137.6 (2 ×
dCH), 147.3 (dC). MS: m/z 413 (M+‚, 3.2), 284 (14), 268 (83),
352 (55), 316 (23), 286 (100), 261 (35), 229 (64), 216 (39), 164
912), 89 (30), 66 (78). HRMS: calcd for C25H36NO4 414.2622,
found 414.2643.
(1′R,3a′R,4′S,7′R,7a′S,1′′R,2′′R,5′′R)-1′-[2′′-(1′′′-Methoxy-
methoxymethylvinyl)-5′′-methylcyclopentylmethyl]-
2′,3′,3a′,4′,7′,7a′-hexahydro-1H-4′,7′-methanoindene-1′-
formyl-3′-spiro-2-[1,3]dioxolane. To a stirred solution of
nitrile 24 (1.5 g, 3.6 mmol) in DCM (50 mL) at -78 °C under
a nitrogen atmosphere was added DIBAL-H/hexane (1.0 M,
9.0 mL, 9.0 mmol). After 30 min, the reaction mixture was
quenched with 0.5 M aqueous oxalic acid (5.0 mL) and allowed
to warm to room temperature. The mixture was further diluted
with 0.5 M aqueous oxalic acid (50 mL) and extracted three
times with ethyl acetate (100 mL). The combined organic
extracts were washed with a saturated solution of potassium
sodium tartrate (300 mL) and brine (300 mL) and dried
(MgSO4). The solvent was removed in vacuo to afford the
aldehyde (1.5 g, 100%) which was used in the next reaction
without further purification. For the purpose of characteriza-
tion a portion of the aldehyde was subjected to flash chroma-
tography on a column of silica gel using 15% ethyl acetate in
petroleum spirits as the eluant to afford analytically pure
aldehyde. [R]20D: -28.1 (c 0.76 CHCl3). IR (film) ν: 2954, 1720,
(1′S,3a′R,4′S,7′R,7a′S)-2′,3′,3a′,4′,7′,7a′-Hexahydro-1H-
4′,7′-methanoindene-1′-cyano-3′-spiro-2-[1,3]dioxolane (23).
A solution of the nitrile (950 mg, 5.5 mmol), ethylene glycol
(766 µL, 13.8 mmol), and Dowex-50W resin (285 mg, 30% w/w)
in benzene (50 mL) was heated at reflux through a Soxhlet
apparatus (MgSO4) under a nitrogen atmosphere. After 6 h,
the reaction mixture was cooled to room temperature and
filtered and the solvent removed in vacuo. The remaining
residue was taken up in ethyl acetate (100 mL) and washed
twice with water (100 mL), and then the combined aqueous
extracts were extracted with ethyl acetate (100 mL). The
combined organic extracts were washed with brine (100 mL)
and dried (MgSO4). Concentration in vacuo, followed by flash
chromatography on a column of silica gel using 50% ethyl
acetate in petroleum spirits as the eluant, afforded ketal 23
(1.02 g, 85%) as a white solid. Mp: 106 °C (petroleum spirits,
ethyl acetate). [R]20D: -38.0 (c 1.15 CHCl3). IR (film) ν: 2985,
2231, 1479, 1430, 1338, 1140, 1107, 1067, 901 cm-1. 1H NMR
δ: 1.33 (d, 1 H, J ) 8.4 Hz), 1.50 (dt, 1 H, J ) 8.4, 1.8 Hz),
1.96 (apparent d, 2 H), 2.42 (td, 1 H, J ) 6.7 Hz, H′1), 2.80
(dd, 1 H, J ) 9.2, 4.1 Hz, H′3a), 2.90, 2.95 (m, 2 × 1 H, H′4+
H′7), 3.03 (m, 1 H, H′7a), 3.80-4.00 (m, 4 H, H4, 4′ + H5, 5′),
6.05 (dd, 1 H, J ) 5.6, 2.9 Hz), 6.23 (dd, 1 H, J ) 5.7, 3.1 Hz).
13C NMR δ: ′27.2 (CH), 41.5 (CH2), 44.9 (CH), 45.2 (CH2), 48.9
(CH), 51.8 (CH2), 53.7 (CH), 63.7 CH2), 64.6 (CH2), 115.6 (C),
122.6 (CN), 132.0, 138.5 (2 × dCH). MS m/z 217 (M+‚, 56),
177 (11), 164 (33), 151 (40), 124 (65), 99 (69), 88 (60), 66 (100).
HRMS: calcd for C13H15NO2 217.1103, found 217.1104. Anal.
Calcd for C13H15NO2: C, 71.9; H, 7.0; N, 6.5. Found: C, 72.2;
H, 7.0; N, 6.4.
1645, 1454, 1435, 1333, 1244, 1211, 1150, 1111, 1052 cm-1
.
1H NMR δ: 0.83 (d, 3 H, J ) 7.0 Hz, CHMe), 1.18 (d, 1 H, J
) 8.1 Hz), 1.26-2.10 (m, 9 H), 2.20 (m, 1 H), 2.62 (dd, 1 H, J
) 8.8, 4.0 Hz), 2.75 (m, 1 H), 2.88, 2.98 (br s, 2 × 1 H, H′4 +
H′7), 3.37 (s, 3 H, OMe), 3.75-3.90 (m, 6 H), 4.63 (s, 2 H, OCH2-
OMe), 4.89, 5.10 (br s, 2 × 1 H, dCH2), 5.76 (dd, 1 H, J ) 5.7,
2.9 Hz), 6.10 (dd, 1 H, J ) 5.6, 2.9 Hz), 9.54 (s, 1 H, CHO). 13
C
NMR δ: 14.6 (Me), 28.3 (CH2), 32.9 (CH2), 35.8, 36.0 (CH),
41.0, 43.7 (CH), 44.4 (CH), 44.8 (CH), 47.9 (CH), 51.3 (CH2),
53.4 (CH), 54.0 (CH), 55.2 (OMe), 56.6 (CH2), 63.4 (CH2), 64.2
(CH2), 68.6 (CH2), 95.6 (CH2), 111.5 (dCH2), 116.3 (C), 132.5,
147.8 (2 × dCH), 147.8 (dC), 204.9 (CHO). MS m/z; 371 ([M
- CH2OMe]+‚, 5), 327 (10), 310 (100), 295 (20), 267 (58), 250
(48), 220 (66), 206 (25), 176 (20), 148 (78), 121 (40), 66 (32).
HRMS: calcd for ([M - CH2OMe]+‚ C25H31O4 371.2222, found
371.2221.
(1′R,3a′R,4′S,7′R,7a′S,1′′R,2′′R,5′′R)-1′-[2′′-(1′′′-Methoxy-
methoxymethylvinyl)-5′′-methylcyclopentylmethyl]-
2′,3′,3a′,4′,7′,7a′-hexahydro-1H-4′,7′-methano-indene-1′-
cyano-3′-spiro-2-[1,3]dioxolane (24). A solution of LDA/THF
(1.0 M, 23.1 mL, 23.1 mmol) was added dropwise to a stirred
solution of nitrile 23 (2.0 g, 9.25 mmol) in THF (60 mL) at
-78 °C under a nitrogen atmosphere. After 30 min, the
reaction mixture was allowed to warm to room temperature
and stir for 1 h before being cooled to -78 °C. HMPA (1.6 mL,
9.25 mmol) and a solution of iodide 158 (1.5 g, 4.63 mmol) in
THF (40 mL) were added, and the mixture was stirred at -78
°C for 2 h. A saturated solution of aqueous ammonium chloride
(10 mL) was added and the mixture warmed to room temper-
ature, diluted with 1.0 M HCl (300 mL), and extracted three
times with diethyl ether (150 mL). The combined organic
extracts were washed with brine (500 mL) and dried (MgSO4).
Concentration in vacuo, followed by flash chromatography on
a column of silica gel using 15% ethyl acetate in petroleum
spirits as the eluant, afforded the desired product 24 (1.1 g,
58% based on iodide) as a pale yellow oil. Further elution
afforded recovered nitrile 23 (1.2 g, 5.53 mmol). Product yield
(3′S,3a′S,4′R,7′S,7a′R,1′′R,2′′R,5′′R)-3′-Hydroxymethyl-
3′-[2′′-(1′′′-methoxymethoxymethylvinyl)-5′′-methylcyclo-
pentylmethyl]-2′,3′,3a′,4′,7′,7a′-hexahydro-4′,7′-methanoin-
dene-1′-spiro-2-[1,3]dioxolane. To a stirred solution of the
aldehyde (1.5 g, 3.6 mmol) in MeOH (50 mL) at 0 °C was added
NaBH4 (275 mg, 7.2 mmol) in portions. After 30 min, the
reaction was quenched with water (15 mL) and stirred for 10
min. The reaction mixture was further diluted with water (50
mL) and extracted three times with ethyl acetate (60 mL). The
combined organic extracts were washed with brine (500 mL)
and dried (MgSO4). The solvent was removed in vacuo to afford
the crude alcohol (1.46 g, 97%) which was used directly in the
next reaction. For the purpose of characterization a portion of
the alcohol was subjected to flash chromatography on a column
of silica gel using 20% ethyl acetate in petroleum spirits as
the eluant to afford pure alcohol. [R]20D: -50.1 (c 0.63 CHCl3).
IR (film) ν: 3498, 2950, 1644, 1470, 1334, 1211, 1150, 1110,
1048 cm-1. 1H NMR δ: 0.92 (d, 3 H, J ) 6.9 Hz, CHMe), 1.18-
1.26 (m, 2 H), 1.36-1.53 (m, 5 H), 1.69-1.98 (m, 4 H), 2.10
(m, 1 H), 2.36-2.44 (m, 3 H), 2.79 (m, 1 H), 2.84, 3.01 (m, 2 ×
1 H, H′4 + H′7), 3.23 (d, 1 H, J ) 11.7 Hz, CH2OH), 3.40 (s, 3
H, OMe), 3.45 (d, 1 H, J ) 11.7 Hz, CH2OH′), 3.76-3.98 (m, 4
H, H4, 4′ + H5, 5′), 4.04 (m, 2 H, CH2OMOM), 4.67 (s, 2 H,
OCH2OMe), 5.06, 5.16 (br s, 2 × 1 H, dCH2), 6.15 (apparent
t, 2 H, J ) 1.9 Hz, 2 × dCH). 13C NMR δ: 14.3 (Me), 27.5,
33.5, 34.1 (2 × CH2 + C), 36.7 (CH), 43.6 (CH2), 43.8 (CH),
45.2 (CH), 45.4 (CH), 45.6 (CH2), 49.0 (CH), 52.1 (CH2), 54.0
(CH), 55.4 (OMe), 56.0 (CH), 63.3 (CH2), 63.8 (CH2), 64.9 (CH2),
68.5 (CH2), 95.9 (CH2), 114.4 (dCH2), 117.1 (C), 133.3, 137.1
based on recovered nitrile 23 was 73%: [R]20 -19.9 (c 0.84
D
CHCl3). IR (film) ν: 2951, 2230, 1646, 1431, 1334, 1210, 1150,
1113, 1052 cm-1. 1H NMR δ: 0.89 (d, 3 H, J ) 7.0 Hz, CHMe),
1.27 (d, 1 H, J ) 8.2 Hz), 1.34-1.54 (m, 4 H), 1.68-2.08 (m, 4
H), 1.88 (d, 1 H, J ) 13.8 Hz, H′2), 2.14 (d, 1 H, J ) 13.9 Hz,
H′2′), 2.28-2.46 (m, 2 H), 2.71 (m, 2 H), 2.93, 3.09 (s, 2 × 1 H,
H′4 + H′7), 3.38 (s, 3 H, OMe), 3.78-3.94 (m, 4 H, H4,4′ +
H5, 5′), 4.04 (s, 2 H, CH2OMOM), 4.65 (s, 2 H, OCH2OMe),
5.01, 5.15 (s, 2 × 1 H, dCH2), 6.22 (dd, 1 H, J ) 5.7, 3.1 Hz),
6.41 (dd, 1 H, J ) 5.6, 2.9 Hz). 13C NMR δ: 15.0 (Me), 28.2
(CH2), 32.9 (CH2), 35.0 (CH), 37.3 (C), 44.4 (CH), 46.0 (CH),
J. Org. Chem, Vol. 70, No. 5, 2005 1665

Mander and Thomson
(2 × dCH), 148.5 (dC). MS m/z: 418 (M+‚, 13), 387 (28), 373
(12), 357 (18), 321 (35), 291 (27), 277 (15), 234 (20), 221 (77),
157 (25), 139 (34), 91 (64), 66 (100). HRMS: calcd for ([M +
H]+‚ C25H39O5 419.2798, found 419.2789.
(4S,1′R,2′R,5′R)-4-Methoxymethoxymethyl-4-[2′-(1′′-
methoxymethoxymethylvinyl)-5′-methylcyclopentyl-
methyl]cyclopent-2-enone (26). A solution of ketone 25 (300
mg, 0.72 mmol) in 1,2-dichlorobenzene (3.0 mL) was heated
at 180 °C under a stream of nitrogen gas from a cylinder for
24 h. After being cooled to room temperature, the mixture was
subjected to flash chromatography on a column of silica gel
using 40% ethyl acetate in hexanes as the eluant to afford
enone 26 (243 mg, 96%) as an oil. [R]20D: -31.3 (c 0.75 CHCl3).
IR (film) ν: 2949, 1715, 1675, 1587, 1465, 1442, 1379, 1213,
(3′S,3a′S,4′R,7′S,7a′R,1′′R,2′′R,5′′R)-3′-Methoxy-
methoxymethyl-3′-[2′′-(1′′′-methoxymethoxymethylvi-
nyl)-5′′-methylcyclopentylmethyl]-2′,3′,3a′,4′,7′,7a′-hexahy-
dro-4′,7′-methanoindene-1′-spiro-2-[1,3]dioxolane. To a
stirred solution of the alcohol (1.46 g, 3.5 mmol) and DMAP
(64 mg, 0.53 mmol) in DCM (35 mL) at 0 °C under a nitrogen
atmosphere were added DIPEA (3.3 mL, 19.3 mmol) and
MOMCl (1.33 mL, 17.5 mmol). The reaction mixture was
allowed to stir at room temperature for 24 h, diluted with 1.0
M HCl (100 mL), and extracted twice with diethyl ether (150
mL). The combined organic extracts were washed with brine
(150 mL) and dried (MgSO4), and the solvent was removed in
vacuo. The resulting crude ether (1.58 g, 97%) was used
directly in the next reaction. For the purpose of characteriza-
tion a portion of the ether was subjected to flash chromatog-
raphy on a column of silica gel using 10% ethyl acetate in
petroleum spirits as the eluant to afford pure MOM ether.
[R]20D: -47.9 (c 0.40 CHCl3). IR (film) ν: 2949, 1646, 1466,
1
1150, 1109, 1044 cm-1. H NMR δ: 0.80 (d, 3 H, J ) 7.0 Hz,
CHMe), 1.25-2.10 (m, 8 H), 2.23 (m, 1 H), 2.24 (s, 2 H, H5),
3.30 (s, 3 H, OMe), 3.34 (s, 3 H, OMe), 3.45 (AB d, 2 H, J )
9.2 Hz, CH2OMOM), 3.94 (s, 2 H, dCCH2OMOM), 4.55, 4.60
(s, 2 × 2 H, 2 × OCH2OMe), 4.89, 5.08 (s, 2 × 1 H, dCH2),
6.11 (d, 1 H, J ) 5.7 Hz, H2), 7.50 (d, 1 H, J ) 5.7 Hz, H3).
13C NMR δ: 15.6 (Me), 28.8 (CH2), 32.9 (CH2), 33.0 (CH2), 35.2
(CH), 42.9 (C), 43.3 (CH2), 47.6 (CH), 49.7 (CH2), 55.4 (2 ×
OMe), 68.9 (CH2), 73.7 (CH2), 95.7 (CH2), 96.5 (CH2), 112.1
(dCH2), 134.0 (CH, C2), 147.5 (dC), 169.0 (CH, C3), 209.0
(CO). MS m/z: 352 (M+‚, 1), 291 (10), 277 (65), 217 (50), 159
(45), 122 (78), 107 (98), 95 (100), 67 (45). HRMS: calcd for
C20H32O5 352.2250, found 352.2247.
1
1335, 1211, 1149, 1107, 1050 cm-1. H NMR δ: 0.88 (d, 3 H,
(5S,1′R,2′R,5′R)-Methyl-2-hydroxy-5-methoxymethoxy-
methyl-5-[2′-(1′′-methoxymethoxymethylvinyl)-5′-meth-
ylcyclopentylmethyl]cyclopenta-1,3-dienecarboxylate (27)
and (2S,1′R,2′R,5′R)-Methyl-2-methoxymethoxymethyl-
2-[2′-(1′′-methoxymethoxymethylvinyl)-5′-methylcyclo-
pentylmethyl]-5-oxocyclopent-3-enecarboxylate (28). LDA/
diethyl ether (1.0 M, 2.76 mL, 27.6 mmol) was added to a
stirred solution of enone 26 (243 mg, 6.9 mmol) in diethyl ether
(7.0 mL) at -78 °C under a nitrogen atmosphere. After 2 h,
methyl cyanoformate (438 µL, 27.6 mmol) was added and the
mixture allowed to warm to room temperature and stir for 1
h. The reaction mixture was quenched with water (2 mL), and
after further dilution with water (20 mL) extracted three times
with diethyl ether (15 mL). The combined organic extracts
were washed with brine (50 mL) and dried (MgSO4). Concen-
tration in vacuo, followed by flash chromatography on a
column of silica gel using 20%, increasing to 40% ethyl acetate
in hexanes as the eluant, afforded an inseparable mixture of
27 and 28 (280 mg, 97%) as a pale yellow oil. 1H NMR δ: 3.69,
3.73 (s, 3 H, 2× CO2Me), 6.19 (d, 1 H, J ) 5.7 Hz), 6.28 (d, 1
H, J ) 5.7 Hz), 6.86 (d, 1 H, J ) 5.7 Hz), 7.53 (d, 1 H, J ) 5.7
Hz).
(5S,1′R,2′R,5′R)-Methyl-5-methoxymethoxymethyl-5-
[2′-(1′′-methoxymethoxymethyl-vinyl)-5′-methylcyclopen-
tylmethyl]-2-trifluoromethanesulfonyloxycyclopenta-
1,3-dienecarboxylate. NaH (60% w/w in oil, 137 mg, 3.4
mmol) and N-phenyltrifluoromethanesulfonimide (488 mg,
1.36 mmol) were carefully added to a stirred solution of 27/28
(280 mg, 0.68 mmol) in THF (7.0 mL) at 0 °C under a nitrogen
atmosphere. The reaction mixture was allowed to warm to
room temperature and stirred for 4 h, after which time water
(5 mL) was carefully added at 0 °C. The resulting mixture was
further diluted with water (80 mL) and extracted twice with
ethyl acetate (100 mL). The combined organic extracts were
washed with brine (100 mL) and dried (MgSO4), and the
solvent was removed in vacuo. The residue was subjected to
flash chromatography on a column of silica gel using 5%,
increasing to 10% ethyl acetate in hexanes as the eluant, to
afford the triflate (230 mg, 62%) as a colorless oil. [R]20D: -62.6
(c 0.74 CHCl3). IR (film) ν: 2953, 1713, 1615, 1535, 1431, 1375,
1213, 1143, 1108, 1044 cm-1. 1H NMR δ: 0.75 (d, 3 H, CHMe),
1.20-1.40 (m, 3 H), 1.60-2.20 (m, 6 H), 3.26 (s, 3 H, OMe),
3.35 (s, 3 H, OMe), 3.51 (d, 1 H, CH2OMOM), 3.76 (s, 3 H,
CO2Me), 3.87 (AB d, 2 H, J ) 13.2 Hz, dCCH2OMOM), 4.00
(d, 1 H, J ) 8.9 Hz, CH2OMOM′), 4.50, 4.60 (s, 2 × 2 H, 2 ×
OCH2OMe), 4.78, 5.02 (br s, 2 × 1 H, dCH2), 6.32 (d, 1 H, J )
5.7 Hz, H3), 6.96 (d, 1 H, J ) 5.7 Hz, H4). 13C NMR δ: 14.7
(Me), 28.9, 29.4, 32.7 (2 × CH2 + C), 35.8 (CH), 43.4 (CH),
47.1 (OMe), 51.4 (OMe), 55.2 (OMe), 60.8 (CH2), 68.9 (CH2),
J ) 6.9 Hz, CHMe), 1.19 (d, 1 H, J ) 7.6 Hz), 1.36-2.14 (m,
14 H), 2.32 (m, 1 H), 2.45 (dd, 1 H, J ) 8.9, 3.7 Hz, H), 2.73
(dd, 1 H, J ) 8.9, 4.5 Hz), 2.82 (br s, 2 × 1 H, H′4 + H′7), 3.32
(AB d, 2 H, J ) 9.4 Hz, CH2OMOM), 3.37, 3.38 (s, 2 × 3 H, 2
× OMe), 3.76-3.84 (m, 4 H, H4, 4′ + H5, 5′), 4.03 (s, 2 H,
dCCH2OMOM), 4.58, 4.64 (s, 2 × 2 H, 2 × OCH2OMe), 4.99,
5.10 (br s, 2 × 1 H, dCH2), 6.09 (dd, 1 H, J ) 5.6, 2.9 Hz),
6.15 (dd, 1 H, J ) 5.4, 2.9 Hz). 13C NMR δ: 15.0 (Me), 28.3,
33.4, 35.4 (2 × CH2 + C), 36.5 (CH), 44.0 (CH), 44.2 (CH2),
45.1 (2 × CH), 46.7 (CH2), 47.7 (CH), 52.1 (CH2), 54.0 (CH),
54.3 (CH), 55.2 (OMe), 55.4 (OMe), 63.4 (CH2), 63.8 (CH2), 68.9
(CH2), 71.8 (CH2), 95.6 (CH2), 96.9 (CH2), 110.6 (dCH2), 117.1
(C), 133.0, 137.4 (2 × dCH), 148.5 (dC). MS m/z: 462 (M+‚,
10), 421 (5), 417 (15), 401 (40), 387 (64), 365 (20), 321 (50),
265 (64), 201 (25), 89 (84), 66 (100). HRMS: calcd for ([M +
H]+‚ C27H43O6 463.3060, found 463.3065.
(3′S,3a′S,4′R,7′S,7a′R,1′′R,2′′R,5′′R)-3-Methoxymethoxy-
methyl-3-[2′-(1′′-methoxymethoxymethylvinyl)-5′-meth-
ylcyclopentylmethyl]-2,3,3a,4,7,7a-hexahydro-4,7-
methanoinden-1-one (25). A solution of the bisMOM ether
(1.6 g, 3.4 mmol) and toluene-4-sulfonic acid (1.29 g, 6.8 mmol)
in acetone (50 mL) was stirred at room temperature for 30
min. The reaction mixture was then diluted with ethyl acetate
(100 mL) and washed twice with saturated aqueous sodium
bicarbonate solution (100 mL). The combined aqueous residues
were washed three times with ethyl acetate (75 mL), and the
combined organic extracts were washed with brine (200 mL)
and dried (MgSO4). Concentration in vacuo, followed by flash
chromatography on a column of silica gel using 20% ethyl
acetate in petroleum spirits as the eluant, afforded the ketone
25 (1.35 g, 90% over four steps) as a pale yellow oil. [R]20
:
D
-150.5 (c 0.50 CHCl3). IR (film) ν: 2948, 1732, 1645, 1465,
1
1404, 1213, 1149, 1108, 1047 cm-1. H NMR δ: 0.80 (d, 3 H,
J ) 7.0 Hz, CHMe), 1.30-1.55 (m, 6 H), 1.70-2.30 (m, 8 H),
2.63 (dd, 1 H, J ) 8.5, 3.5 Hz, H3a), 2.93 (dd, 1 H, J ) 8.5, 3.5
Hz, H7a), 3.06, 3.14 (br s, 2 × 1 H, H4 + H7), 3.36, 3.39 (s, 2
× 3 H, 2 × OMe), 3.40 (AB d, 2 H, J ) 9.4 Hz, CH2OMOM),
3.97 (s, 2 H, dCCH2OMOM), 4.62 (s, 4 H, 2 × OCH2OMe),
4.92, 5.09 (br s, 2 × 1 H, dCH2), 6.02 (dd, 1 H, J ) 5.7, 3.1
Hz, dCH), 6.20 (dd, 1 H, J ) 5.4, 2.8 Hz, dCH). 13C NMR δ:
15.5 (Me), 28.1, 33.2, 37.8 (2 × CH2 + C), 35.8 (CH), 42.9 (CH),
45.5 (CH), 46.5 (CH), 48.2 (CH), 50.2 (CH), 50.2 (CH2), 52.9
(CH2), 53.8 (CH), 55.2 (OMe), 55.5 (OMe), 68.7 (CH2), 71.9
(CH2), 95.6 (CH2), 96.6 (CH2), 111.3 (dCH2), 134.6, 135.6 (2 ×
dCH), 147.7 (dC), 220.1 (CO). MS m/z 418 (M+‚, <1), 373 (1),
321 (54), 291 (22), 229 (15), 187 (17), 159 (23), 121 (30), 107
(39), 91 (44), 66 (100). HRMS: calcd for ([M + H]+‚ C25H39O5
419.2798, found 419.2790.
1666 J. Org. Chem., Vol. 70, No. 5, 2005

Total Synthesis of Sordaricin
71.6 (CH2), 95.6 (CH2), 96.6 (CH2), 110.7 (dCH2), 118.4 (q, J
) 319.9 Hz, CF3), 125.8 (C), 129.4 (CH), 147.6 (dC), 151.6 (C),
153.7 (C), 160.9 (CO2Me). MS m/z: 542 (M+‚, <1), 448 (10),
435 (32), 333 (85), 301 (100), 271 (70), 241 (86), 213 (88), 121
(55), 93 (62), 67 (41). HRMS: calcd for C26H33O9F3S 542.1797,
found 542.1792.
43.7 (CH), 47.5 (CH), 51.3 (OMe), 64.0 (CH2), 64.6 (CH2), 67.4
(CH2), 108.8 (dCH2), 130.3 (CH), 131.1 (C), 149.3 (CH, C4),
151.5 (dC), 166.4 (C), 167.0 (CO2Me). MS m/z: 348 (M+‚, 5),
330 (40), 300 (42), 285 (57), 241 (45), 225 (37), 178 (47), 133
(70), 119 (100), 105 (94), 91 (91). HRMS: calcd for C21H32O4
348.2301, found 348.2301.
(5S,1′R,2′R,5′R)-Methyl-2-isopropyl-5-methoxy-
methoxymethyl-5-[2′-(1′′-methoxymethoxymethylvi-
nyl)-5′-methylcyclopentylmethyl]cyclopenta-1,3-diene-
carboxylate. n-BuLi/hexanes (1.6 M, 398 µL, 0.63 mmol) was
added to a stirred solution of thiophene (76 µL, 0.63 mmol) in
THF (1.0 mL) at 0 °C under a nitrogen atmosphere. After 20
min, the resulting solution was transferred via a cannula to a
stirred suspension of CuCN (57 mg, 0.63 mmol) in THF (2.0
mL) at -78 °C. The mixture was allowed to slowly warm to
-40 °C and stirred for a further 30 min after which time the
solution was cooled to -78 °C. Isopropylmagnesium chloride/
THF (2.0 M, 318 µL, 0.63 mmol) was added, followed by the
addition a solution of the triflate (230 mg, 0.42 mmol) in THF
(3.0 mL). After 1 h, aqueous ammonium chloride solution (2.0
mL) was added and the mixture allowed to warm to room
temperature. The mixture was diluted with water (20 mL) and
10% aqueous ammonia solution (10 mL) and then extracted
three times with diethyl ether (25 mL). The combined organic
extracts were washed with 1.0 M HCl (50 mL) and brine (50
mL) and dried (MgSO4). Concentration in vacuo followed by
flash chromatography on a column of silica gel using 10% ethyl
acetate in hexanes as the eluant, afforded the product (170
mg, 93%) as an oil. [R]20D: -88.2 (c 0.68 CHCl3). IR (film) ν:
2950, 1698, 1647, 1603, 1530, 1465, 1435, 1377, 1238, 1150,
1106, 1046 cm-1. 1H NMR δ: 0.71 (d, 3 H, J ) 7.0 Hz, CHMe),
1.07 (d, 3 H, CHMe2), 1.08 (d, 3 H, J ) 6.9 Hz, CHMe2′), 1.10-
1.35 (m, 6 H), 1.56 (m, 1 H), 1.70-2.16 (m, 5 H), 3.24 (s, 3 H,
OMe), 3.30 (obscured d, 1 H, CH2OMOM), 3.31 (s, 3 H, OMe),
3.65 (s, 3 H, CO2Me), 3.70-3.80 (m, 2 H), 3.83 (d, 1 H, J ) 7.6
Hz, dCCH2OMOM), 3.98 (d, 1 H, J ) 8.9 Hz, dCCH2OMOM′),
4.49 (AB d, 2 H, J ) 7.0 Hz, OCH2OMe), 4.56 (AB d, 2 H, J )
6.6 Hz, OCH2OMe′), 4.73, 4.98 (br s, 2 × 1 H, dCH2), 6.42 (d,
1 H, J ) 5.4 Hz, H3), 6.75 (d, 1 H, J ) 5.4 Hz, H4). 13C NMR
δ: 14.7 (Me), 21.5 (Me), 21.8 (Me), 27.2 (CH), 28.8, 29.2, 32.7
(2 × CH2 + C), 35.6 (CH), 43.5 (CH), 47.2 (CH), 50.4 (OMe),
55.0 (OMe), 55.1 (OMe), 62.5 (CH2), 68.7 (CH2), 73.1 (CH2),
95.5 (CH2), 96.5 (CH2), 110.1 (dCH2), 129.3 (CH), 129.8 (C),
147.8 (dC), 149.9 (CH), 164.3 (C), 167.2 (CO2Me). MS m/z: 436
(M+‚, 5), 404 915), 374 (26), 342 (73), 329 (83), 297 (99), 269
(78), 253 (55), 179 (54), 147 (94), 133 (86), 119 (100), 91 (87).
HRMS: calcd for C25H40O6 436.2825, found 436.2826.
(5S,1′R,2′R,5′R)-Methyl-5-[2′-(1′′-formylvinyl)-5′-meth-
ylcyclopentylmethyl]-5-hydroxymethyl-2-isopropylcy-
clopenta-1,3-dienecarboxylate (9). Manganese dioxide (250
mg) was added to a solution of diol 32 (50 mg, 0.15 mmol) in
diethyl ether (2 mL) at room temperature. After 30 min, the
solution was filtered through a pad of Celite and the solvent
removed in vacuo to afford pure 9 (50 mg, 100%). [R]20
:
D
-180.0 (c 0.38 CHCl3). IR (film) ν: 3435, 2954, 1639, 1527,
1464, 1435, 1377, 1324, 1241, 1191, 1096 cm-1 1H NMR δ:
.
0.80 (d, 3 H, J ) 6.9 Hz, CHMe), 1.11 (d, 3 H, J ) 6.7 Hz,
CHMe2), 1.15 (d, 3 H, J ) 6.7 Hz, CHMe2′), 1.20-1.42 (m, 3
H), 1.64-2.00 (m, 5 H), 2.55 (m, 1 H), 3.54 (d, 1 H, J ) 10.4
Hz, CH2OH), 3.65 (obscured m, 1 H, CHMe2), 3.74 (s, 3 H,
OMe), 3.75 (obscured d, 1 H, CH2OH′), 5.91 (s, 1 H, dCH2),
6.09 (s, 1 H, dCH2′), 6.49 (d, 1 H, J ) 5.4 Hz, H3), 6.58 (d, 1
H, J ) 5.4 Hz, H4), 9.48 (s, 1 H, CHO). 13C NMR δ: 14.7 (Me),
21.7 (Me), 21.9 (Me), 27.6 (CH), 28.7, 29.3, 32.9 (2 × CH2 +
C), 36.1 (CH), 41.9 (CH), 44.1 (CH), 51.1 (OMe), 62.5 (CH2),
67.3 (CH2), 130.3 (CH), 131.1 (dCH2), 133.4 (C), 149.2 (CH),
153.3 (dC), 166.0 (CO2Me), 166.8 (C), 194.4 (CHO). MS m/z:
346 (M+‚, 13), 328 (38), 316 (40), 284 (100), 269 (36), 256 (44),
241 (34), 180 (57), 147 (83), 133 (57), 119 (79), 105 (65), 91
(72). HRMS: calcd for C21H30O4 346.2144, found 346.2147.
Methyl 19-Hydroxy-17-oxosordaric-1-en-18-oate (30).
A solution of aldehyde 9 (60 mg, 0.17 mmol) in d8-toluene (1.5
mL) was heated at 40 °C for 3 days after which time the
solvent was removed, in vacuo to give pure ester 30 (60 mg,
100%). [R]20 synthetic: -65.1 (c 0.38 CHCl3), natural: -66.4
D
(c 0.38 CHCl3). IR (film) ν: 3434, 2955, 2869, 1721, 1435, 1382,
1
1291, 1268, 1066 cm-1. H NMR δ: 0.79 (d, 3 H, J ) 7.2 Hz,
H20), 0.89, 1.05 (d, 2 × 3 H, J ) 6.9 Hz, H15 + H16), 1.24 (m,
3 H), 1.70-1.80 (m, 3 H), 1.90-2.12 (m, 5 H), 2.25 (sep d, 1 H,
J ) 6.9, 1.0 Hz, H14), 2.58 (t, 1 H, J ) 4.1 Hz, H3), 3.53, 3.90
(AB d, 2 × 1 H, J ) 11.3 Hz, CH2OH), 3.80 (s, 3 H, OMe), 6.08
(dd, 1 H, J ) 3.5, 1.3 Hz, H2), 9.64 (s, 1 H, CHO). 13C NMR δ:
17.4 (Me, C20), 21.0, 22.1 (2 × Me, C15 + C16), 26.5 (CH2,
C11), 27.8 (CH, C14), 27.9, 30.0 (2 × CH2, C8 + C12), 31.1
(CH, C10), 32.0 (CH2, C4), 41.3, 41.4, 47.0 (3 × CH, C3, C9 +
C13), 52.3 (C, C5), 66.8, 66.9 (2 × C, C6 + C7), 72.6 (CH2,
C19), 130.5 (CH, C2), 147.8 (C, C1), 173.6 (C, C18), 203.7 (CH,
C17). MS m/z: 346 (M+‚, 34), 328 (36), 315 (50), 284 (100), 269
(32), 255 (37), 239 (24), 180 (48), 147 (84), 133 (50), 119 (74),
105 (60), 91 (74). HRMS: calcd for C21H30O4 346.2144, found
346.2144.
(5S,1′R,2′R,5′R)-Methyl-5-hydroxymethyl-5-[2′-(1′′-meth-
oxymethoxymethylvinyl)-5′-methylcyclopentylmethyl]-
2-isopropylcyclopenta-1,3-dienecarboxylate (32). A so-
lution of the bisMOM ether (160 mg, 0.37 mmol), MgBr2‚Et2O
(948 mg, 3.7 mmol), and 1-butanethiol (472 µL, 4.4 mmol) in
diethyl ether (10 mL) was stirred at room temperature for 24
h. A further portion of reagents was added and the mixture
stirred a further 24 h. The resulting solution was then diluted
with 1.0 M HCl (50 mL) and extracted three times with ethyl
acetate (50 mL). The combined organic extracts were washed
with brine (50 mL) and dried (MgSO4), and the solvent was
removed in vacuo. The residue was subjected to flash chro-
matography on a column of silica gel using 20%, increasing to
70% ethyl acetate in hexanes as the eluant, to afford 32 (110
mg, 86%) as a colorless oil. [R]20D: -143.3 (c 0.81 CHCl3). IR
(film) ν: 3400, 2952, 1674, 1601, 1527, 1464, 1436, 1377, 1325,
Sordaricin (3). Freshly distilled propanethiol (700 µL, 7.72
mmol) was added to a stirred suspension of NaH (240 mg, 10
mmol) in HMPA (5.0 mL) at room temperature under a
nitrogen atmosphere. The solution was stirred for 2 h and then
allowed to stand for 1 h to give a 1.35 M solution of pro-
panethiolate. To a dried flask containing the ester 30 (60 mg,
0.17 mmol) and a stirrer bar was added a solution of pro-
panethiolate/HMPA (1.35 M, 2.0 mL, 2.7 mmol) and the
solution stirred under a nitrogen atmosphere for 48 h. The
reaction mixture was diluted with ethyl acetate (20 mL) and
washed twice with water (30 mL). The combined aqueous
extracts were extracted twice with ethyl acetate (20 mL), and
then the combined organic extracts were washed with brine
(25 mL) and dried (MgSO4). Concentration in vacuo followed
by flash chromatography on a column of silica gel using 20%
ethyl acetate in hexanes, then 60% ethyl acetate in hexane as
the eluant afforded sordaricin (3) (45 mg, 79%) as a white solid
that was identical in all respects to an authentic sample of
sordaricin (3). Mp: 189-191 °C (diethyl ether, DCM and
hexanes) (lit.3 mp 190-191 °C). [R]20D synthetic: -55.3 (c 0.19
MeOH), natural: -58.4 (c 0.19 MeOH) [lit.31 -64 (c 0.374
MeOH)]. IR (film) ν: 3350, 2954, 2868, 1712, 1446, 1378, 1289,
1
1244, 1192, 1055 cm-1. H NMR δ: 0.76 (d, 3 H, J ) 7.0 Hz,
CHMe), 1.09 (d, 3 H, J ) 6.7 Hz, CHMe2), 1.13 (d, 3 H, J ) 6.7
Hz, CHMe2′), 1.10-1.36 (m, 3 H), 1.56-1.86 (m, 4 H), 2.02-
2.18 (m, 2 H), 2.71 (br s, 2 H, 2 × OH), 3.63 (obscured m, 1 H,
CHMe2), 3.67 (AB d, 2 H, J ) 10.4 Hz, CH2OH), 3.74 (s, 3 H,
OMe), 3.92 (AB d, 2 H, J ) 14.4 Hz, dCCH2OH), 4.73, 5.02
(br s, 2 × 1 H, dCH2), 6.47 (d, 1 H, J ) 5.4 Hz, H3), 6.59 (d,
1 H, J ) 5.4 Hz, H4). 13C NMR δ: 15.2 (Me), 21.8 (Me), 21.9
(Me), 27.6 (CH), 28.4, 28.6, 23.9 (2 × CH2 + C), 35.9 (CH),
J. Org. Chem, Vol. 70, No. 5, 2005 1667

Mander and Thomson
1
1234, 1017 cm-1. H NMR (d5-pyridine) δ: 0.80 (d, 3 H, J )
added at 0 °C. The resulting mixture was further diluted with
water (80 mL) and extracted twice with diethyl ether (100 mL).
The combined organic extracts were washed with brine (100
mL) and dried (MgSO4), and the solvent was removed in vacuo.
The residue was subjected to flash chromatography on a
column of silica gel using 5%, increasing to 10%, ethyl acetate
in petroleum spirits as the eluant to afford the triflate (740
mg, 89%) as a colorless oil. [R]20D: -17.8 (c 1.02 CHCl3). IR
(film) ν: 2952, 2251, 1723, 1647, 1426, 1337, 1292, 1212, 1144,
1048 cm-1. 1H NMR δ: 0.88 (d, 3 H, J ) 7.0 Hz, CHMe), 1.28
(d, 1 H, J ) 8.4 Hz), 1.34-1.62 (m, 4 H), 1.76-2.00 (m, 4 H),
2.16 (m, 2 H), 2.58 (dd, 1 H, J ) 8.4, 3.7 Hz), 3.08, 3.25 (br s,
2 × 1 H, H4 + H7), 3.37 (s, 3 H, OMe), 3.42 (s, 3 H, OMe),
3.53 (m, 2 H, H3a + CH2OMOM), 3.67 (s, 3 H, CO2Me), 3.78
(d, 1 H, J ) 9.7 Hz, CH2OMOM′), 3.92 (AB d, 2 H, J ) 13.2
Hz, dCCH2OMOM), 4.63, 4.64 (s, 2 × 2 H, 2 × OCH2OMe),
4.87, 5.04 (br s, 2 × 1 H, dCH2), 5.96 (dd, 1 H, J ) 5.6, 2.9
Hz), 6.17 (dd, 1 H, J ) 5.7, 2.8 Hz). 13C NMR δ: 15.8 (Me),
28.4, 33.3 (CH), 36.3 (CH), 36.7, 43.2 (CH), 45.4 (CH), 46.0
(CH), 47.7 (CH), 47.9 (CH), 50.6 (OMe), 51.0 (CH2), 51.5 (CH),
51.6 (CH2), 55.2 (OMe), 55.7 (OMe), 68.9 (CH2), 72.1 (CH2),
95.5 (CH2), 97.3 (CH2), 111.0 (dCH2), 118.1 (q, J ) 319.3 Hz,
CF3), 126.6 (C), 134.1, 135.1 (2 × dCH), 147.9 (dC), 156.6 (C),
161.9 (CO2Me). MS m/z: 607 (M+‚, 2), 501 (12), 434 (12), 369
(20), 348 (58), 301 (41), 241 (40), 215 (41), 79 (40), 66 (100).
HRMS: calcd for ([M + H]+‚ C28H39O9F3S 608.2267, found
608.2266.
(1S,3aR,4S,7R,7aS,1′R,2′R,5′R)-Methyl-3-isopropyl-1-
methoxymethoxymethyl-1-[2′-(1′′-methoxymethoxy-
methylvinyl)-5′-methylcyclopentylmethyl]-3a,4,7,7a-tetra-
hydro-1H-4,7-methanoindene-2-carboxylate. n-BuLi/hex-
anes (1.6 M, 357 µL, 0.58 mmol) was added to a stirred solution
of thiophene (91 µL, 0.58 mmol) in THF (1.0 mL) at 0 °C under
a nitrogen atmosphere. After 20 min, the resulting solution
was transferred via a cannula to a stirred suspension of CuCN
(51 mg, 0.58 mmol) in THF (2.0 mL) at -78 °C. The mixture
was allowed to slowly warm to -40 °C and stirred for a further
30 min, after which time the solution was cooled to -78 °C.
Isopropylmagnesium chloride/THF (2.0 M, 285 µL, 0.58 mmol)
was added, followed by the addition a solution of the triflate
(170 mg, 0.29 mmol) in THF (3.0 mL). After 1 h, aqueous
ammonium chloride solution (2.0 mL) was added and the
mixture allowed to warm to room temperature. The mixture
was diluted with water (20 mL) and 10% aqueous ammonia
solution (10 mL) and then extracted three times with diethyl
ether (25 mL). The combined organic extracts were washed
with 1.0 M HCl (50 mL) and brine (50 mL) and dried (MgSO4).
Concentration in vacuo followed by flash chromatography on
a column of silica gel using 10% ethyl acetate in petroleum
spirits as the eluant afforded the product (130 mg, 90%) as a
pale yellow oil. [R]20D: -110.5 (c 0.76 CHCl3). IR (film) ν: 2952,
1705, 1645, 1604, 1434, 1229, 1150, 1107, 1047 cm-1. 1H NMR
δ: 0.88 (d, 3 H, J ) 7.0 Hz, CHMe), 1.06 (d, 3 H, J ) 7.2 Hz,
CHMe2), 1.10 (d, 3 H, J ) 7.2 Hz, CHMe2′), 1.20-2.00 (m, 9
H), 2.18 (m, 2 H), 2.44 (dd, 1 H, J ) 8.4, 3.7 Hz, H7a), 3.04,
3.12 (br s, 2 × 1 H, H4 + H7), 3.17 (sep, 1 H, J ) 6.7 Hz,
CHMe2), 3.33, 3.34 (s, 2 × 3 H, 2 × OMe), 3.36 (m, 1 H, H3a),
3.45 (d, 1 H, J ) 9.5 Hz, CH2OMOM), 3.56 (s, 3 H, CO2Me),
3.60 (d, 1 H, J ) 9.5 Hz, CH2OMOM′), 3.87 (AB d, 2 H, J )
13.9 Hz, dCCH2OMOM), 4.59, 4.60 (s, 2 × 2 H, 2 × OCH2-
OMe), 4.80, 5.00 (br s, 2 × 1 H, dCH2), 5.75 (dd, 1 H, J ) 5.7,
2.9 Hz), 6.06 (dd, 1 H, J ) 5.6, 2.8 Hz). 13C NMR δ: 16.0 (Me),
21.6 (Me), 21.7 (Me), 28.4 (C), 28.8 (CH), 33.6 (CH2), 36.5 (CH2),
37.0 (CH2), 43.1 (CH), 45.8 (CH), 47.8 (CH), 48.2 (CH), 48.3
(CH), 50.5 (CH), 52.2 (CH2), 53.3 (OMe), 53.7 (CH2), 55.2
(OMe), 55.5 (OMe), 68.6 (CH2), 73.2 (CH2), 95.6 (CH2), 97.3
(CH2), 110.6 (dCH2), 131.2 (C), 134.5, 135.2 (2 × dCH), 148.1
(dC), 165.0 (C), 166.1 (CO2Me). MS m/z: 502 (M+‚, 3), 404 (37),
374 (52), 342 (100), 300 (90), 269 (39), 243 (55), 119 (40), 81
(40), 66 (52). HRMS: calcd for C30H46O6 502.3294, found
502.3298.
6.6 Hz, H20), 1.08 (m, 6 H, H15 + H16), 1.48 (d, 1 H, J ) 12.5
H, H4R), 1.74 (m, 1 H), 1.95 (m, 5 H), 2.20-2.50 (m, 3 H), 2.72
(sep, 1 H, J ) 6.7 Hz, H14), 2.97 (t, 1 H, J ) 3.8 Hz, H3), 4.20,
4.37 (AB d, 2 × 1 H, J ) 10.5 Hz, CH2OH), 6.13 (d, 1 H, J )
3.1 Hz, H2), 8.85 (variable br s, 1 H, CO2H), 10.24 (s, 1 H,
CHO). 13C NMR (d5-pyridine) δ: 17.7 (Me, C20), 21.3, 22.7 (2
× Me, C15 + C16), 26.9 (CH2, C11), 28.2 (CH, C14), 29.1, 29.7
(2 × CH2, C8 + C12), 31.6 (CH, C10), 32.4 (CH2, C4), 41.9,
42.0, 47.1 (3 × CH, C3, C9 + C13), 59.4 (C, C5), 66.9, 67.5 (2
× C, C6 + C7), 73.8 (CH2, C19), 130.9 (CH, C2), 148.9 (C, C1),
176.0 (C, C18), 204.8 (CH, C17). MS m/z: 332 (M+‚, 24), 314
(33), 302 (40), 284 (90), 256 (37), 241 (40), 227 (35), 166 (64),
147 (67), 119 (64), 105 (72), 91 (100). HRMS: calcd for C20H28O4
332.1988, found 332.1986. Anal. Calcd for C20H28O4: C, 72.3;
H, 8.5. Found: C, 70.9; H, 8.7. Anal. Calcd for C20H29O4: C,
70.4; H, 8.6.
(1S,3aR,4S,7R,7aS,1′R,2′R,5′R)-Methyl-3-hydroxy-1-
methoxymethoxymethyl-1-[2′-(1′′-methoxymethoxy-
methylvinyl)-5′-methylcyclopentylmethyl]-3a,4,7,7a-tetra-
hydro-1H-4,7-methanoindene-2-carboxylate (31). LiH-
MDS/hexanes (1.0 M, 2.15 mL, 2.15 mmol) was added to a
stirred solution of ketone 25 (600 mg, 1.43 mmol) in diethyl
ether (2.0 mL) at 0 °C under a nitrogen atmosphere. After 3
h, the solution was cooled to -78 °C and diluted with diethyl
ether (4 mL) and methyl cyanoformate (1.1 mL, 14.4 mmol)
added. After 20 min, the reaction mixture was allowed to warm
to room temperature and stirred for a further 30 min. The
reaction mixture was diluted with water (100 mL) and
extracted three times with diethyl ether (50 mL). The com-
bined organic residues were washed with brine (100 mL) and
dried (MgSO4), and the solvent was removed in vacuo. The
residue was dissolved in methanol (15 mL) and potassium
carbonate (500 mg) added. After 30 min, the reaction mixture
was diluted with ethyl acetate (50 mL) and washed with 1.0
M HCl (50 mL). The aqueous layer was extracted twice with
ethyl acetate (50 mL), and the combined organic extracts were
washed with brine (100 mL) and dried (MgSO4). Concentration
in vacuo, followed by flash chromatography on a column of
silica gel using 10% ethyl acetate in petroleum spirits as the
eluant, afforded the ester 31 (360 mg, 86% based on recovered
starting material) as an oil. Increasing to 20% ethyl acetate
in petroleum spirits as the eluant, afforded starting material
25 (230 mg). [R]20D: -111.7 (c 0.41 CHCl3). IR (film) ν: 2952,
1766, 1651, 1609, 1443, 1342, 1281, 1256, 1230, 1208, 1107,
1047 cm-1. 1H NMR δ: 0.90 (d, 3 H, J ) 7.0 Hz, CHMe), 1.25-
1.55 (m, 7 H), 1.60-2.20 (m, 7 H), 2.42 (dd, 1 H, J ) 8.5, 3.7
Hz, H7a), 3.10, 3.30 (br s, 2 × 1 H, H4 + H7), 3.34 (m, 1 H,
H3a), 3.36 (s, 3 H, OMe), 3.40 (m, 1 H, CH2OMOM), 3.44 (s, 3
H, OMe), 3.63 (s, 3 H, CO2Me), 3.65 (m, 1 H, CH2OMOM′),
3.85 (AB d, 2 H, J ) 13.0 Hz, dCCH2OMOM), 4.60, 4.66 (s, 2
× 2 H, 2 × OCH2OMe), 4.76, 4.98 (br s, 2 × 1 H, dCH2), 5.93
(dd, 1 H, J ) 5.7, 3.1 Hz), 6.08 (dd, 1 H, J ) 5.4, 2.5 Hz), 10.96
(br s, 1 H, OH). 13C NMR δ: 16.4 (Me), 28.8, 29.8, 33.5, 36.1
(3 × CH2 + C), 36.5 (CH), 42.8 (CH), 45.2 (CH), 46.0 (CH),
47.7 (CH), 48.5 (CH), 49.1 (CH2), 50.8 (CH), 51.3 (OMe), 52.0
(CH2), 55.3 (OMe), 55.6 (OMe), 68.9 (CH2), 73.6 (CH2), 95.7
(CH2), 97.3 (CH2), 104.5 (C), 110.3 (dCH2), 133.8, 134.4 (2 ×
dCH), 148.2 (dC), 170.5 (C), 179.1 (CO2Me). MS m/z: 445 ([M
- OMe]+‚, 7), 399 (14), 369 (37), 351 (23), 339 (53), 307 (50),
261 (60), 229 (69), 191 (56), 159 (76), 91 (100). HRMS: calcd
for ([M - OMe]+‚ C26H37O6 445.2590, found 445.2584.
(1S,3aR,4S,7R,7aS,1′R,2′R,5′R)-Methyl-1-methoxy-
methoxymethyl-1-[2′-(1′′-methoxymethoxymethylvinyl)-
5′-methylcyclopentylmethyl]-3-trifuoromethanesulfonyl-
oxy-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-2-
carboxylate. NaH (60% w/w in oil, 277 mg, 7.0 mmol) and
N-phenyltrifluoromethanesulfonimide (1.2 g, 2.8 mmol) were
carefully added to a stirred solution of 31 (660 mg, 1.4 mmol)
in THF (20 mL) at 0 °C under a nitrogen atmosphere. The
reaction mixture was allowed to warm to room temperature
and stirred for 4 h, after which time water (5 mL) was carefully
1668 J. Org. Chem., Vol. 70, No. 5, 2005

Total Synthesis of Sordaricin
(1S,3aR,4S,7R,7aS,1′R,2′R,5′R)-Methyl-1-hydroxymethyl-
1-[2′-(1′′-hydroxymethylvinyl)-5′-methylcyclopentyl-
methyl]-3-isopropyl-3a,4,7,7a-tetrahydro-1H-4,7-methano-
indene-2-carboxylate (34). A solution of the MOM ether (200
mg, 0.4 mmol), MgBr2‚Et2O (823 mg, 3.2 mmol), and 1-bu-
tanethiol (299 µL, 2.8 mmol) in diethyl ether (10 mL) was
stirred at room temperature for 24 h. A further portion of
reagents was added and the mixture stirred a further 24 h.
The resulting solution was then diluted with 1.0 M HCl (50
mL) and extracted three times with ethyl acetate (50 mL). The
combined organic extracts were washed with brine (50 mL),
dried (MgSO4) and the solvent removed in vacuo. The residue
was subjected to flash chromatography on a column of silica
gel using 20%, increasing to 70% ethyl acetate in hexanes as
Sordaricin (3) and iso-Sordaricin (iso-3). Freshly dis-
tilled propanethiol (700 µL, 7.72 mmol) was added to a stirred
suspension of hexane-washed NaH (240 mg, 10 mmol) in
HMPA (5.0 mL) at room temperature under a nitrogen
atmosphere. The solution was stirred for 2 h and then allowed
to stand for 1 h to give a 1.35 M solution of propanethiolate.
To a dried flask containing a 1:1 mixture of 30 and iso-30 (70
mg, 0.2 mmol) and a stirrer bar was added a solution
propanethiolate/HMPA (1.35 M, 2.5 mL, 3.4 mmol) and the
solution stirred under a nitrogen atmosphere for 48 h. The
reaction mixture was diluted with ethyl acetate (15 mL) and
washed twice with water (50 mL). The combined aqueous
extracts were extracted twice with ethyl acetate (15 mL), then
the combined organic extracts were washed with brine (20 mL)
and dried (MgSO4). Concentration in vacuo followed by flash
chromatography on a column of silica gel using 20% ethyl
acetate in hexanes and then 60% ethyl acetate in hexane as
the eluant afforded a mixture of sordaricin (3) and isosorda-
ricin (iso-3, 50 mg combined). The mixture was dissolved in
HPLC grade acetonitrile (3 mL) and 50:50:0.05 water/aceto-
nitrile/acetic acid (5 drops) and subjected to semipreparative
HPLC separation using a mixture of 55% acetonitrile (contain-
ing 0.005% acetic acid) and 45% water (containing 0.005%
acetic acid), at a flow rate of 5.0 mL/min. The compounds were
detected at 210 nm. Concentration of the fractions containing
the first eluting compound afforded isosordaricin (iso-3, 17 mg,
25% from mixture of esters). Concentration of the fractions
containing the second eluting compound afforded sordaricin
(3, 25 mg, 38%), which was identical in all respects to an
authentic sample. Isosordaricin (iso-3). [R]20D: -35.7 (c 0.23
CHCl3). IR (film) ν: 3413, 2956, 1703, 1649, 1465, 1255, 1096,
1017, 800 cm-1. 1H NMR (d5-pyridine) δ: 0.73 (d, 3 H, J ) 7.0
Hz, H20), 1.07, 1.09 (2 × d, 2 × 3 H, J ) 6.7 Hz, H15 + H16),
1.11 (obscured m, 2 H), 1.40 (m, 1 H), 1.55 (m, 1 H), 1.75-
2.08 (m, 6 H), 2.39 (d, 1 H, J ) 12.7 Hz), 2.49 (d, 1 H, J ) 12.7
Hz, exo-H5), 2.84 (d, 1 H, J ) 12.7 Hz, endo-H5), 2.95 (m, 1 H,
H14), 3.50 (d, 1 H, J ) 3.2 Hz, H3), 4.26, 4.41 (2 × AB d, 2 ×
1 H, J ) 10.5 Hz, H19,19′), 5.68 (br s, 1 H, H2), 6.85 (variable
br s, 1 H, CO2H), 9.80 (s, 1 H, H17). 13C NMR (d5-pyridine) δ:
17.7 (Me, C20), 20.9, 22.1 (2 × Me, C15 + C16), 26.2 (CH2),
28.4 (CH, C14), 28.6 (CH2), 29.8 (CH, C10), 34.3 (CH2), 37.8
(C, C6), 46.3 (CH), 46.4 (CH2, C5), 46.8 (CH), 49.6 (CH), 58.3
(C, C4), 65.3 (CH2, C19), 69.5 (C, C7), 121.3 (CH, C2), 158.4
(C, C1), 175.8 (C, C18), 203.9 (CH, C17). MS m/z: 332 (M+‚,
7), 314 (25), 302 (72), 284 (100), 274 (44), 256 (40), 241 (34),
227 (25), 166 (51), 147 (62), 133 (37), 105 (50), 91 (66). HRMS:
calcd for C20H28O4 332.1988, found 332.1985.
the eluant, to afford 34 (153 mg, 92%) as a colorless oil. [R]20
:
D
-78.6 (c 0.59 CHCl3). IR (film) ν: 3429, 2955, 1765, 1702, 1436,
1
1252, 1121, 1042 cm-1. H NMR δ: 0.88 (d, 1 H, J ) 7.0 Hz,
CHMe), 1.05 (d, 3 H, J ) 7.0 Hz, CHMe2), 1.13 (d, 3 H, J ) 7.0
Hz, CHMe2′), 1.26 (d, 1 H, J ) 8.1 Hz), 1.38 (m, 2 H), 1.50 (d,
1 H, J ) 8.1 Hz), 1.60-1.90 (m, 5 H), 2.20 (m, 2 H), 2.43 (dd,
1 H, J ) 8.4, 3.8 Hz, H7a), 2.97, 3.07 (br s, 2 × 1 H, H4 + H7),
3.23 (sep, 1 H, J ) 6.9 Hz, CHMe2), 3.39 (dd, 1 H, J ) 8.4, 4.5
Hz, H3a), 3.56 (d, 1 H, J ) 11.3 Hz, CH2OH), 3.66 (s, 3 H,
OMe), 3.75 (d, 1 H, J ) 11.3 Hz, CH2OH′), 3.98 (AB d, 2 H, J
) 14.4 Hz, dCCH2OH), 4.78, 5.03 (br s, 2 × 1 H, dCH2), 5.73
(dd, 1 H, J ) 5.7, 2.9 Hz), 6.04 (dd, 1 H, J ) 5.7, 2.9 Hz). 13C
NMR δ: 16.2 (Me), 21.6 (Me), 21.8 (Me), 28.0, 28.9 (CH), 33.6,
35.7, 36.5 (CH), 42.4 (CH), 45.3 (CH), 47.8 (CH), 48.5 (2 × CH),
51.4 (CH), 52.5 (CH2), 52.8 (Me), 54.6 (CH2), 64.0 (CH2), 66.9
(CH2), 109.4 (dCH2), 132.0 (C), 134.1, 134.3 (2 × dCH), 151.9
(dC), 165.0 (C), 168.1 (CO2Me). MS m/z: 382 ([M - MeOH]+‚,
17), 357 (13), 287 (26), 244 (83), 215 (42), 197 (48), 121 (50),
109 (75), 91 (100), 66 (75). HRMS: calcd for ([M - MeOH]+‚
C25H34O3 382.2508, found 382.2505.
(1S,3aR,4S,7R,7aS,1′R,2′R,5′R)-Methyl-1-[2′-(1′′-formylvi-
nyl)-5′-methylcyclopentylmethyl]-1-hydroxymethyl-3-
isopropyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-2-
carboxylate (8). Manganese dioxide (600 mg) was added to
a solution of diol 34 (120 mg, 29.0 mmol) in diethyl ether (3
mL) at room temperature. After 30 min, the solution was
filtered through a pad of Celite and the solvent removed in
vacuo to afford pure 8 (120 mg, 100%). [R]20D: -133.8 (c 0.50
CHCl3). IR (film) ν: 3467, 2957, 1694, 1601, 1466, 1434, 1345,
1
1233, 1122, 1016 cm-1. H NMR δ: 0.90 (d, 3 H, J ) 7.0 Hz,
CHMe), 1.04 (d, 3 H, J ) 7.0 Hz, CHMe2), 1.13 (d, 3 H, J ) 7.0
Hz, CHMe2′), 1.23 (d, 1 H, J ) 7.2 Hz), 1.40-1.52 (m, 4 H),
1.73 (dd, 1 H, J ) 14.4, 8.4 Hz), 1.80-1.98 (m, 3 H), 2.24 (m,
1 H), 2.37 (dd, 1 H, J ) 8.5, 3.8 Hz, H7a), 2.58 (m, 1 H), 2.91,
3.06 (br s, 2 × 1 H, H4 + H7), 3.20 (sep, 1 H, J ) 7.0 Hz,
CHMe2), 3.28 (br s, 1 H, OH), 3.36 (dd, 1 H, J ) 8.4, 4.4 Hz,
H3a), 3.49 (br d, 1 H, CH2OH), 3.64 (s, 3 H, OMe), 3.70 (d, 1
H, J ) 11.3 Hz, CH2OH′), 5.71 (dd, 1 H, J ) 5.7, 2.9 Hz), 5.88,
6.12 (br s, 2 × 1 H, dCH2), 6.00 (dd, 1 H, J ) 5.6, 2.9 Hz),
9.43 (s, 1 H, CHO). 13C NMR δ: 15.8 (Me), 21.5 (Me), 21.8
(Me), 28.7 (CH2), 28.9 (CH), 29.7, 33.6, 35.9 (2 × CH2 + C),
37.1 (CH), 43.4 (CH), 43.5 (CH), 45.1 (CH), 47.9 (CH), 48.4
(CH), 51.2 (CH), 52.5 (CH2), 52.6 (OMe), 54.4 (CH2), 66.6 (CH2),
132.1 (dCH2), 134.1 (2 × dCH), 153.5 (C, dCCHO), 165.6 (C),
167.8 (CO2Me), 194.3 (CHO). MS m/z: 412 (M+‚, <1), 380 (5),
346 (9), 328 (45), 284 (100), 256 (30), 180 (35), 147 (55), 119
(50), 91 (52), 66 (56). HRMS: calcd for C26H36O4 412.2614,
found 412.2615.
Methyl 17,19-Dihydroxysodaric-1-en-18-oate (33). A
solution of diol 34 (15 mg, 36 µmol) in 1,2-dichlorobenzene (1.0
mL) was heated at 180 °C under a stream of nitrogen gas from
a cylinder for 3 h. After being cooled to room temperature, the
mixture was subjected to flash chromatography on a column
of silica gel using 100% hexanes then 30%, increasing to 50%,
ethyl acetate in hexanes as the eluant to afford diol 33 (8 mg,
64%) as a white solid. [R]20D: -70.4 (c 0.27 CHCl3). IR (film)
1
ν: 3400, 2953, 1718, 1697, 1435, 1295, 1270, 1028 cm-1. H
NMR δ: 0.21 (d, 1 H, J ) 12.5 Hz, H4R), 0.76 (d, 3 H, J ) 6.7
Hz, H20), 0.87, 1.12 (d, 2 × 3 H, J ) 6.6 Hz, H15 + H16), 1.20
(obscured m, 3 H), 1.60-2.10 (m, 9 H), 2.47 (sep, 1 H, J ) 6.6
Hz, H14), 2.55 (t, 1 H, J ) 4.3 Hz, H3), 3.24, 3.37 (AB d, 2 ×
1 H, J ) 12.2 Hz, H17), 3.67, 3.72 (AB d, 2 × 1 H, H19), 3.78
(s, 3 H, OMe), 5.95 (d, 1 H, J ) 2.2 Hz, H2). 13C NMR δ: 17.5
(Me, C20), 20.9, 22.4 (2 × Me, C15 + C16), 26.2 (CH2, C11),
27.7 (CH, C14), 28.9 (CH2, C12), 31.8 (CH, C10), 31.9, 32.2
(2× CH2, C4 + C8), 41.5, 42.5, 45.0 (3 × CH, C3, C9 + C13),
50.4 (C, C5), 52.2 (OMe), 67.1, 67.2, 68.4, 71.4 (2 × C + 2 ×
CH2, C6, C7, C17 + C19), 128.7 (CH, C2), 149.0 (C, C1), 176.7
(C, C18). MS m/z: 348 (M+‚, 5), 330 (70), 317 (46), 299 (59),
285 (100), 257 (40), 225 (26), 197 (32), 147 (70), 119 (78), 105
(70), 91 (86), 81 (75). HRMS: calcd for C21H32O4 348.2301,
found 348.2298.
Methyl 19-Hydroxy-17-oxo-sordaric-1-en-18-oate (33)
and Isomethyl 19-Hydroxy-17-oxosordaric-1-en-18-oate
(iso-30). A solution of aldehyde 8 (30 mg, 73 µmol) in
dichlorobenzene (1.0 mL) was heated at 180 °C under a stream
of nitrogen gas from a cylinder for 1 h. After being cooled to
room temperature, the mixture was subjected to flash chro-
matography on a column of silica gel using 100% hexanes then
15% ethyl acetate in hexanes as the eluant, to afford an
inseparable 4:1 mixture of 30 and iso-30 (19 mg, 76%) as a
white solid. The mixture was then used in the next reaction.
J. Org. Chem, Vol. 70, No. 5, 2005 1669

Mander and Thomson
Supporting Information Available: All experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. Jim Balkovec
(Merck) for an authentic sample of sordaricin. Amano
Pharmaceuticals is thanked for supplying the lipase
used for the preparation of enantiopure 10.
JO048199B
1670 J. Org. Chem., Vol. 70, No. 5, 2005