Solution-phase parallel synthesis with oligoethylene glycol sorting tags. Preparation of all four stereoisomers of the hydroxybutenolide fragment of murisolin and related acetogenins

Article abstract of DOI:10.1021/jo060217x

The principles of the oligoethylene glycol (OEG) mixture synthesis are illustrated with the synthesis of all four possible stereoisomers of a hydroxybutenolide fragment common to murisolin and many other acetogenins. Modified dimethoxybenzyl groups with varying numbers of OEG units (-CH ₂CH₂O-) are used to protect alcohols and serve as codes for configurations at two stereocenters. The encoded isomers are carried through several steps in a sequence of mixing prior to the reaction and then demixing during the separation to give individual pure products. A new tagging scheme is introduced in which a stereocenter bearing a hydroxy group is given two different tags. These initially redundant tags then serve to encode the configuration of another (untagged) stereocenter by appropriate pairwise reactions of the tagged precursors. The experimental features (reaction, analysis, separation, and characterization) of OEG mixture synthesis are detailed and are compared to and contrasted with those of fluorous mixture synthesis.

Full text of DOI:10.1021/jo060217x

Solution-Phase Parallel Synthesis with Oligoethylene Glycol Sorting
Tags. Preparation of All Four Stereoisomers of the
Hydroxybutenolide Fragment of Murisolin and Related Acetogenins
Venugopal Gudipati, Dennis P. Curran, and Craig S. Wilcox*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
daylite@pitt.edu
ReceiVed February 1, 2006
The principles of the oligoethylene glycol (OEG) mixture synthesis are illustrated with the synthesis of
all four possible stereoisomers of a hydroxybutenolide fragment common to murisolin and many other
acetogenins. Modified dimethoxybenzyl groups with varying numbers of OEG units (-CH2CH2O-) are
used to protect alcohols and serve as codes for configurations at two stereocenters. The encoded isomers
are carried through several steps in a sequence of mixing prior to the reaction and then demixing during
the separation to give individual pure products. A new tagging scheme is introduced in which a stereocenter
bearing a hydroxy group is given two different tags. These initially redundant tags then serve to encode
the configuration of another (untagged) stereocenter by appropriate pairwise reactions of the tagged
precursors. The experimental features (reaction, analysis, separation, and characterization) of OEG mixture
synthesis are detailed and are compared to and contrasted with those of fluorous mixture synthesis.
Introduction
the orchestrated preparation of individual pure products by way
of intermediate mixtures was a fluorous-mixture synthesis.2
Analogues or isomers are “coded” by the attachment of fluorous
tags that differ in fluorine content.3 The tagged compounds are
mixed and carried through a synthesis as if they were a single
compound. The last mixture is ultimately sorted into its
individual components just prior to detagging to give the final
products.
The traditional “one at a time” synthesis of stereoisomers
has recently been supplemented by both solid-phase and
solution-phase mixture synthesis techniques.1 Mixture syntheses
can be divided into two broad classes on the basis of whether
the final target products are isolated as mixtures or as individual
pure products. The first solution-phase technique to provide for
(1) (a) Houghten, R. A.; Pinilla, C.; Appel, J. R.; Blondelle, S. E.; Dooley,
C. T.; Eichler, J.; Nefzi, A.; Ostresh, J. M. J. Med. Chem. 1999, 42, 3743-
3778. (b) An, H.; Cook, P. D. Chem. ReV. 2000, 100, 3311-3340. (c) Boger,
D. L.; Goldberg, J. In Combinatorial Chemistry; Fenniri, H., Ed.; Oxford
University Press: New York, 2000, pp 303-326.
(2) (a) Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. Science
2001, 291, 1766-1769. (b) Short review: Zhang, W. ArkiVoc 2004, 101-
107.
We recognized that sorting tags applicable to predictable
chromatographic separations should feature an incremental
change that can be targeted by a complementary chromato-
graphic separation technique. In a fluorous mixture synthesis,
the incremental change is homologation of the tags by the
addition of CF2 groups, and the complementary separation
10.1021/jo060217x CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/28/2006
J. Org. Chem. 2006, 71, 3599-3607
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Gudipati et al.
FIGURE 1. Mixtures of esters can be sorted by their differing OEG
tags.
technique that sorts mixtures on the basis of this increment is
specially prepared fluorous chromatography media.
In an effort to further empower the concept of chromato-
graphic tagging strategies and to extend the concept of mixture
synthesis, we conceived the idea that the oligoethylene glycol
(OEG) unit (-OCH2CH2-) might be a suitable component for
sorting tagged molecules and that the separation of OEG tags
could be accomplished by standard silica gel chromatography
without recourse to special fluorous media.4 We prepared a
series of 18 OEG esters 1 (Figure 1) with assorted substituents
(R) and bearing incremented tags consisting of 1-4 OEG units
(n ) 1-4). TLC and HPLC experiments demonstrated that the
retention effects on standard silica gel induced by changing the
OEG increment (n) were much larger than the effects of
changing the ester substituents (R). These results suggest that
OEG tags can be useful for mixture synthesis, but the idea has
not been tested before this time. Herein we describe the first
example of OEG mixture synthesis.
FIGURE 2. Structure of murisolin and target diastereomers.
the hydroxyl butenolide fragment and to assign which side chain
is on which end (C15 or C20) of the dihydroxy THF fragment.8
To create unambiguous stereoisomers of the complete molecule,
one must create each diastereomer of the hydroxyl butenolide
entity and attach each isomer to uniquely identified isomers of
the tetrahydrofuran moiety.
This first OEG mixture synthesis was undertaken to support
the synthesis of new diasteromers of the murisolin class of
acetogenins (Figure 2).5-7 Curran and co-workers have sub-
stantial experience in the fluorous mixture synthesis of these
molecules,3c and we recognized the opportunity to leverage the
planned OEG mixture synthesis by using the products of this
work in a double mixture synthesis.5
Making multiple stereoisomers of the hydroxyl butenolide
fragment (the right portion) of murisolin is important because
structure assignments of murisolin and related acetogenins are
complicated by similarities of the spectra of diastereomers that
arise in combinations between the dihydroxy THF ring (the left
portion of murisolin) and the hydroxyl butenolide fragment (the
right portion). Experience shows that it is difficult to assign
the configurations of the dihydroxy THF fragment relative to
Curran and co-workers prepared 16 stereoisomers of the
dihydroxy THF fragment of murisolin 2, (the left half) all of
which have the 4R,34S configuration in the hydroxyl butenolide
fragment, and found that these exhibit only six different sets of
1H (600 MHz) and 13C (150 MHz) NMR spectra.3c,9 We
envisioned that our OEG approach would allow the synthesis
of four new diastereomers of the right half of this natural
product, each diastereomer encoded by a chosen OEG tag, and
that the synthesis of these isomers might be accomplished in
parallel. When connected to four of Curran’s isomers, we would
have in hand four known isomers and 12 new isomers of
murisolin.
The OEG-tagged hydroxybutenolide mixture M-3 (Figure 2,
the prefix “M” denotes a quasi-isomeric mixture) represents the
entire set of stereoisomers possible for the right half of
murisolin, an unexplored domain of stereoisomer space. These
four diastereomers were chosen as our target, because any of
these isomers might be attached to known intermediates of the
murisolin synthesis by a Kocienski-Julia reaction, followed by
hydrogenation, and would thereby lead to new examples of the
family of murisolin stereoisomers.
(3) (a) Curran, D. P.; Furukawa, T. Org. Lett. 2002, 4, 2233-2235. (b)
Zhang, W.; Luo, Z.; Chen, C. H. T.; Curran, D. P. J. Am. Chem. Soc. 2002,
124, 10443-10450. (c) Zhang, Q. S.; Lu, H. J.; Richard, C.; Curran, D. P.
J. Am. Chem. Soc. 2004, 126, 36-37. (d) Dandapani, S.; Jeske, M.; Curran,
D. P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12008-12012. (e) Manku,
S.; Curran, D. P. J. Comb. Chem. 2005, 7, 63-68. (f) Manku, S.; Curran,
D. P. J. Org. Chem. 2005, 70, 4470-4473. (g) Jian, H. H.; Tour, J. M. J.
Org. Chem. 2005, 70, 3396-3424.
(4) Wilcox, C. S.; Turkyilmaz, S. Tetrahedron Lett. 2005, 46, 1827-
1829.
(5) (a) Wilcox, C. S.; Gudipati, V.; Lu, H.; Turkyilmas, S.; Curran, D.
P. Angew. Chem., Int. Ed. 2005, 44, 6938-6940. (b) Parts of this work are
described in the following provisional patent application: Wilcox, C. S.;
Curran, D. P. US 2005/0048541 A1, 2005.
(6) (a) Woo, M. H.; Zeng, L.; Ye, Q.; Gu, Z.-M.; Zhao, G.-X.;
McLaughlin, J. L. Bioorg. Med. Chem. Lett. 1995, 5, 1135-1140. (b) Myint,
S. H.; Laurens, A.; Hocquemiller, R.; Cave´, A.; Davoust, D.; Cortes, D.
Heterocycles 1990, 31, 861-867. (c) Maezaki, N.; Tominaga, H.; Kojima,
N.; Yanai, M.; Urabe, D.; Tanaka, T. Chem. Commun. 2004, 406-407. (d)
Maezaki, N.; Tominaga, H.; Kojima, N.; Yanai, M.; Urabe, D.; Ueki, R.;
Tanaka, T.; Yamori, T. Chem.sEur. J. 2005, 6237-6245.
(7) Reviews covering acetogenins: (a) Hoppe, R.; Scharf, H. D. Synthesis
1995, 1447. (b) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod.
1998, 62, 504-540.
The object of this paper is to report the full details of the
OEG mixture synthesis of M-3.5b We will also present the details
of the use of OEG tags and compare OEG tags to the use of
fluorous tags. To accomplish the synthesis of four diastereomers,
each encoded by a separate identifiable tag, we needed to create
(8) (a) Hoye, T. R.; Suhadolnik, J. C. J. Am. Chem. Soc. 1987, 109,
4403-4404. (b) Hoye, T. R.; Zhuang, Z. J. Org. Chem. 1988, 53, 5580-
5582.
(9) For alternative approaches to acetogenins stereoisomer libraries,
see: (a) Sinha, S. C.; Sinha, A.; Yazbak, A.; Keinan, E. J. Org. Chem.
1996, 61, 7640-7641. (b) Das, S.; Li, L.-S.; Abraham, S.; Chen, Z.; Sinha,
S. C. J. Org. Chem. 2005, 70, 5922-5931.
3600 J. Org. Chem., Vol. 71, No. 9, 2006

OEG Parallel Synthesis
SCHEME 1. Synthesis of OEG DMB Imidate Protecting
Reagents 8a-d
FIGURE 3. Strategy and tagging plan for the OEG mixture synthesis.
M-9 (Figure 3). To make all isomers, we need to code
configurations of the stereocenters on both the butenolide (C34)
and the side chain (C4) of 3 with OEG tags. We opted to code
both stereocenters through the side-chain protecting group by
making two different quasiracemates of M-9, reacting each
quasiracemate with a different enantiomer of 10, and then
mixing the resulting pairs of quasidiastereomers. In this way,
the stereocenter of the butenolide (C34) is coded unambiguously
even though the tags are all located on the hydroxy group at
C4.
the tagging reagents and incorporate them at the right time to
arrange for a unique relationship between the tag and the
stereoconfiguration of the tagged molecules.
Results and Discussion
Tosylates 16a-d are the immediate precursors of the required
iodides M-9, and the syntheses of these molecules are sum-
marized in Scheme 2. In the previous synthesis of murisolin,3c
a Sharpless asymmetric dihydroxylation was employed to install
the stereocenter at C4. However, the enantiomer ratios of the
products of these reactions were only about 90/10. When carried
through the synthesis, the minor enantiomers ultimately resulted
in minor diastereomeric impurities in the final murisolin isomers.
To avoid the careful chromatographic effort that was required
to isolate pure isomers in the earlier work, we decided in this
work to modify the synthesis to make enantiopure precursors.
After briefly exploring other options, we settled on an approach
based on the Jacobsen hydrolytic kinetic resolution.11
Silylation of 8-nonen-1-ol 11 with TBSCl and exposure of
the resulting silyl ether to mCPBA provided rac-12 in 97%
overall yield. Hydrolytic kinetic resolution of rac-12 with (R,R)-
13 under standard conditions provided 43% of alcohol (S)-14
along with 56% of epoxide 12, now enriched in the other
enantiomer. Resolution of this epoxide sample with (S,S)-13
then provided (R)-14 in 45% overall yield from the racemate.
Both samples exhibited ee’s >98%, according to a Mosher ester
analysis. Selective monotosylation of (R)- and (S)-14 was
accomplished by the treatment with TsCl, Et3N, and 2 mol %
dibutyltin oxide,12 to provide the enantiomeric tosylates 15. In
the last steps prior to the mixture synthesis, tosylate (R)-15 was
alkylated with each of the shorter OEG imidates 8a and 8b,
and (S)-15 was alkylated with the two longer OEG imidates 8c
and 8d. This establishes a “short/long” code in which the (S)
configuration at C4 is indicated by two shorter OEG increments
(n ) 1 or 2) and the (R) configuration is indicated by the two
To succeed in our goal of preparing four diastereomers in a
one-pot parallel synthesis, we were required to prepare four
different stereoisomers and to end with a mixture in which each
steroisomer bore a unique tagged OEG protecting group. The
goal is well-represented by the concept of a code; each tagged
isomer, when decoded based on the tag, reports the identity of
the stereocenters. Furthermore, and of great practical importance,
each encoding protecting group, differing in the OEG attach-
ment, functions as a means of separation of these stereoisomers.
The physical basis of separation was to be based on the OEG
choice, but the means of attachment was an open question. We
chose the link between the OEG tag and the stereoisomer to be
through a well-known protecting group entity, the dimethoxy-
benzyl ether (DMB) structure, because the successful removal
of the OEG tag can be confidently predicted based on organic
chemists’ experience with DMB protecting groups.
The needed OEG-tagged DMB protecting reagents were
readily prepared, as summarized in Scheme 1. The synthesis of
the smallest and least-polar analogue 8a (n ) 1) is representative
of the series. O-Alkylation of methyl vanillate 4 with com-
mercial 1-chloro-2-methoxyethane 5a, employing K2CO3 and
KI in DMF, provided ester 6a, which was reduced to the alcohol
7a with LiAlH4. In turn, this was converted to the imidate 8a
by treatment with NaH in THF followed by the addition of
trichloroacetonitrile.10 The other chlorides, 5b-d, were prepared
by treating the commercially available alcohols with thionyl
chloride and were then taken through the same series of steps.
Yields were uniformly high, and each of the imidate reagents,
8a-d, was isolated as a clear oil in good purity.
Following previous syntheses of molecules such as M-3,3c
the key step in the OEG mixture-synthesis plan is the alkylation
of thiophenyl butenolide enantiomers 10 with quasiracemates
(11) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1315.
(12) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhoket, U. P.;
Pawlak, M. V.; Vaidyanathan, R. Org. Lett. 1999, 1, 447-450.
(10) Wessel, H.-P.; Iverson, T.; Bundle, D. R. J. Chem. Soc., Perkin
Trans. 1 1985, 2247-2255.
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Gudipati et al.
SCHEME 2. Premix Stage: Synthesis of the OEG-Tagged
Tosylates 16
SCHEME 3. OEG Mixture Synthesis of Target Aldehydes 3
longer ones (n ) 3 or 4). The double coding is initially
redundant but will presently permit the coding of the C34
butenolide stereocenter without bringing in additional tags.
Mixture Synthesis Stage. The mixture synthesis stage of the
work is summarized in Scheme 3. Quasiracemate tosylates
M-16a,c and M-16b,d were separately converted to the corre-
sponding iodides M-9 by treatment with sodium iodide in
refluxing acetone. After 20 h, the reactions were complete by
TLC analysis (see below), and each mixture exhibited only two
spots for the corresponding iodides (9a and 9c, or 9b and 9d),
with no detectable spots for starting tosylates. Accordingly, the
reactions were worked up, and the crude iodide mixtures were
used directly in the next step.
Quasiracemate M-9a,c was alkylated with the enolate derived
from butenolide (S)-10 under standard conditions (NaHDMS,
THF/HMPA, reflux). After workup, the crude product of this
reaction was subjected to standard silica flash chromatography.
As expected, this resulted in demixing and provided the less-
polar quasidiastereomer (R,S)-17a (66%, n ) 1), followed by
the more-polar (S,S)-17c (73%, n ) 3). In turn, quasiracemate
M-9b,d was reacted with enantiomeric butenolide (R)-10 to give
(S,S)-17b (71%, n ) 2) and (S,R)-17d (70%, n ) 4) after flash
chromatography. Each of the four isolated quasidiastereomers
was characterized by the usual battery of spectroscopic tech-
niques (see below and Supporting Information). The use of the
two different quasiracemates of 11 establishes an “odd/even”
coding of the butenolide stereocenter (C34), with an odd number
of OEG increments (1,3) encoding the (S) configuration and
an even number of increments (2,4) encoding the (R) config-
uration. Each of the four quasi-isomers of 17 now has a unique
OEG tag.
Remixing to make the four component mixture M-17a-d
was followed by mCPBA-mediated oxidation to the sulfoxide
and direct elimination at 160 °C (microwave) to provide a
mixture of four butenolides, M-18a-d.13 Standard silica chro-
matography then provided the four pure butenolides, 18a-d,
in yields ranging from 85 to 89%. Finally, the four butenolides
were remixed, and the mixture M-18a-d was desilylated with
a catalytic amount of HCl in MeOH.14 Without purification,
the resulting mixture of crude alcohols was oxidized with
o-iodoxybenzoic acid (IBX),15 and the crude product was
purified by flash chromatography with concomitant demixing
to provide the target aldehydes (R,S)-3a, (R,R)-3b, (S,S)-3c, and
(13) Moghaddam, F. M.; Ghaffarzadeh, M. Tetrahedron Lett. 1996, 37,
1855-1858.
(14) Khan, A. T.; Mondal, E. Synlett 2003, 5, 694-696.
(15) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
3602 J. Org. Chem., Vol. 71, No. 9, 2006

OEG Parallel Synthesis
chromatography of M-3a-d, shown in Figure 4b, with 25%
EtOAc in hexanes initially provided (R,S)-3a. The eluent
composition was then changed in three subsequent stages to
35, 50, and finally 70% EtOAc to elute in sequence (R,R)-3b,
(S,S)-3c, and (S,R)-3d. Each step gradient was treated like a
standard flash chromatographysfractions were analyzed by TLC
and those containing impurities were not combined with the
pure fractions. The impurities were generally small and did not
arise from the late elution of the preceding OEG tag or the early
elution of the subsequent one. Instead, they were minor
compounds bearing the same tag as the target compound.
In practice, OEG mixture synthesis is an iterative process of
mixing to conduct a reaction, followed by demixing during a
subsequent separation. The demixing can be avoided when crude
reaction products are taken directly to the next step without
purification. This is very different from fluorous mixture
synthesis, where demixing is typically used for analysis but not
for preparative purification of intermediates. Fluorous techniques
such as LCMS or LC NMR over fluorous silica gel allow the
individual analysis and identification of mixture components;2b
however, the components can often be purified without demixing
by flash chromatography over standard silica gel.
FIGURE 4. Typical TLC analyses of OEG-tagged product mixtures.
(S,R)-3d. In work not reported here but communicated sepa-
rately, these aldehydes were mixed and applied to the synthesis
of 12 new isomers of murisolin.5
Analysis, Separation, and Identification Features of an
OEG Mixture Synthesis. Any solution-phase mixture-synthesis
technique based on separation tagging must provide for methods
for the characterization of intermediates during a synthesis. In
short, it must be possible to analyze, separate, and identify
components of a mixture. In an OEG mixture synthesis, tag-
based separation is accomplished by silica gel chromatography,
and we used standard techniques in this work both to follow
reactions of mixtures and to purify products.
Figure 4 shows two representative TLC analyses of reaction
products from this work. On the left is a diagram of the TLC
analysis (50% EtOAc in hexane) of the reaction mixture from
the Finkelstein reaction of quasiracemic tosylates M-16a,c after
treatment to provide iodides M-9a,c. The starting material (Lane
1) shows an upper spot corresponding to (R)-16a with the
smaller OEG tag (n ) 1) and a lower spot corresponding to
(S)-16c with the larger tag (n ) 3). After heating M-16a,c at
reflux in acetone in the presence of sodium iodide for 8 h, the
two starting spots remain, but there are two new spots that
indicate partial conversion to the products 9. After heating for
20 h, both tosylate spots disappear, and only the spots
corresponding to iodides (R)-9a and (S)-9c are visible. In effect,
the TLC analyses of the mixtures behave like two (or four)
standard TLCs stacked on top of each other, with the larger
(primary) separation dictated by the OEG increment and the
smaller (secondary) separation dictated by the structural change
in the molecule.
The right side of Figure 4 shows a photograph of the TLC
analysis of the final crude reaction product, aldehyde M-3a-
d, following the IBX oxidation. This is representative of the
TLC analyses of the four-product mixture reactions and shows
four spots, implying clean conversion of the precursors to the
products. Because of the wide range of Rf values for the spots,
preparative flash chromatography under standard isocratic
conditions was not practicalseither the products with shorter
OEG tags came off too fast to separate, or the products with
longer tags never eluted. This problem was readily solved by
conducting preparative separations with step gradients. The
solvent compositions of the steps were selected by standard TLC
experiments that determined the amount of the more-polar
solvent (EtOAc) needed to move each successive product off
the baseline to an R×c4 of about 0.15-0.3. For example, flash
The question of whether the iterative “mix/demix” feature
of an OEG mixture synthesis is an advantage or a disadvantage
depends on your point of view. On one hand, it is a disadvantage
because a little additional work is generated each time a mixture
is separated into its components. For example, preparative
purification of a four-compound fluorous mixture3 might entail
the collection of a single spot, while the same purification of
an OEG mixture requires the collection of four spots in the
successive step gradient. The four compounds must briefly be
handled individually prior to remixing for the next reaction. On
the other hand, the enforced demixing by OEG tags is an
advantage because the individual products can be analyzed and
characterized by traditional means. For example, in fluorous
mixture synthesis, “average yields” are usually calculated based
on the weight of a mixture and the mol % of its underlying
components. And the individual components of mixtures are
1
only occasionally characterized by H NMR spectroscopy and
even less frequently by 13C NMR spectroscopy. In contrast, we
have recorded, herein, accurate weight yields of all the purified
components of several mixtures. (These yields are identical to
standard yields of individual reactions.) All of the demixed
products from the mixture synthesis stage of this work have
been characterized by the usual spectroscopic means (see
Supporting Information).
1
Copies of the H NMR and 13C NMR spectra from repre-
sentative quasi-isomers are shown in the Supporting Information.
These spectra are readily interpretable, and as expected, the
quasienantiomeric pairs exhibit essentially identical spectra,
except for the region with the OEG peaks. The quasidiastere-
omers exhibit very similar spectra, but there are small differ-
ences.
Polyethylene glycol (PEG) tags have been used by Janda and
Gravert and others for the synthesis of individual small
molecules,16 and the spectra of OEG-tagged molecules resemble
these, except that the integration of the ethylene glycol
resonances is much smaller with respect to the rest of the
resonances. Entities bearing PEG-tags are heterogeneous materi-
als, because PEG is a mixture consisting of a range of
macromolecules of differing molecular weights. In contrast,
(16) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489-509.
J. Org. Chem, Vol. 71, No. 9, 2006 3603

Gudipati et al.
OEG-tagged compounds are single molecular entities, because
each molecule of a precursor is tagged with a single OEG tag.
Experimental Section
General Procedure 1. Synthesis of Alkyl Chlorides (5): A
solution of thionyl chloride (92 mmol) in CHCl3 (15 mL) was added
slowly over 15 min to a stirred solution of OEG monomethyl ether
(72 mmol) and pyridine (72 mmol) in CHCl3 (60 mL) under argon,
followed by refluxing the above reaction mixture for 3 h. The above
reaction mixture was washed with 300 mL of water, dried with
MgSO4, and concentrated under reduced pressure. The crude
product (yellow to brown colored) was spectroscopically pure and
can be used in the next step without further purification. However,
bulb-to-bulb (kugelrohr distillation) distillation into a cold receiving
flask (-78 °C) under reduced pressure gave the desired alkyl
chloride as colorless to pale yellow oils.
Conclusions
The first multistep OEG mixture synthesis has been success-
fully completed, and the features of the new method are
beginning to emerge. The components of the quasi-isomeric
mixtures of this work all showed similar reactivity during the
reaction stages, but they showed very different separation
properties on standard silica gel. As projected, the nature of
the OEG-tag dominated in all cases over the molecule that was
tagged, with mixture components reliably eluting in order of
the increasing size of the OEG group. This dominance may be
expected in other applications as well, provided that the
structures of the tagged components are reasonably analogous.
1-Chloro-2-(2-methoxyethoxy)ethane (5b): Performing the
general procedure 1 with 2-(2-methoxyethoxy)ethanol (15b; 8.7 g,
72 mmol) gave 1-chloro-2-(2-methoxyethoxy)ethane (5b; 9.2 g,
92%) as a colorless oil. See Supporting Information for 5c,d.
3-Methoxy-4-(2-methoxyethoxy)benzoic Acid Methyl Ester
(6a): Potassium carbonate (10 g, 72 mmol) and potassium iodide
(1.5 g, 9.0 mmol) were added to a solution of methyl vanillate (4;
5.0 g, 27 mmol) and 1-chloro-2-methoxyethane (5a; 3.4 g, 36 mmol)
in dry DMF, and the reaction mixture was stirred for 24 h under
argon. The DMF was removed by concentrating the reaction mixture
with a rotovap equipped with a dry ice/acetone bath (-78 °C
condenser). Dichloromethane (15 mL) was added to the above crude
product, and the resulting solution was filtered to remove the
potassium salts. The filtrate was concentrated, and the traces of
solvents (CH2Cl2 and DMF) present in it were removed in vacuo
(0.08 mmHg, 45 °C) into a cold receiving flask (-78 °C) by bulb-
to-bulb (kugelrohr) distillation. The resulting residue was distilled
bulb-to-bulb (0.08 mmHg, 55-60 °C) into a cold receiving flask
(-78 °C) to yield 3-methoxy-4-(2-methoxyethoxy)benzoic acid
methyl ester (6a; 6.1 g, 93%) as a pale yellow oil: 1H NMR (300
MHz, CDCl3) δ 3.43 (s, 3H), 3.77-3.80 (m, 2H), 3.87 (s, 3H),
3.89 (s, 3H), 4.19-4.22 (m, 2H), 6.89 (d, J ) 8.2 Hz, 1H), 7.52
(d, J ) 1.6 Hz, 1H), 7.63 (dd, J ) 8.5, 1.9 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 51.7, 55.7, 58.9, 67.9, 70.5, 111.6, 112.0, 122.6,
123.1, 148.7, 152.0, 166.5; IR (neat) 1720, 1600, 1513; EIMS m/z
240 (M+); HRMS calcd for C12H16O5, 240.0998; found, 240.0985.
3-Methoxy-4-[2-(2-methoxyethoxy)ethoxy]benzoic Acid Meth-
yl Ester (6b): Potassium carbonate (10 g, 72 mmol) and potassium
iodide (1.5 g, 9.0 mmol) were added to a solution of methyl vanillate
(4; 5.0 g, 27 mmol) and 1-(2-chloroethoxy)-2-methoxyethane (5a;
4.9 g, 36 mmol) in dry DMF (125 mL), and the reaction mixture
was stirred at 60 °C for 24 h under argon. The DMF was removed
from the reaction mixture by concentrating it with a rotovap
equipped with a dry ice/acetone bath (-78 °C condenser). Dichlo-
romethane (15 mL) was added to the above crude product, and the
resulting solution was filtered to remove the potassium salts. The
filtrate was concentrated, and the traces of solvents (CH2Cl2, DMF)
and the excess of alkyl halide present in it were removed in vacuo
(0.08 mmHg, 50-55 °C) into a cold receiving flask (-78 °C) by
bulb-to-bulb distillation. The resulting residue was distilled bulb-
to-bulb (0.08 mmHg, 68-72 °C) into a cold (-78 °C) receiving
flask to yield 3-methoxy-4-[2-(2-methoxyethoxy)ethoxy] benzoic
While only four OEG tags have been used in this work, it is
easy to envision lower homologation to a null tag (n ) 0, that
is, a bare methoxy group) as well as higher homologation into
the range of n ≈ 10. Beyond this point, the highly polar tagged
molecules will probably exhibit significant water solubility as
their properties begin to converge on those of PEG-tagged
molecules.
This report also introduces a pro-tagging method used to
encode the configuration of a stereocenter in a portion of the
molecule (the butenolide ring) that has no convenient function-
ality for the attachment of a tag. Instead, two pairs of
(apparently) redundant tags were introduced to encode the
hydroxy-bearing stereocenter, and then an appropriate pairwise
combination of these tagged compounds with the untagged
butenolide enantiomers provided an unambiguous coding scheme.
Ultimately, the final aldehyde mixture M-3a-d in this work
was used as a key component in a double mixture synthesis
that yielded sixteen stereoisomers of the acetogenin murisolin.5
Four of these 16 stereoisomers were identical to existing
samples,3c thereby confirming the success of the reaction
sequence and the encoding scheme in both this single OEG
mixture synthesis and the subsequent OEG-fluorous double
mixture synthesis.
At this early stage, OEG mixture synthesis shares features
of mixture synthesis by separation tagging and with features of
traditional synthesis of individual pure compounds. This hybrid
nature originates because of the “mix/demix” feature, with
mixing occurring prior to every reaction and demixing occurring
in the subsequent separation. The demixing has the disadvantage
that a bit more work is needed, but a dividend of much more
information (accurate yields, characterization data) is paid back
in return. In practice, OEG mixture synthesis has considerable
flexibility, because the automatic demixing can be avoided either
by taking the crude mixtures ahead into the next step or by
changing the fraction collection criteria in the flash chroma-
tography.
1
acid methyl ester (6b; 7.5 g, 96%) as a yellow oil: H NMR (300
MHz, CDCl3) δ 3.39 (s, 3H), 3.56-3.59 (m, 2H), 3.72-3.75 (m,
2H), 3.90-3.94 (m, 8H), 4.94 (t, J ) 5.0 Hz, 2H), 6.93 (d, J ) 8.5
Hz, 1H), 7.55 (d, J ) 1.9 Hz, 1H), 7.65 (dd, J ) 8.5, 1.9 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 51.8, 55.8, 58.9, 68.2, 69.3, 70.7,
71.8, 111.8, 112.2, 122.7, 123.3, 148.8, 152.1, 166.7; IR (neat) 2928,
2888, 1714, 1599; EIMS m/z 284 (M+); HRMS calcd for C14H20O6,
284.1260; found, 284.1265.
3-Methoxy-4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ben-
zoic Acid Methyl Ester (6c): Potassium carbonate (10 g, 72 mmol)
and potassium iodide (1.5 g, 9.0 mmol) were added to a solution
of methyl vanillate (4; 5.0 g, 27 mmol) and 1-[2-(2-chloroethoxy)-
ethoxy]-2-methoxyethane (5c; 6.6 g, 36 mmol) in dry DMF (125
Despite the shared conceptual basis for separation tagging
in solution-phase mixture synthesis, the techniques of fluorous
mixture synthesis and OEG mixture synthesis are proving to
be quite different in practice. Taken separately, the techniques
are complementary, with different strengths and weakness that
may dictate which is preferred for a given problem. Taken
together, they allow for a double mixture synthesis in which
the number of encoded products in the mixture is the multiple
of the number of each class of tags rather than the sum.
3604 J. Org. Chem., Vol. 71, No. 9, 2006

OEG Parallel Synthesis
mL), and the reaction mixture was stirred at 60 °C for 24 h under
argon. The DMF was removed from the reaction mixture by
concentrating it with a rotovap equipped with a dry ice/acetone
bath (-78 °C condenser). Dichloromethane (15 mL) was added to
the above crude product, and the resulting solution was filtered to
remove the potassium salts. The filtrate was concentrated, and the
traces of solvents (CH2Cl2, DMF) and excess of alkyl halide present
in it were removed in vacuo (0.08 mmHg, 65 °C) into a cold
receiving flask (-78 °C) by bulb-to-bulb distillation. The resulting
residue was distilled bulb-to-bulb (0.08 mmHg, 85-90 °C) to yield
3-methoxy-4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}benzoic acid
methyl ester (6c; 8.5 g, 95%) as a yellow oil: 1H NMR (300 MHz,
CDCl3) δ 3.24 (s, 3H), 3.39-3.42 (m, 2H), 3.48-3.56 (m, 4H),
3.60-3.63 (m, 2H), 3.76-3.80 (m, 8H), 4.11 (t, J ) 5.0 Hz, 2H),
6.80 (d, J ) 8.4 Hz, 1H), 7.41 (d, J ) 1.8 Hz, 1H), 7.51 (dd, J )
8.4, 2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 51.5, 55.5, 58.6,
68.0, 69.0, 70.1, 70.2, 70.5, 71.5, 111.6, 111.9, 122.4, 123.0, 148.6,
152.0, 166.4; IR (neat) 3085, 2870, 1716, 1508; EIMS m/z 328
(M+); HRMS calcd for C16H24O7, 328.1522; found, 328.1523.
3-Methoxy-4-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-
benzoic Acid Methyl Ester (6d): Potassium carbonate (10 g, 72
mmol) and potassium iodide (1.5 g, 9.0 mmol) were added to a
solution of methyl vanillate (4; 5.0 g, 27 mmol) and 1-[2-(2-
chloroethoxy)ethoxy]-2-(2-methoxyethoxy)ethane (5d; 8.1 g, 36
mmol) in dry DMF (125 mL), and the reaction mixture was stirred
at 60 °C for 24 h under argon. The DMF was removed from the
reaction mixture by concentrating it with a rotovap equipped with
a dry ice/acetone bath. Dichloromethane (15 mL) was added to
the above crude product, and the resulting solution was filtered to
remove the potassium salts. The filtrate was concentrated, and the
traces of solvents (CH2Cl2, DMF) and excess alkyl halide present
in it were removed in vacuo (0.08 mmHg, 65 °C) into a cold
receiving flask (-78 °C) by bulb-to-bulb distillation. The resulting
residue was distilled bulb-to-bulb (0.08 mmHg, 85-90 °C) into a
cold receiving flask (-78 °C) to yield 3-methoxy-4-(2-{2-[2-(2-
methoxyethoxy)ethoxy]ethoxy}ethoxy)benzoic acid methyl ester
(6d; 9.3 g, 91%) as yellow oil: 1H NMR (500 MHz, CDCl3) δ
3.19 (s, 3H), 3.35-3.38 (m, 2H), 3.46-3.51 (m, 8H), 3.55-3.59
(m, 2H), 3.71-3.75 (m, 8H), 4.06 (t, J ) 5 Hz, 2H), 6.75 (d, J )
8.5 Hz, 1H), 7.36 (d, J ) 1.5 Hz, 1H), 7.46 (dd, J ) 8.5, 1.5 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 51.4, 55.5, 58.5, 67.9, 69.0,
70.0, 70.1, 70.4, 71.4, 111.6, 111.9, 122.4, 122.9, 148.5, 151.9,
166.24; IR (neat) 2941, 2873, 1716, 1598, 1509; EIMS m/z 373
(M + H), 372 (M+); HRMS calcd for C18H28O8, 372.1784; found,
372.1796.
General Procedure 2. Reduction of Esters 6a-d to Alcohols
7a-d with LiAlH4: A solution of ester 6 (1.0 equiv) in THF was
added slowly to a suspension of LiAlH4 (0.55 equiv) in THF at 0
°C, and the resulting reaction mixture was stirred at 0 °C for 15
min, followed by 30 min at room temperature. The reaction mixture
was quenched with methanol and diluted with ethyl acetate and
saturated sodium potassium tartarate (1:1), followed by vigorous
stirring for 3.5 h. The organic layer was separated, and the aqueous
layer was extracted twice with ethyl acetate. The combined organic
extracts were dried over MgSO4 and concentrated under reduced
pressure to yield the alcohol 7 as an oil.
[3-Methoxy-4-(2-methoxyethoxy)phenyl]methanol (7a): Per-
forming the general procedure 2 with 3-methoxy-4-(2-methoxy-
ethoxy)benzoic acid methyl ester (6a; 5.9 g, 24 mmol) gave
[3-methoxy-4-(2-methoxyethoxy)phenyl]methanol (7a; 4.7 g, 91%)
as an oil. 1H NMR (300 MHz, CDCl3) δ 3.50 (s, 3H), 3.78 (t, J )
5.1 Hz, 2H), 3.87 (s, 3H), 4.15 (t, J ) 3.1 Hz, 2H), 4.62 (s, 2H),
6.87-6.93 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 55.9, 59.2, 65.1,
68.5, 71.1, 110.8, 113.6, 119.2, 134.3, 147.7; IR (neat) 3400, 2940,
2868, 1588, 1516. See Supporting Information for 7b-d.
THF (25 mL) under argon. The reaction mixture was stirred at room
temperature for 20 min and then cooled to 0 °C, followed by the
slow addition of trichloroacetonitrile (2.1 mL, 21 mmol) over 15
min. The reaction mixture was allowed to warm to room temper-
ature over 1 h, followed by concentration under reduced pressure.
To the concentrate was added a mixture of pentane/methanol (49:
1, 50 mL), followed by vigorous shaking, filtration, and concentra-
tion of filtrate and pentane washings17 (3 × 30 mL), resulting in
2,2,2-trichloroacetimidic acid 3-methoxy-4-(2-methoxyethoxy)-
benzyl ester (8a; 6.8 g, 90%) as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 3.45 (s, 3H), 3.79 (t, J ) 4.9 Hz, 2H), 3.87 (s,
3H), 4.18 (t, J ) 4.9 Hz, 2H), 5.29 (s, 2H), 6.90-6.98 (m, 3H),
8.38 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 55.7, 59.0, 68.3,
70.6, 70.8, 91.3, 111.5, 113.3, 120.4, 128.4, 148.2, 149.4, 162.3;
IR (neat) 3320, 2939, 1665, 1594, 1513; EIMS m/z 355 (M+);
HRMS calcd for C13H16NO4Cl3, 355.0145; found, 355.0127. See
Supporting Information for 8b-d.
tert-Butyldimethyl-non-8-enyloxysilane: tert-Butyldimethylsilyl
chloride (19 g, 0.13 mol) was added to a stirred solution of non-
8-en-1-ol (11; 14 g, 0.1mol) and imidazole (9.3 g, 0.14 mol) in
dichloromethane at 0 °C. The reaction mixture was stirred at 0 °C
for 20 min and then for 1 h at room temperature. The reaction
mixture was diluted with water, the organic layer was separated,
and the aqueous layer was further extracted with dichloromethane.
The combined organic layers were dried over MgSO4 and concen-
trated to give tert-butyldimethyl-non-8-enyloxy-silane (25 g, 99%)
as a colorless oil. The crude reaction mixture was taken to the next
1
step without further purification. H NMR (300 MHz, CDCl3) δ
0.06 (s, 6H), 0.91 (s, 9H), 1.32 (s, 8H), 1.40-1.55 (m, 2H), 2.05
(q, J ) 7.0 Hz, 2H), 3.61 (t, J ) 6.3 Hz, 2H), 4.92-5.02 (m, 1H),
5.74-5.88 (ddt, J ) 17.0, 10.3, 6.7 Hz, 1H); 13C NMR (76 MHz,
CDCl3) δ -5.2, 18.4, 25.9, 26.1, 29.0, 29.2, 29.4, 33.0, 33.9, 63.3,
114.2, 139.2; IR (neat, cm-1) 2933, 2858, 1471; EIMS m/z 241
(M - CH3), 199 (M - C4H9); HRMS calcd for (M - CH3)+ C14H29-
OSi, 241.1987; found, 241.1984.
(7R,7S)-tert-Butyldimethyl-(7-oxiranylheptyloxy)silane (rac-
12): m-Chloroperbenzoic acid (25 g, 0.11 mol, 75% w/w in H2O)
was added to a solution of tert-butyldimethyl-non-8-enyloxysilane
(25 g, 98 mmol) in dichloromethane (325 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 20 min and at room temperature
for 1 h and treated with saturated NaHCO3. The layers were
separated, and the aqueous layer was further extracted with
dichloromethane. The combined organic layers were dried over
MgSO4, concentrated under reduced pressure, and purified by flash
column chromatography (SiO2, 20% ethyl acetate/hexanes) to give
tert-butyldimethyl-(7-oxiranylheptyloxy)silane (rac-12; 26 g, 98%)
as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 6H),
0.87 (s, 9H), 1.30-1.51 (m, 12H), 2.43 (dd, J ) 4.9, 2.7 Hz, 1H),
2.69-2.73 (m, 1H), 2.84-2.90 (m, 1H), 3.57 (t, J ) 6.59 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ -5.3, 18.4, 25.7, 26.0, 29.4, 29.5,
32.5, 32.8, 47.1, 52.3, 63.2; IR (neat) 2933, 2856, 1464; EIMS m/z
215 (M - C4H9)+; HRMS calcd for (M - C4H9)+ C11H23O2Si,
215.1467; found, 215.1471.
9-(tert-Butyldimethylsilanyloxy)nonane-1,2-diol (14): The (R,R)-
Jacobson catalyst (0.28 g, 0.46 mmol) was dissolved in tert-
butyldimethyl-(7-oxiranylheptyloxy)silane (rac-12; 25 g, 92 mmol),
AcOH (110 µL, 1.8 mmol), and 0.3 mL THF. The solution was
cooled to 0 °C, treated with H2O (0.74 mL, 41 mmol), and stirred
for 12 h at room temperature. The reaction mixture was distilled
bulb-to-bulb (kugelrohr) under reduced pressure (0.08 mmHg, 120-
130 °C) to remove the residual epoxide (14 g, 52 mmol), followed
by a second distillation (0.08 mmHg, 180-190 °C) to yield (S)-
9-(tert-butyldimethylsilanyloxy)nonane-1,2-diol ((S)-14; 12 g, 43%,
>99% enantiomeric excess based on a Mosher ester analysis) as a
colorless oil. Similar procedure with the above recovered epoxide
(14 g, 51.3 mmol) and (S,S)-Jacobson catalyst (0.28 g, 0.46 mmol)
General Procedure 3. 2,2,2-Trichloroacetimidic Acid 3-Meth-
oxy-4-(2-methoxyethoxy)benzyl Ester (8a): [3-Methoxy-4-(2-
methoxyethoxy)phenyl]methanol (7a; 4.5 g, 21 mmol) was added
slowly to a suspension of sodium hydride (51 mg, 2.1 mmol) in
(17) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin.
Trans. 1, 1985, 2247.
J. Org. Chem, Vol. 71, No. 9, 2006 3605

Gudipati et al.
resulted in (R)-9-(tert-butyl-dimethylsilanyloxy) nonane-1,2-diol
((R)-14; 12 g, 45%, >99% ee by a Mosher ester analysis) as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 6H), 0.87 (s,
9H), 1.28-1.50 (m, 12H), 3.38-3.44 (m, 1H), 3.57 (t, J ) 6.6
Hz, 2H), 3.65-3.78 (br m, 4H); 13C NMR (75 MHz, CDCl3) δ
-5.2, 18.4, 25.6, 25.8, 26.0, 29.4, 29.7, 32.9, 33.1, 63.3, 66.8, 72.4.
EIMS m/z 259 (M - CH3O)+; HRMS calcd for (M - CH3O)+
C14H31O2Si, 259.2093; found, 259.2091.
Toluene-4-sulfonic Acid 9-(tert-Butyldimethylsilanyloxy)-2-
hydroxynonyl Ester (15): To a solution of (R)-9-(tert-butyldi-
methylsilanyloxy)nonane-1,2-diol ((R)-14; 12 g, 41 mmol) in CH2-
Cl2 (80 mL) were added Bu2SnO (2.0 g, 8.1 mmol), p-TsCl (7.7 g,
41 mmol), and Et3N (5.6 mL, 41 mmol), followed by stirring the
above reaction mixture for 3 h. The reaction mixture was
concentrated and purified by flash chromatography (SiO2, EtOAc/
hexanes ) 1:3) to yield toluene-4-sulfonic acid (R)-9-(tert-
butyldimethylsilanyloxy)-2-hydroxynonyl ester ((R)-15; 14 g, 76%)
as white waxy solid; similar procedure with (S)-diol (11 g, 38 mmol)
yielded (S)-sulfonyl ester ((S)-15; 12 g, 72%) as a white waxy
solid: 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.86 (s, 9H),
1.20-1.48 (m, 12H), 2.41 (s, 3H), 2.54 (br s, 1H), 3.56 (t, J ) 6.4
Hz, 2H), 3.74-3.89 (m, 2H), 3.98 (dd, J ) 9.9, 3.0 Hz, 1H), 7.32
(d, J ) 8.0 Hz, 1H), 7.77 (d, J ) 8.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ -5.3, 18.3, 21.5, 25.1, 25.6, 25.9, 29.2, 29.4, 32.6, 32.7,
63.2, 69.2, 73.9, 127.9, 129.9, 132.7, 144.9; HRMS calcd for
C22H40O5SSiNa, 467.2263; found, 467.2287.
General Procedure 4. Toluene-4-sulfonic Acid (R)-9-(tert-
Butyldimethylsilanyloxy)-2-[3-methoxy-4-(2-methoxyethoxy)-
benzyloxy]nonyl Ester (16a): A solution of (R)-9-(tert-butyldi-
methylsilanyloxy)-2-hydroxynonyl ester ((R)-15; 2.3 g, 5.2 mmol),
2,2,2-trichloroacetimidic acid 3-methoxy-4-(2-methoxyethoxy)-
benzyl ester (8a; 3.7 g, 10 mmol), and 10-camphorsulfonic acid
(0.12 g, 0.52 mmol) in CH2Cl2 (30 mL) was stirred at room
temperature for 24 h and then diluted with saturated NaHCO3. The
layers were separated, and the aqueous layer was extracted twice
with CH2Cl2. The combined organic layers were dried over MgSO4,
concentrated, and purified by flash chromatography (SiO2, EtOAc/
hexanes ) 3:7) to yield 16a (2.0 g, 60%): 1H NMR (300 MHz,
CDCl3) δ 0.03 (s, 6H), 0.88 (s, 9H), 1.18-1.46 (m, 12 H), 2.43 (s,
3H), 3.44 (s, 3H), 3.55-3.60 (m, 3H), 3.76-3.79 (m, 2H), 3.86
(s, 3H), 4.00 (t, J ) 4.39 Hz, 2H), 4.14 (t, J ) 4.39 Hz, 2H), 4.41
(d, J ) 11.5 Hz, 1H), 4.49 (d, J ) 11.5 Hz, 1H), 6.74-6.86 (m,
3H), 7.31 (d, J ) 8.2 Hz, 2H), 7.76 (d, J ) 8.2 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ -5.3, 18.4, 21.6, 25.1, 25.7, 26.0, 29.3, 29.5,
31.3, 32.8, 55.8, 59.1, 63.2, 68.2, 70.9, 71.7, 72.0, 76.1, 111.6,
113.1, 120.3, 127.9, 129.9, 131.3, 132.8, 144.9, 147.8, 149.4; IR
(neat) 2927, 2856, 1597, 1514, 1461; HRMS (M + Na)+ calcd for
C33H54O8SiS, 661.3206; found, 661.3209. See Supporting Informa-
tion for 16b-d.
General Procedure 5. tert-Butyl-{(R)-9-iodo-8-[3-methoxy-4-
(2-methoxyethoxy)benzyloxy]nonyloxy}dimethylsilane (9a) and
tert-Butyl-[(S)-9-iodo-8-(3-methoxy-4-{2-[2-(2-methoxyethoxy)-
ethoxy]ethoxy}benzyloxy)nonyloxy]dimethylsilane (9c): A solu-
tion of 16a (1.9 g, 3.0 mmol), 16c (2.3 g, 3.2 mmol), and NaI (9.2
g, 61 mmol) in acetone (35 mL) was refluxed for 20 h, followed
by concentration under reduced pressure. The concentrate was
treated with water and extracted with ethyl acetate. The combined
organic extracts were dried over MgSO4 and concentrated to yield
a mixture of 9a and 9c as a light brown oil (3.9 g, 98%), which
was used in the next step without further purification. However,
for characterization purposes, a small sample (0.1 g) of the mixture
M-9a,c was subjected to flash column chromatography (SiO2) and
gave 9a (ethyl acetate/hexanes ) 1:4), followed by 9c (ethyl acetate/
hexanes ) 1:1), as colorless oils. For 9a: 1H NMR (500 MHz,
CDCl3) δ 0.05 (s, 6H), 0.90 (s, 9H), 1.30-1.64 (m, 12H), 3.21-
3.33 (m, 3H), 3.46 (s, 3H), 3.60 (t, J ) 6.6 Hz, 2H), 3.76-3.82
(m, 2H), 3.88 (s, 3H), 4.18 (t, J ) 4.9 Hz, 2H), 4.47 (d, J ) 11.0
Hz, 1H), 4.58 (d, J ) 11.0 Hz, 1H), 6.84-6.89 (m, 2H), 6.98 (s,
1H); 13C NMR (126 MHz, CDCl3) δ -5.2, 10.5, 18.5, 25.3, 25.8,
26.1, 29.4, 29.6, 32.9, 34.7, 56.0, 59.4, 63.3, 68.5, 71.0, 71.4, 77.7,
111.9, 113.6, 120.4, 131.7, 147.7, 149.7; IR (neat) 2929, 2857, 1593,
1514, 1463; HRMS [ESI, (M + Na)+] calcd for C26H47O5SiI,
617.2135; found, 617.2152. For 9c: 1H NMR (500 MHz, CDCl3)
δ 0.05 (s, 6H), 0.90 (s, 9H), 1.30-1.62 (m, 12H), 3.26-3.34 (m,
3H), 3.39 (s, 3H), 3.55-3.63 (m, 4H), 3.65-3.72 (m, 4H), 3.75
(dd, J ) 6.2, 3.4 Hz, 2H), 3.88-3.90 (m, 5H), 4.17-4.22 (m, 2H),
4.44 (d, J ) 11.5 Hz, 1H), 4.55 (d, J ) 11.5 Hz, 1H), 6.87-6.89
(m, 2H), 6.98 (s, 1H); 13C NMR (126 MHz, CDCl3) δ -5.2, 10.5,
18.4, 25.3, 25.8, 26.1, 29.4, 29.6, 32.9, 34.7, 56.0, 59.1, 63.3, 68.6,
69.6, 70.5, 70.6, 70.7, 71.3, 71.9, 77.6, 111.9, 113.5, 120.4, 131.4,
147.9, 149.6; IR (neat) 2929, 2857, 1593, 1515; HRMS (M + Na)+
calcd for C30H55O7SiI, 705.2660; found, 705.2686. See Supporting
Information for 9b,d.
General Procedure 6. (3RS,5S)-3-{(R)-9-(tert-Butyldimethyl-
silanyloxy)-2-[3-methoxy-4-(2-methoxyethoxy)benzyloxy]nonyl}-
5-methyl-3-phenylsulfanyldihydrofuran-2-one (17a) and (3RS,5S)-
3-[(S)-9-(tert-Butyldimethylsilanyloxy)-2-(3-methoxy-4-{2-[2-(2-
methoxyethoxy)ethoxy]ethoxy}benzyloxy)nonyl]-5-methyl-3-
phenylsulfanyldihydrofuran-2-one (17c): A solution of NaHMDS
(1.0 M in THF, 5.9 mL, 5.9 mmol) was added to a solution of
(S)-5-methyl-3-phenylsulfanyldihydrofuran-2-one ((S)-10; 1.2 g, 5.9
mmol) in THF (20 mL) at 0 °C. The mixture was stirred for 30
min at this temperature, and then a solution of iodide M-9a,c (3.6
g, 5.6 mmol) in HMPA (3.5 mL) was added. The reaction mixture
was allowed to warm to room temperature over 2 h, followed by
refluxing it for 14 h. Then the reaction mixture was cooled to room
temperature and quenched with saturated NH4Cl. The organic layer
was separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic extracts were washed with brine,
dried over MgSO4, and then concentrated under reduced pressure.
The residue was purified by flash chromatography (SiO2) to give
17a (25% ethyl acetate/hexanes; 1.3 g, 69%), followed by 17c (50%
ethyl acetate/hexanes; 1.5 g, 71%) as oils. For 17a: 1H NMR (300
MHz, CDCl3, major isomer) δ 0.05 (s, 6H), 0.90 (s, 9H), 1.03 (d,
J ) 6.0 Hz, 6H), 1.21-1.37 (m, 10H), 1.48-1.56 (m, 2H), 1.90-
2.15 (m, 3H), 2.69 (dd, J ) 13.7, 7.1 Hz, 1H), 3.41 (s, 3H), 3.60
(t, J ) 6.6 Hz, 2H), 3.66-3.75 (m, 3H), 3.84 (s, 3H), 4.10-4.14
(m, 2H), 4.22 (d, J ) 10.4 Hz, 1H), 4.25-4.33 (m, 1H), 4.41 (d,
J ) 10.4 Hz, 1H), 6.78-6.88 (m, 2H), 6.92 (s, 1H), 7.29-7.40
(m, 3H), 7.55 (dd, J ) 8.0, 1.4 Hz, 2H); IR (neat) 2929, 1763,
1516, 1458. For 17c: 1H NMR (500 MHz, CDCl3, major isomer)
δ 0.03 (s, 6H), 0.88 (s, 9H), 1.14 (d, J ) 6.4 Hz, 3H), 1.21-1.28
(m, 8H), 1.46-1.52 (m, 3H), 1.55-1.62 (m, 1H), 1.86 (dd, J )
14.2, 6.0 Hz, 1H), 1.92-2.09 (m, 2H), 2.81 (dd, J ) 14.2, 7.8 Hz,
1H), 3.35 (s, 3H), 3.51-3.52 (m, 2H), 3.58 (t, J ) 6.4 Hz, 2H),
3.62-3.66 (m, 4H), 3.71-3.72 (m, 2H), 3.84-3.94 (m, 6H), 4.15
(t, J ) 5.3 Hz, 2H), 4.32-4.40 (m, 2H), 4.53 (d, J ) 11.0 Hz,
1H), 6.78-6.91 (m, 3H), 7.30-7.38 (m, 3H), 7.54 (d, J ) 7.8 Hz,
2H); 13C NMR (126 MHz, CDCl3) δ -5.3, 18.3, 21.3, 24.5, 25.7,
25.9, 29.3, 29.7, 32.8, 33.4, 39.4, 40.1, 54.8, 55.9, 58.9, 63.2, 68.6,
69.5, 70.2, 70.4, 70.6, 70.7, 71.8, 73.0, 75.4, 76.8, 77.3, 111.7,
113.5, 119.8, 128.9, 129.6, 130.3, 131.4, 136.6, 147.6, 149.5, 177.3;
IR (neat) 2929, 1763, 1515, 1463; MS m/z 785 (M + Na); HMRS
(ESI) calcd for C41H66O9SSiNa, 785.4095; found, 785.4124. See
Supporting Information for 17b,d.
Lactone Mixture (M-18a-d): m-Chloroperbenzoic acid (0.28
g, 1.6 mmol) was added to a mixture of 17a (0.27 g, 0.4 mmol),
17b (0.29 g, 0.4 mmol), 17c (0.31 g, 0.4 mmol), and 17d (0.32 g,
0.4 mmol) in CH2Cl2 (30 mL) at 0 °C. The reaction mixture was
stirred for 30 min and then quenched with saturated NaHCO3
solution. The layers were separated, and the aqueous layer was
further extracted with CH2Cl2, followed by drying the combined
organic layers with MgSO4 and concentrating the organic layers.
The concentrate, in 3.5 mL of DMF, was heated in a microwave
(personal chemistry microwave, 150 W, ramped to 160 °C over 2
min and heated for 5 min at that temperature) for 5 min at 160 °C.
Removal of DMF under reduced pressure, followed by purification
by flash column chromatography on silica gel under gradient elution
3606 J. Org. Chem., Vol. 71, No. 9, 2006

OEG Parallel Synthesis
gave 18a (0.20 g, 88%; 25% ethyl acetate/hexanes), 18b (0.21 g,
85%; 40% ethyl acetate/hexanes), 18c (0.23 g, 89%; 60% ethyl
acetate/hexanes), and 18d (0.24 g, 85%; 80% ethyl acetate/hexanes)
as pale yellow oils.
5.5 Hz, 2H), 3.43 (s, 3H), 3.61-3.72 (m, 1H), 3.75-3.78 (m, 2H),
3.85 (s, 3H), 4.11-4.16 (m, 2H), 4.44 (s, 2H), 4.95 (q, J ) 6.6
Hz, 1H), 6.78-6.89 (m, 3H), 7.07 (s, 1H), 9.75 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 19.2, 22.0, 25.1, 29.1, 29.4, 29.6, 33.9, 43.9,
55.9, 59.2, 68.5, 71.1, 76.5,111.8, 113.6, 120.4, 130.5, 131.7, 147.8,
149.6, 151.6, 174.0, 202.8; IR (neat) 2927, 1751, 1720, 1514, 1465;
HRMS [ESI, (M + Na)+] calcd for C25H36O7, 471.2359; found,
471.2380.
(S)-3-{(R)-9-(tert-Butyldimethylsilanyloxy)-2-[3-methoxy-4-(2-
methoxyethoxy)benzyloxy]nonyl}-5-methyl-5H-furan-2-one (18a):
1H NMR (500 MHz, CDCl3) δ 0.02 (s, 6H), 0.86 (s, 9H), 1.23-
1.31 (m, 8H), 1.35 (d, J ) 6.9 Hz, 3H), 1.42-1.49 (m, 2H), 1.53-
1.58 (m, 2H), 2.48 (d, J ) 6.0 Hz, 2H), 3.41 (s, 3H), 3.56 (t, J )
6.6 Hz, 2H), 3.62-3.67 (m, 1H), 3.72 (t, J ) 4.6 Hz, 2H), 3.82 (s,
3H), 4.11-4.13 (m, 2H), 4.40 (d, J ) 11.5 Hz, 1H), 4.44 (d, J )
11.5 Hz, 1H), 4.92 (q, J ) 6.6 Hz, 1H), 6.78-6.84 (m, 3H), 7.05
(s, 1H); 13C NMR (126 MHz, CDCl3) δ -5.3, 18.3, 19.1, 25.2,
25.7, 25.9, 29.3, 29.6, 32.7, 33.9, 55.8, 59.1, 63.2, 68.5, 70.9, 76.5,
77.5, 111.7, 113.6, 120.2, 130.5, 131.7, 147.7, 149.6, 151.4, 173.9;
IR (neat) 2930, 2856, 1756, 1515, 1464. See Supporting Information
for 18b-d.
(R)-8-{3-Methoxy-4-[2-(2-methoxyethoxy)ethoxy]benzyloxy}-
1
9-((R)-5-methyl-2-oxo-2,5-dihydrofuran-3-yl)nonanal (3b): H
NMR (500 MHz, CDCl3) δ 1.27-1.32 (m, 8H), 1.35 (d, J ) 6.9
Hz, 3H), 1.41-1.59 (m, 2H), 2.39 (t, J ) 6.6 Hz, 2H), 2.49 (br s,
2H), 3.36 (s, 3H), 3.52-3.57 (m, 2H), 3.62-3.67 (m, 1H), 3.67-
3.72 (m, 2H), 3.82 (s, 3H), 3.85 (t, J ) 5.3 Hz, 2H), 4.15 (t, J )
5.3 Hz, 2H), 4.42 (s, 2H), 4.94-4.98 (m, 1H), 6.79-6.85 (m, 3H),
7.09 (s, 1H), 9.73 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 19.0,
21.9, 25.0, 29.0, 29.3, 29.6, 33.8, 43.8, 55.9, 59.0, 68.6, 69.6, 70.7,
71.0, 71.9, 76.5, 77.5, 111.9, 113.6, 120.3, 130.5, 131.6, 147.8,
149.5, 151.6, 173.9, 202.7; HRMS [ESI, (M + Na)+] calcd for
C27H40O8, 515.2621; found, 515.2625.
(S)-8-(3-Methoxy-4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-
benzyloxy)-9-((S)-5-methyl-2-oxo-2,5-dihydrofuran-3-yl)nona-
nal (3c): 1H NMR (300 MHz, CDCl3) δ 1.24-1.28 (m, 8H), 1.35
(d, J ) 6.6 Hz, 2H), 1.41-1.59 (m, 2H), 2.40 (t, J ) 7.4 Hz, 2H),
2.49 (br s, 2H), 3.36 (s, 3H), 3.42-3.54 (m, 2H), 3.60-3.76 (m,
9H), 3.83-3.93 (m, 5H), 4.15 (t, J ) 5.2 Hz, 2H), 4.33 (s, 2H),
4.97 (q, J ) 6.2 Hz, 1H), 6.79-6.86 (m, 3H), 7.08 (s, 1H), 9.74
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.0, 21.9, 25.1, 29.0, 29.3,
29.6, 33.8, 43.8, 55.9, 59.0, 68.6, 69.6, 70.5, 70.7, 71.0, 71.9, 76.5,
76.6, 77.5, 111.9, 113.6, 120.4, 130.5, 131.6, 147.8, 149.5, 151.6,
174.0, 202.8; IR (neat) 2927, 1751, 1515, 1457; EIMS m/z 537 (M
+ H), 536 (M+); HRMS calcd for C29H44O9, 536.2985; found,
536.2986.
(S)-8-[3-Methoxy-4-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-
ethoxy)benzyloxy]-9-((R)-5-methyl-2-oxo-2,5-dihydrofuran-3-yl)-
nonanal (3d): 1H NMR (300 MHz, CDCl3) δ 1.26-1.37 (m, 8H),
1.39 (d, J ) 6.6 Hz, 2H), 1.43-1.65 (m, 2H), 2.42 (td, J ) 7.1,
1.6 Hz, 2H), 2.51 (d, J ) 5.5 Hz, 2H), 3.38 (s, 3H), 3.53-3.56 (m,
2H), 3.61-3.76 (m, 13H), 3.82-3.92 (m, 5H), 4.17 (t, J ) 5.2
Hz, 2H), 4.44 (s, 2H), 4.91-5.03 (m, 1H), 6.84 (m, 3H), 7.08 (s,
1H), 9.76 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.1, 21.9, 25.1,
29.1, 29.4, 29.7, 33.9, 43.8, 55.9, 59.0, 68.6, 69.6, 70.6, 70.8, 71.0,
71.9, 76.5, 76.7, 77.5, 111.9, 113.6, 120.4, 130.5, 131.6, 147.8,
149.6, 151.6, 174.0, 202.8; IR (neat) 2926, 2855, 1751, 1719, 1515,
1457; HRMS [ESI, (M + Na)+] calcd for C31H48O10, 603.3145;
found, 603.3154.
Alcohol Mixture: Acetyl chloride18 (11 µL) was added to a
1:1:1:1 mixture of 18a, 18b, 18c, and 18d (0.26 g, 0.39 mmol) in
methanol at 0 °C and stirred for 15 min. Then the solution was
concentrated to yield the alcohol. The resulting mixture of alcohols
(0.20 g, 99%) was spectroscopically pure and was used in the next
step without further purification. However, spectroscopic data for
individual compounds was obtained by repeating the above
experimental procedure with individual compounds.
General Procedure 11. (S)-3-{(R)-9-Hydroxy-2-[3-methoxy-
4-(2-methoxyethoxy)benzyloxy]nonyl}-5-methyl-5H-furan-2-
one: Acetyl chloride (11 µL) was added to a solution of 18a (30
mg, 0.053 mmol) in methanol, and the mixture was stirred for 15
min. The concentration of the reaction mixture gave the alcohol
1
(23 mg, 99%) as a colorless oil. H NMR (300 MHz, CDCl3) δ
1.26-1.34 (m, 8H), 1.37 (d, J ) 7.1 Hz, 3H), 1.40-1.56 (m, 4H),
1.85 (br s, 1H), 2.49 (d, J ) 5.5 Hz, 2H), 3.42 (s, 3H), 3.59 (t, J
) 6.6 Hz, 2H), 3.63-3.67 (m, 1H), 3.73-3.79 (m, 2H), 3.84 (s,
3H), 4.13 (t, J ) 4.94 Hz, 2H), 4.43 (s, 2H), 4.94 (q, J ) 6.59 Hz,
1H), 6.78-6.86 (m, 3H), 7.07 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 19.1, 25.2, 25.6, 29.3, 29.5, 29.6, 32.7, 33.9, 55.8, 59.2, 62.8,
68.5, 70.9, 76.4, 111.8, 113.5, 120.4, 130.5, 131.7, 147.8, 149.6,
151.6, 174.0; IR (neat) 3406, 2928, 1751, 1515, 1456; EIMS m/z
450 (M+); HRMS calcd for C25H38O7, 450.2617; found, 467.2637.
See Supporting Information for acylations of 18b-d.
Aldehyde Mixture (M-3): IBX (0.40 g, 1.1 mmol) was added
to a mixture of alcohols (0.18 g, 0.36 mmol) in ethyl acetate (10
mL). The resulting suspension was heated, open to the atmosphere,
in an oil bath set to 80 °C until TLC indicated complete conversion
(3 h). Then the reaction mixture was cooled to room temperature,
filtered, and concentrated to yield a mixture of aldehyde that on
column chromatography on silica gel by gradient elution (25-70%
EtOAc/hexanes) gave the four aldehydes 3 (0.16 g, 0.32 mmol,
90%) as separate oils.
(R)-8-[3-Methoxy-4-(2-methoxyethoxy)benzyloxy]-9-((S)-5-
methyl-2-oxo-2,5-dihydrofuran-3-yl)nonanal (3a): 1H NMR (300
MHz, CDCl3) δ 1.25-1.35 (m, 8H), 1.38 (d, J ) 7.1 Hz, 3H),
1.44-1.63 (m, 2H), 2.41 (td, J ) 7.1, 1.6 Hz, 2H), 2.50 (d, J )
Acknowledgment. We thank the National Institutes of
Health (Institute of General Medical Sciences) for funding this
work. We also thank Mr. Serhan Turklyilmaz for help preparing
OEG tagging reagents.
Supporting Information Available: Contains additional ex-
perimental data and copies of spectra of all purified intermediates
(90 pages). This material is available free of charge via the Internet
at http://pubs.acs.org.
(18) Khan, A. T.; Mondal, E. Synlett 2003, 5, 694.
JO060217X
J. Org. Chem, Vol. 71, No. 9, 2006 3607