Synthesis of all 16 stereoisomers of pinesaw fly sex pheromones - Tools and tactics for solving problems in fluorous mixture synthesis

Synthesis of All 16 Stereoisomers of Pinesaw Fly Sex Pheromones

- Tools and Tactics for Solving Problems in Fluorous Mixture

Synthesis

Sivaraman Dandapani, Mario Jeske, and Dennis P. Curran*

Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

curran@pitt.edu

Received July 21, 2005

The application of fluorous mixture synthesis (FMS) for accessing natural products and their

stereoisomers was validated by the total synthesis of all 16 stereoisomers of the pine sawfly sex

pheromone. Four fluorous p-methoxybenzyl groups were used as tags, and a “4-mix-4-split” approach

was employed in a divergent synthesis. This paper presents the details of the FMS of pine sawfly

sex pheromones with an emphasis on identification and solving of problems encountered when

working with fluorous mixtures.

Introduction

individual pure compounds in order of fluorous tag from

smallest to largest. In the post-mix stage, the fluorous

tags are removed in separate detagging steps and the

individual target compounds are purified.

The emerging technique of fluorous mixture synthesis

(FMS)^1,2allows solution-phase organic synthesis to be

carried out on mixtures of compounds with predictable

separation of the products and hence offers unique

advantages for library generation. FMS has three stages:

pre-mix, mixture synthesis, and post-mix (Figure 1). The

pre-mix stage consists of synthesis of required precursors,

their tagging with a unique fluorous tag, and mixing of

the resulting tagged precursors. The fluorous-tagged

compounds are taken through a series of synthetic steps

during the mixture synthesis phase. Splitting is some-

times used to further leverage the tags and provide

additional products. At the end of the synthesis, the

mixture is subjected to chromatography over fluorous

silica gel in a process called demixing.³This provides the

In solution-phase mixture synthesis methods based on

separation tagging, the structure of the tag “encodes” a

key structural feature of the molecule to which it is

attached.^1,4This feature is “decoded” during demixing by

the order of elution. Proof-of-principle work on fluorous

mixture synthesis with the natural product mappicine

used fluorous tags to encode absolute configuration at a

single stereocenter (enantiomers) and to encode the

structure of a substituent (analogues), as shown in Figure

2.^1cWhen enantiomers are tagged, the order of demixing

has to be controlled by the tag so decoding cannot go

wrong. When analogues are tagged, the final detagged

products have different molecular weights, so the decod-

ing process can be confirmed by mass spectroscopy.

The coding of diastereomers with fluorous tags pre-

sents a problem because the final detagged diastereomers

all have the same molecular weight. Of course, their

structures could be confirmed by other spectroscopic

means, but the exercise then becomes circular because

the goal in making multiple diastereomers of a compound

(1) (a) Luo, Z. Y.; Zhang, Q. S.; Oderatoshi, Y.; Curran, D. P. Science

2001, 291, 1766-1769. (b) Curran, D. P.; Oderaotoshi, Y. Tetrahedron

2001, 57, 5243-5253. (c) Zhang, W.; Luo, Z.; Chen, C. H. T.; Curran,

D. P. J. Am. Chem. Soc. 2002, 124, 10443-10450. (d) Curran, D. P.;

Furukawa, T. Org. Lett. 2002, 4, 2233-2235. (e) Manku, S.; Curran,

D. P. J. Comb. Chem. 2005, 7, 63-68.

(2) Short review: Zhang, W. Arkivoc 2004, 101-109.

(3) For reviews of chromatography with fluorous silica gel, see: (a)

Curran, D. P. Synlett 2001, 1488-1496. (b) Curran, D. P. In The

Handbook of Fluorous Chemistry; Gladysz, J. A., Horvath, I. T.,

Curran, D. P., Eds.; Wiley-VCH: Weinheim, 2004; pp 128-156. (c)

Zhang, W. Tetrahedron 2003, 59, 4475-4489.

(4) Wilcox, C. S.; Turkyilmaz, S. Tetrahedron Lett. 2005, 46, 1827-

1829.

Published on Web 10/14/2005

J. Org. Chem. 2005, 70, 9447-9462

9447

Dandapani et al.

FIGURE 1. The stages of fluorous mixture synthesis.

FIGURE 2. Fluorous tags encode absolute configuration or

substituent information in mappicine syntheses.

is to assign spectra from a known structure, not the

reverse. The decoding of a set of diastereomers with

homologous fluorous tags should be possible by demixing

coupled with mass spectrometric analysis because all of

the tagged compounds have the same molecular weight

but the tags are different. In principle, the independent

verification of the decoding on the detagged products

should not be needed.

FIGURE 3. Structures of the pine sawfly sex pheromones.

area.⁶Mori and co-workers synthesized two diastereo-

mers (2S,3S,7S,11R and 2S,3R,7R,11R) of 1.^7,8Heden-

strom and co-workers synthesized the complete 16-

stereoisomer library of 1 as a mixture and in pure form.

Both syntheses relied heavily on lipase-catalyzed dia-

stereoselective acylations.

To confirm this proposition and to show the utility of

fluorous mixture synthesis in a diastereomer setting, we

decided to make all 16 diastereomers of a natural product

and then to confirm the success of the exercise by

comparing the products with known samples. This re-

quires that the complete set of stereoisomers of the target

compound, hereafter called the stereoisomer library,

already be known. Outside of the simple sugars, very few

natural products with four stereocenters have complete

stereoisomer libraries. This reflects the difficulties of

making multiple isomers by traditional solution-phase

syntheses; a large amount of effort is required even for

relatively simple compounds.

The female sex pheromone of the minor sawfly

Microdiprion pallipes comprises at least two stereo-

isomers of the propionate esters of 3,7,11-trimethyl-2-

tridecanol 1 (Figure 3).⁵Pine sawflies are serious pests

on pine trees, and pheromones 1 can be used for pest

control by placing them in suitable traps in an infested

We recently communicated the total synthesis of all

16 stereoisomers of pine sawfly sex pheromone 1 by a

combination of FMS and parallel synthesis.⁹By compari-

son of our data with Hedenstrom’s,^5bwe were able to

validate that FMS is a useful technique for the rapid

synthesis of natural product stereoisomer libraries.¹⁰

That communication focused on conceptual and strategic

aspects of FMS. In this full paper, we report a detailed

account of our split-parallel FMS approach to the total

(6) (a) Smith, D. R. In Sawfly Life History Adaptations to Woody

Plants; Wagner, M. R., Raffa, K. F., Eds.; Academic Press: San Diego,

1993; pp 3-32. (b) Tai, A.; Higashiura, Y.; Kakizaki, M.; Naito, T.;

Tanaka, T.; Fukita, M.; Sugimura, T.; Hara, H.; Hayashi, N. Biosci.

Biotechnol. Biochem. 1998, 62, 607-608.

(7) Nakamura, Y.; Mori, K. Eur. J. Org. Chem. 1999, 2175, 5-2182.

(8) The phermone structures are consistently drawn such that a

stereocenter with an “up” group is R and a stereocenter with a “down”

group is S. Configurations are always listed in the order C2, C3, C7,

C11.

(9) Dandapani, S.; Jeske, M.; Curran, D. P. Proc. Natl. Acad. Sci.

U.S.A. 2004, 101, 12008-12012.

(10) (a) Fluorous mixture synthesis has recently been used to make

a 16-member stereoisomer library of murisolins for rigorous structure

assignment. See: Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P. J. Am.

Chem. Soc. 2004, 126, 36-37. (b) For a recent Concept Article and

quasi-enantiomers and other quasi-isomers, see: Zhang, Q.; Curran,

D. P. Chem.-Eur. J. 2005, 11, 4866-4880.

(5) (a) Bergstrom, G.; Wassgren, A.-B.; Anderbrant, O.; Hedenstrom,

E.; Hogberg, H.-E. Naturwissenschaften 1998, 85, 244-249 (b) Larsson,

M.; Nguyen, B.-V.; Hogberg, H.-E.; Hedenstrom, E. Eur. J. Org. Chem.

2001, 353-363.

9448 J. Org. Chem., Vol. 70, No. 23, 2005

Stereoisomers of Pinesaw Fly Sex Pheromones

SCHEME 1. Synthesis of Fluorous Acetals 8a-d

FIGURE 4. Retrosynthesis for FMS of all 16 stereoisomers

of pine sawfly sex pheromone 1.

synthesis of all 16 stereoisomers of the pine sawfly sex

pheromone. We provide the customary descriptions of

chemical reactions and complete characterization data

for intermediates and products. In addition, we focus on

practical methods for identifying and solving problems

in FMS.

Because we needed reliable access to all stereoisomers

of 1 in high ee, the retrosynthesis in Figure 4 was

designed such that all of the stereocenters come directly

from the precursors and are not introduced during the

course of the synthesis. Desaturation of 1 with introduc-

tion of three double bonds leads to triene 2. This triene

can be readily assembled from aldehyde 4 by iterative

application of Julia olefinations¹¹with sulfone 3, followed

by deprotection, oxidation, and capping with methylene

triphenylphosphorane (Ph₃PdCH₂).

To make all 16 isomers, we envisioned tagging each of

the four stereoisomers of 4 with fluorous p-methoxy-

benzyl (^FPMB) protecting groups differing in fluorine

content.¹²The mixture of aldehydes M-4¹³is split in half

for separate coupling with each enantiomer of 3 by Julia

olefination. The resulting two mixtures of alkenes (not

shown) are carried forward in parallel to a second split

and Julia olefination with the enantiomeric pair 3.

Finally, the Wittig reaction with Ph₃PdCH₂then gives

four mixtures of trienes M-2 that fully encode all 16

stereoisomers. Each of the four mixtures contains mol-

ecules with one of the four possible configurations at C7

and C11 and all four possible configurations at C2 and

C3. These mixtures are reduced, demixed, detagged, and

acylated to give the 16 individual isomers of 1.

ity by Frater-Seebach alkylation.¹⁴Direct ^FPMB protec-

tion of the secondary alcohol in RR-5 by the trichloro-

acetimidate¹⁵route was low yielding, so RR-5 was

reduced by lithium aluminum hydride to the anti diol

RS-6 in 82% yield. To prepare syn diol SS-6, ester RR-5

was inverted by a Mitsunobu reaction with p-nitrobenzoic

acid to give SR-9 (70%), followed by reductive cleavage

with LiBH₄(82%).

Formation of the fluorous PMP acetal was accom-

plished by using Noyori’s protocol.¹⁶Diol SS-6 was

silylated with TMSCl, and then ^FPMB aldehyde 7a

bearing the perfluorobutyl (C₄F₉) group¹⁷was added

along with TMSOTf to provide SS-8a in 68% yield.

(Hereafter, the letters a-d designate the fluorous tags,

as shown in Scheme 1.) Likewise, the anti diol RS-6 was

converted to the anti acetal RS-8b bearing the per-

fluorohexyl group (C₆F₁₃) in two steps in 86% overall

Results and Discussion

Pre-Mix Stage. Fluorous PMP (para-methoxyphenyl)

acetals 8a-d proved to be suitable precursors of alde-

hydes 4, and the syntheses of these acetals are shown in

Scheme 1. Ester RR-5 was prepared in 20:1 anti selectiv-

(14) (a) Frater, G.; Muller, U.; Gunther, W. Tetrahedron 1984, 40,

1269-1277. (b) Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1983,

63, 109-120.

(15) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic

Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; pp 86-87.

(16) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,

1357-1358.

(11) Review: Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,

2563-2585.

(12) ^FPMB tags have been previously employed for the synthesis of

discodermolide [ref 1d] and murisolin analogues [ref 10a].

(13) The prefix M denotes mixture of fluorous-tagged compounds.

(17) Fluorous compounds and FluoroFlash silica gel were purchased

from Fluorous Technologies, Inc. (www.fluorous.com). D.P.C. holds an

equity interest in the company.

J. Org. Chem, Vol. 70, No. 23, 2005 9449

Dandapani et al.

SCHEME 2. Synthesis of Sulfones R-3-BT and

R-3-PT

SCHEME 3. Julia Olefinations with BT and PT

Sulfones R-3

yield. An identical sequence of reactions was used to

prepare SR-6 and RR-6 (not shown), and these were

reacted with 7c and 7d, respectively, to provide the quasi-

enantiomeric^10bacetals SR-8c and RR-8d.

The diastereomeric purities of all of the acetals 8 were

determined by a single GC experiment immediately after

mixing. Both the syn acetals SS-8a and RR-8d were

diastereomerically pure, while the two anti acetals RS-

8b and SR-8c had diastereomeric ratios (anti/syn) of 25:1

and 29:1, respectively. Details of this mixture analysis

method are provided below in the section on analytical

tools for FMS.

The Kocienski-Julia coupling was initially tested with

both benzothiazolyl (BT) sulfone¹¹R-3-BT and N-phenyl-

tetrazolyl (PT) sulfone R-3-PT,¹⁸and the syntheses of

these reagents are outlined in Scheme 2. Primary alcohol

R-13 was prepared according to Kitahara¹⁹with some

modifications (see Supporting Information for details).

TBS protection (100% yield) of primary alcohol of S-10

followed by DIBAL reduction gave the alcohol R-11 in

96% yield. This was converted to the corresponding

tosylate in 92% yield. Cyanide displacement gave R-12

in 96% yield. The nitrile in R-12 was first reduced by

DIBAL to the corresponding aldehyde (93% yield), which

in turn was further reduced by sodium borohydride to

alcohol R-13 in 97% yield. The ee of alcohol R-13 was

determined to be greater than 95% by ¹H NMR spectro-

scopic analysis of a Mosher ester of a derivative of R-13

(see Supporting Information).

(PT-SH) to R-3-PT in 84% yield by a one-pot Mitsunobu/

oxidation process developed by Kocienski.²⁰

Enantiomeric sulfones S-3-BT and S-3-PT (not shown)

were synthesized by the same reactions starting from

R-10. The ee of intermediate alcohol S-13 was determined

1

to be 96% from H NMR analysis as above.

Kocienski-Julia Olefination with BT and PT

Sulfones 3. Prior to starting the mixture synthesis in

earnest, we carried out Julia olefinations with sulfones

R-3-BT and R-3-PT to probe for epimerization of the

R-stereocenter of aldehyde M-4a-d. Mixture M-8a-d,

prepared by blending equimolar amounts of the four

fluorous acetals SS-8a, SR-8b, RS-8c, and RR-8d, was

reduced with DIBAL to give M-14a-d in 99% yield

(Scheme 3). This alcohol mixture was subsequently

oxidized to aldehyde M-4a-d in 93% yield by using

Dess-Martin periodinane (DMP). Portions of M-4a-d

were subjected to Kocienski-Julia olefination¹¹with

sulfones R-3-BT and R-3-PT to give two mixtures

M-15a-d in 81% and 93% yield, respectively.

Mixture M-15a-d from coupling with benzothiazolyl

sulfone R-3-BT was demixed by using a FluoroFlash

semiprep column under gradient elution (80:20 aceto-

nitrile:water to 100% acetonitrile in 30 min) to give the

four individual fluorous PMB ethers 15a-d. However,

these were difficult to characterize because it was not

clear whether minor peaks in the their ¹³C NMR spectra

arose from E/Z isomers or epimers. Accordingly, each of

the crude ethers 16 was directly hydrogenated to reduce

the double bond and remove the fluorous PMB group. The

resulting alcohols SSR-17, RSR-17, SRR-17, and RRR-

17 were analyzed by ¹H and ¹³C NMR spectroscopy. In a

similar way, mixture M-15a-d obtained from R-3-PT

was also demixed. The alkenes SRR-16a and RRR-16b

Alcohol R-13 was coupled with benzothiazolyl sulfide

(BT-SH) under Mitsunobu conditions to give the inter-

mediate sulfide (88% yield). This was directly oxidized

by m-CPBA to sulfone R-3-BT in 89% yield. Correspond-

ingly, R-13 was converted with N-phenyltetrazolyl sulfide

(18) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett

1998, 26-28.

(19) (a) Kitahara, T.; Shimizu, H. J. Nat. Prod. 1998, 61, 551-554.

(b) Eguchi, T.; Arakawa, K.; Terachi, T.; Kakinuma, K. J. Org. Chem.

1997, 62, 1924-1933.

(20) Bellingham, R.; Jarowicki, K.; Kocienski, P. J.; Martin, V.

Synthesis 1996, 285-296.

9450 J. Org. Chem., Vol. 70, No. 23, 2005

Stereoisomers of Pinesaw Fly Sex Pheromones

It is known that metal-catalyzed hydrogenations of an

alkene can epimerize stereocenters at the allylic carbon

through reversible hydrometalation.²²We decided to

postpone investigating this problem until later in the

synthesis when all stereocenters were present. Hence,

our efforts turned toward a large-scale synthesis of triene

M2.

These results show the power of using mixture syn-

thesis methods to solve common problems in mixture

synthesis. With only two Kocienski-Julia olefinations of

the four-compound mixtures, we learned that all four

aldehydes M-4a-d produced two sets of minor products

when reacted with R-3-BT. The larger of the two minor

products is readily attributed to the C3 epimer because

the mixture is “self-indexed”. In other words, all epimers

at C2 and C3 are present, so the minor peaks from one

spectrum can simply be aligned with the major peaks of

another spectra for identification. The smaller set of

minor peaks from R-3-BT was also in the spectra from

R-3-PT; these peaks are not in the index (that is, they

do not arise from epimers at C2 or C3), and their origin

is not known. The experiments show that N-phenyltet-

razolyl sulfone R-3-PT is clearly the superior reagent.

Even though the problem of the presence of a minor

product (<10%) still remains, that problem has been

identified for later solution.

Split-Parallel Mixture Synthesis Stage. The split-

parallel stage of the synthesis from aldehyde M-4 through

to four mixtures containing all 16 stereoisomers of triene

2 is summarized in Scheme 4. Aldehyde M-4 (6.0 g) was

split into two portions, and the first portion (3.1 g) was

coupled with sulfone R-3-PT to give alkene MR-16 in 93%

yield. This was subjected to TBS deprotection to give

alcohol MR-18 (100% yield), which was oxidized by Dess-

Martin periodinane to give aldehyde MR-19 (87% yield,

2.6 g). In parallel, the second portion of aldehyde

M-4 (2.8 g) was subjected to Julia olefination with S-3-

PT to give MS-16 in 94% yield. TBS deprotection (100%

yield) and oxidation (81% yield) gave aldehyde MS-19

(2.6 g).

Each of the two aldehydes MR/S-19 was split into two

portions, and these were taken through the same se-

quence of olefination, deprotection, and oxidation; Scheme

4 shows exemplary reactions in the “MRR” series. Cou-

pling of the appropriate mixture of 19 with sulfones S-3-

PT or R-3-PT gave four alkenes MRR-20 (1.4 g, 93% yield,

shown in Scheme 4), MRS-20 (1.6 g, 92% yield, not

shown), MSR-20 (1.1 g, 92% yield, not shown), and MSS-

20 (1.4 g, 92% yield, not shown). Alkene MRR-20 was

subjected to TBS deprotection (100% yield) to give alco-

hol MRR-21, which was oxidized in 82% yield to the

aldehyde MRR-22. Aldehyde MRR-22 was subjected to

a Wittig reaction with methylene triphenylphosphorane

to give triene MRR-2 (612 mg) in 95% yield. Following

the same protocol, the other three mixtures MRS-20,

MSR-20, and MSS-20 were transformed in parallel to the

corresponding mixtures of trienes 2 shown at the bottom

of Scheme 4 (MRS-2, 625 mg; MSR-2, 520 mg; MSS-2,

544 mg).

FIGURE 5. Expanded regions of ¹³C NMR spectra of SRR-

17 pbtained from R-3-BT (top) and R-3-PT (bottom). Arrows

show the additional peaks attributed to epimers formed in

Julia olefinations with BT sulfone R-3-BT.

FIGURE 6. Expanded region of the ¹³C NMR spectrum of

SRR-17 obtained from R-3-PT. Arrow shows the additional

peak attributed to an epimer formed in Pd-mediated hydro-

genation.

were isolated in pure form,²¹and each was hydrogenated

to give alcohols SRR-17 and RRR-17, respectively.

Analysis of the two sets of samples 17 by ¹³C NMR

spectroscopy showed that none of the samples was pure.

However, the spectra from samples derived from the

N-phenyltetrazolyl sulfones R-3-PT were clearly superior

to those from the benzothiazolyl sulfone R-3-BT. Figure

5 compares expanded parts of the ¹³C NMR spectra

(32.5-33.5 ppm) of SRR-17 obtained from R-3-BT (top)

and R-3-PT (bottom). The top spectrum exhibits two pairs

of major peaks and minor peaks, while the bottom

spectrum exhibits only the major pair. The chemical

shifts of these and several other minor peaks match those

of the corresponding major peaks of alcohol SSR-17, so

we conclude that the side product is a C3 epimer. This is

present only in the spectra of 17 derived from the R-3-

BT sulfone, so we conclude that partial epimerization

during the Julia olefination occurred with this sulfone

only and not with phenyltetrazolyl sulfone R-3-PT.

Importantly, the products 17 from the PT sulfones also

had small additional peaks in their ¹³C NMR spectra. For

example, an expanded region of the ¹³C NMR spectrum

of SRR-17 obtained from R-3-PT shows a minor peak at

36.7 ppm adjacent to a major peak at 35.7 ppm (Figure

6). All of the additional peaks present in the sample

obtained from R-3-PT were also present in the corre-

sponding samples obtained from R-3-BT, and the minor

peaks in the spectrum did not appear to match the major

peaks of any of the four isomers of 17 in hand. These

results suggest that epimerization was also occurring

during Pd-catalyzed hydrogenations, presumably at C7.

(22) (a) Chan K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.;

Saucy, G. J. Org. Chem. 1976, 41, 3497-3505. (b) Schwartz, B. D.;

Hayes, P. Y.; Kitching, W.; De Voss, J. J. J. Org. Chem. 2005, 70, 3054-

3065.

(21) The other two fractions (SSR-17 and RSR-17) obtained during

this demixing were contaminated with diol by partial deprotection of

the TBS group. The source of this deprotection was not investigated.

J. Org. Chem, Vol. 70, No. 23, 2005 9451

Dandapani et al.

SCHEME 4. Split-Parallel Fluorous Mixture Synthesis

SCHEME 5. Reduction of MRS-2 and Demixing of

MSR-23

min followed by isocratic acetonitrile to 50 min to give

individual compounds SSSR-23a, RSSR-23b, SRSR-23c,

1

and RRSR-23d, all of which were analyzed by H and

¹³C NMR spectroscopy.

Samples of fluorous PMB ethers 23 obtained from

Raney Ni-catalyzed reduction were found to have ad-

ditional minor peaks in their ¹³C NMR spectra, while the

¹³C NMR spectra of the corresponding samples from

diimide reduction showed only the expected number of

resonances. Expanded segments of the ¹³C NMR spectra

(150 MHz) of RSSR-23b obtained from both of the

reduction procedures are shown in Figure 7. The top

spectrum is from the sample of RSSR-23b obtained from

Raney Ni reduction, while the bottom spectrum corre-

sponds to the same compound obtained from diimide

reduction. Minor peaks can clearly be seen in the top

spectrum (shown with downward arrows), while the

bottom spectrum is clean. These results suggest that

Raney Ni epimerizes the allylic stereocenters in competi-

tion with hydrogenation, while diimide does not.

Having established a reliable procedure for reduction

of the triene, we preparatively reduced all four mixtures

of M-2 with diimide to the corresponding saturated

analogues M-23, each of which was subjected to demix-

ing. The results of all four demixings are summarized in

Table 1. For example, mixture MSS-23 (451 mg) was

demixed by using a FluoroFlash semiprep HPLC column

(20 × 250 mm) under a gradient elution from 95:5

acetonitrile:water to 100% acetonitrile in 30 min and

Triene Reduction and Demixing. The model study

in Scheme 3 identified potential problems in the hydro-

genation step, so this was initially investigated with a

single mixture. Small amounts of triene MRS-2 were

reduced to the saturated analogue MSR-23 with Raney

Ni (100% yield) and diimide (95% yield) (Scheme 5, note

the change in CIP priorities at C7 and C11 in going from

2 to 23). Unlike the Pd/C reaction, hydrogenation by

Raney Ni or diimide did not result in hydrogenolysis of

the fluorous PMB group. The two mixtures MRS-23 were

individually demixed by using a FluoroFlash semiprep

HPLC column (20 × 250 mm) under a gradient elution

from 95:5 acetonitrile:water to 100% acetonitrile in 30

FIGURE 7. Segments of the ¹³C NMR spectrum of RSSR-

23b obtained from Raney Ni (top) and diimide (bottom)

reductions. Arrows show the additional peaks attributed to

epimers formed in Raney Ni-mediated hydrogenation.

9452 J. Org. Chem., Vol. 70, No. 23, 2005

Stereoisomers of Pinesaw Fly Sex Pheromones

TABLE 1. Summary of Four Semiprep Demixings of 23

demonstrates that demixing is more than simple separa-

tion of tagged compounds. Ancillary separations observed

during demixing enable purification of the each of the

compounds.

The overall mass recovery during the demixing of MSS-

23 was 93%. The four saturated fluorous PMB ethers

accounted for 97-98% of the recovered mass, while

byproducts accounted for the remaining 2-3%. The mole

ratio of the tagged compounds (C₄F₉:C₆F₁₃:C₇F₁₅:C₈F₁₇)

isolated from demixing of MSS-23 was 1:1:1:1. This is

same as the composition of the four acetals in the first

mixture M-8, indicating that all of the fluorous com-

pounds showed similar reactivities in all of the steps

involved in the FMS.

The other three mixtures 23 were similarly demixed,

and the results are summarized in entries 2-4 of Table

1. The total recovery of the desired products from all

three mixtures was 89-96%. Mixture MRS-23 had the

highest amount of byproducts (5%), while the other two

mixtures had 2-3% byproducts. The molar composition

of the tagged products isolated from all of the demixings

was close to 1:1:1:1.

overall

mass

recovery

structure

mixture

of desired of product fluorous

entry (amount) recovery products

MSS-23

(451 mg)

(amount)

tag

1

2

3

4

93%

94%

98%

91%

89%

96%

SSSS-23a

(86 mg)

C₄F₉

RSSS-23b

(103 mg)

SRSS-23c

(108 mg)

RRSS-23d

(113 mg)

SSSR-23a

(92 mg)

RSSR-23b

(106 mg)

SRSR-23c

(111 mg)

RRSR-23d

(119 mg)

SSRS-23a

(81 mg)

RSRS-23b

(103 mg)

SRRS-23c

(108 mg)

RRRS-23d

(117 mg)

SSRR-23a

(96 mg)

C₆F₁₃

C₇F₁₅

C₈F₁₇

C₄F₉

MSR-23

(471 mg)

C₆F₁₃

C₇F₁₅

C₈F₁₇

C₄F₉

MRS-23

(460 mg)

C₆F₁₃

C₇F₁₅

C₈F₁₇

C₄F₉

Post-Mix Stage. The four fluorous PMB ethers SSSS-

23a, RSSS-23b, SRSS-23c, and RRSS-23d were detagged

by hydrogenolysis to give the corresponding alcohols 24,

which were then acylated to give the corresponding

propionates 1 (Scheme 6). The acylation reactions were

carried out with excess propionyl chloride, and the excess

was quenched with polymer-supported trisamine (PS-

trisamine).²³Filtration of the crude reaction mixture then

provided pure 1. The purity of the resulting propionates

MRR-23

(476 mg)

RSRR-23b

(113 mg)

SRRR-23c

(120 mg)

RRRR-23d

(128 mg)

C₆F₁₃

C₇F₁₅

C₈F₁₇

1

was excellent as assayed by H and ¹³C NMR spectros-

copy. The rest of the 12 ^FPMB ethers 23 were also

detagged and propionylated (not shown) to provide all

16 isomers of 1. The corresponding alcohols 24 were

synthesized in 24-36 mg scale, and roughly half of each

alcohol was acylated to the corresponding esters 1 (16-

23 mg each).

Spectral data (¹H and ¹³C NMR) obtained for all 32

compounds (16 alcohols 24 and the corresponding 16

propionates 1) matched well with Hedenstrom’s pub-

lished data.^5bWe were also able to identify unique sets

of methyl group resonances in the ¹H NMR spectra (600

MHz) of the eight diastereomeric alcohols of 24 (shown

elsewhere⁹) and the corresponding propionates 1. These

resonances are shown in expanded NMR spectra of 1 in

Figure 9, which originate from the family of enantiomers

having R configuration at C2 carbon.

FIGURE 8. Chromatogram for the semiprep demixing of

MSS-23. Peak 1 SSSS-23a, peak 2, RSSS-23b, peak 3, SRSS-

23c, peak 4 RRSS-23d.

The patterns of lines in the spectra of Figure 9 emanate

from four of the five methyl groups: the three methyl

groups attached to C3, C7, C11 and the C13 methyl group

(the doublet of the C1 methyl group is further downfield).

A total of nine lines are expected from these four methyl

groups (three doublets and one triplet). The partial

overlap of these resonances from the four methyl groups

generates unique patterns in the region between 0.92 and

isocratic acetonitrile to 50 min to give four fluorous PMB

ethers SSSS-23a, RSSS-23b, SRSS-23c, and RRSS-23d

(Table 1, entry 1). Up to 86 mg of the mixture was

demixed in a single injection.

A typical chromatogram of semiprep demixing of MSS-

23 is shown in Figure 8. In addition to the four major

peaks labeled 1-4, the four minor peaks (highlighted by

arrows) were also collected. The products from each of

the major peaks were identified by spectroscopic methods

to be the desired fluorous PMB ethers 23. Proton NMR

analysis of the fractions from the minor peaks revealed

the presence of alkene protons. Hence, these side prod-

ucts are probably partially reduced alkenes carried over

from MSS-2. The ability to separate under-reduced

byproducts from the desired fully reduced products

1

0.82 ppm in the 600 MHz H NMR spectrum of each of

the diastereomers. The resonance of the methyl group

at C3 carbon atom of the esters 1 is easily recognizable

as the most downfield doublet in all nine spectra. This

(23) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882-

4886. PS-trisamine was purchased from Argonaut Technologies

(www.argotech.com).

J. Org. Chem, Vol. 70, No. 23, 2005 9453

Dandapani et al.

SCHEME 6. Detagging and Acylation in the (7S,11S) Series

group resonates at about 0.90 ppm in the four C2,C3 syn

isomers, and 0.88 ppm in the four C2,C3 anti isomers.

In the propionate ester series, the spectra for the four

anti isomers are well resolved and clearly different; all

nine lines can be identified in each spectrum. The

patterns of the syn isomers are much more similar, and

typically only seven lines can be identified because the

doublets for the methyl groups on C7 and C11 overlap.

The resonances of the syn isomers are better resolved in

the alcohol 24, while the resonances of the anti isomers

are better resolved in the ester 1. This allows each of the

eight isomers to be readily identified.

Analytical Tools for FMS. Effective use of spectro-

scopic and chromatographic methods, both modern and

traditional, is crucial for troubleshooting problematic

reactions and products in any total synthesis, and fluo-

rous mixture synthesis is no exception. How can one

follow reactions, assess purities, and characterize prod-

ucts when molecular mixtures are involved? This section

highlights the various techniques used in this project that

are also broadly applicable for other FMS projects as well.

These techniques can be classified as nonfluorous (mix-

ture NMR and normal phase TLC) or fluorous (LC-MS,

LC NMR, and GC).

Nonfluorous Techniques. Just as in standard solu-

tion-phase transformations of single compounds, the

relative retention factors (R_f) of the starting and product

mixtures on thin-layer chromatography (TLC) can be a

valuable guide for evaluating the progress of a reaction.

Although every mixture in this work consisted of four

compounds (two quasidiastereomeric pairs of quasi-

enantiomers, neglecting the geometric isomers around

double bonds), each mixture behaved like a single

compound during normal phase TLC analysis. “Spot-to-

spot” conversions were observed in clean reactions, and

the components of mixtures containing the same func-

tionalities but different configurations and fluorous tags

never separated either on TLC analysis or on flash

chromatography on normal silica gel. Thus, reactions

were routinely followed by TLC, and crude product

mixtures were typically chromatographed to provide pure

product mixtures. However, this ideal behavior of fluo-

rous mixtures is not always observed when structurally

diverse starting materials are tagged with different

fluorous protecting groups.^1e

The conversion of a starting fluorous mixture to a

1

product mixture was also followed by comparing the H

NMR spectra of the starting and the product samples.

Although a complete analysis of the NMR spectra of these

mixture spectra is complicated by the presence of quasi-

diastereomers having different chemical shifts (and also

by the presence of alkene isomers in some mixtures), the

partial analysis of key resonances of functional groups

involved in the transformation was frequently informa-

tive. For example, the conversion of an aldehyde mixture

to an alkene mixture in the Julia olefinations was readily

assessed by mixture NMR by looking for the appearance/

disappearance of characteristic resonances.

Fluorous Techniques. The single most useful tool for

following reactions in FMS is LC-MS. All of the mixtures

involved in this project were characterized by LC-MS

over a Fluofix column with APCI ionization. In all of the

cases, tag-based separation (demixing) was observed.

When mixtures were impure, secondary separations of

products with different functionalities were often ob-

served. For example, the product of an incomplete reac-

tion might exhibit eight peaks in four pairs each for

starting material and product. The identity of the eluting

compounds could be readily ascertained by the presence

of molecular ion in the associated mass spectrum. In a

given pure mixture, the tagged products are all quasi-

isomers and every CF₂group has MW ) 50 amu, making

1

FIGURE 9. Fingerprint resonances in the H NMR spectra

of pine sawfly sex pheromones 1.

9454 J. Org. Chem., Vol. 70, No. 23, 2005

Stereoisomers of Pinesaw Fly Sex Pheromones

FIGURE 11. GC chromatogram showing separation of a

mixture of fluorous acetals M-8. Peak 1 SS-8a, peak 2 RS-8b,

peak 3 SR-8c, peak 4 RR-8d, peak 5 RR-8b, peak 6 SS-8c.

Although these NMR spectra were adequate for our

purposes, even the best NMR spectrum obtained from

LC NMR experiments was poorly resolved as compared

to a standard spectrum of the same quantity of sample

dissolved in CDCl₃. Over the same 4 h period of an LC

NMR experiment, it is possible to semipreparatively

demix a 0.8 mg sample, evaporate and dry the fractions,

dissolve in CDCl₃, and collect data for all four spectra.

While there is more sample handling in this procedure,

that extra effort is more than compensated for by the

better quality of the spectra that are obtained. These

spectra exhibit both better resolution and better sensitiv-

ity because the entire sample from the demixing fraction

is in the probe in every case and because no solvent

suppression is needed.

Despite the added mass of the fluorous tags, gas

chromatography (GC) with a flame ionization de-

tector (FID) was also routinely used for the analysis of

fluorous mixtures. Most components of the quasi-isomeric

fluorous mixtures eluted in order of increasing tag size.

In effect, GC provides an alternative to fluorous LC for

analytical demixing, and it is now the regular increase

in molecular weight that provides the basis for the

demixing.

The GC analysis of the starting mixture M-8 shown

in Figure 11 is representative of conditions and results.

Injection of M-8 into a [HP-1 methyl siloxane (length 30

m, diameter 320 µm, film thickness 0.25 µm)] GC column

[50 °C (2 min); 15 °C/min, 300 °C] provided four major

peaks (labeled 1-4) and two minor peaks (5 at 14.6 and

6 at 14.9 min, highlighted with downward arrows in

Figure 11). The major peaks in order are SS-8a (syn),

RS-8b (anti), SR-8c (anti), and RR-8d (syn). The minor

peaks were assigned as syn isomers RR-8b and SS-8c,

and in this case the assignment was confirmed by

preparation of authentic samples. Generally speaking,

this is not necessary because the library is “self-indexed”;

in other words, RR-8b can be identified by comparison

to its higher homologue RR-8d and its lower quasi-

enantiomer SS-8a.

FIGURE 10. ¹H NMR spectra from LC NMR analysis of an

intermediate derived from diimide reduction of MS-18.

interpretation especially easy; each mass spectrum is

essentially identical to its predecessor, but the peaks are

shifted to either 50 or 100 atomic mass units higher

depending on whether the tag size increases by one or

two CF₂groups.

LC NMR spectroscopy was also used to characterize

seven of the intermediate mixtures. Alcohol M-14 (Scheme

3) was analyzed directly, while small quantities of the

subsequent alkenes were reduced first by diimide to the

corresponding saturated analogues prior to LC NMR

analysis to eliminate complications emanating from the

presence of alkene isomers. A representative set of 600

MHz LC NMR spectra derived from the diimide reduction

of MS-18 is shown in Figure 10. Copies of other LC NMR

spectra are given in the Supporting Information.

A typical LC NMR experiment of a four-compound

mixture needed about 0.8 mg per injection. A gradient

of CH₃CN/H₂O was used for the separation, and the

peaks were collected and transferred directly to the probe

for data acquisition with a standard routine including

solvent suppression. Experiments took about 4 h for LC

separation and NMR data collection, and the quality of

the spectra was adequate for standard analyses of

chemical shift, multiplicity, and integration. The later-

emerging compounds required more acquisition time

because peaks broaden and the sample injected into the

NMR probe is more dilute, but satisfactory spectra were

obtained for all four components of all seven mixtures.

From these GC chromatograms, the diastereomeric

purities of anti acetals RS-8b and SR-8c were determined

to be 25:1 and 29:1, respectively. The syn acetals SS-8a

and RR-8a show a single peak in GC, so they are not

contaminated with corresponding anti acetals. Because

the starting compounds 5 for the Mitsunobu reaction to

J. Org. Chem, Vol. 70, No. 23, 2005 9455

Dandapani et al.

acetate (2 × 100 mL) and dichloromethane (2 × 100 mL). The

organic layers were combined, washed with brine, dried with

magnesium sulfate, and concentrated. Flash column chroma-

tography on silica gel (1:1 hexane:ethyl acetate) gave (2R,3S)-

2-methylbutane-1,3-diol RS-6 as a colorless viscous oil (1.77

make these compounds (Scheme 1) were not diastereo-

pure, the minor anti diastereomer must have been

removed during the chromatographic purification of syn

diesters SR-9 and RS-9.

1

g, 82%). [R]_D+3.2 (c 0.57, CHCl₃); H NMR (CDCl₃) δ 3.78-

3.69 (m, 2H), 3.61 (dd, J ) 8.0, 10.7 Hz, 1H), 1.74-1.60 (m,

1H), 1.24 (d, J ) 6.3 Hz, 3H), 0.85 (d, J ) 7.0 Hz, 3H); ¹³C

NMR (CDCl₃) δ 72.9, 67.4, 41.6, 21.5, 13.4; IR (thin film) 3307

(b), 2970, 1455, 1028 cm^-1; LRMS 89 ((M - Me)⁺, 17%), 71

(100%), 56 (91%); HRMS calculated (for C₅H₁₀O (M - H₂O))

86.0732, found 86.0727.

Conclusions

All 16 stereoisomers of the sex pheromone of the

pinesaw fly have been synthesized by split-parallel

fluorous mixture synthesis. Spectral data (¹H and ¹³C

NMR) obtained for all 32 compounds (16 alcohols 24 and

the corresponding propionates 1) matched well with

Hedenstrom’s data.^5bThe 4-mix/4-split approach success-

fully encoded the configurations of all of the library

members, and hence FMS is recommended for expedient

synthesis of stereoisomers of the natural products.

It is a common practice to synthesize several stereo-

isomers of chiral compounds for structural identification

or for biological testing. When high purity and reliability

are required, solution-phase synthesis is the method of

choice. Traditionally, each stereoisomer is synthesized in

sequence or in parallel, but such efforts are time-

consuming. For example, consider the traditional parallel

synthesis of 16 stereoisomeric alcohols 24 by the same

synthetic scheme outlined above. Each of the alcohols

requires 11 steps to make from one of the four acetals 8.

Hence, a traditional approach would require 176 reaction

steps to synthesize all 16 stereoisomers. However, the

split-parallel fluorous mixture approach with four fluo-

rous tags in this work needed only 44 steps to make all

16 isomers.

Unlike previous “proof-of-principle” fluorous mixture

syntheses,¹the steps involved in the mixture syntheses

of this project were never rehearsed on a single com-

pound. Problems were identified and solved directly on

fluorous mixtures. This represents an important techni-

cal advance because rehearsals on single compounds are

time-consuming and in effect require two syntheses to

be conducted in serial or parallel, one on the single

compound and one on the mixture. In this work, modern

tools such as LC-MS and LC NMR were used to

characterize mixtures of compounds. Even the time-

honored analytical tools of TLC and GC were found to

be routinely useful for analyzing fluorous mixtures. A

total of 132 steps were saved in FMS as compared to a

traditional one-compound/one-flask approach. The ef-

ficiency and ease of fluorous mixture synthesis can be

used to leverage effort in both diversity-oriented synthe-

sis and total synthesis by providing more compounds per

unit work.

(2S,3R)-2-Methylbutane-1,3-diol (SR-6). Synthesized

by General Procedure 1. Yield 84%; [R]_D-2.2 (c 0.59,

1

CHCl₃); H NMR (CDCl₃) δ 3.79-3.71 (m, 2H), 3.64 (dd, J )

7.8, 10.8 Hz, 1H), 1.75-1.62 (m, 1H), 1.25 (d, J ) 6.2 Hz, 3H),

0.86 (d, J ) 7.0 Hz, 3H); ¹³C NMR (CDCl₃) δ 73.3, 67.8, 41.7,

21.7, 13.5; IR (thin film) 3356 (b), 2971, 1455, 1028 cm^-1

;

LRMS 89 ((M - Me)⁺, 9%), 73 (100%), 61 (80%); HRMS

calculated (for C₅H₁₃O₂(M⁺+ H)) 105.0913, found 105.0916.

General Procedure 2. Mitsunobu Reaction of â-Hy-

droxy Ester. 4-Nitrobenzoic Acid (1S,2R)-2-Ethoxy-

carbonyl-1-methylpropyl Ester (SR-9). A solution of diiso-

propyl azodicarboxylate (11.1 mL, 56.3 mmol) in THF (50 mL)

was added dropwise from an addition funnel to a solution of

ethyl (2R,3R)-3-hydroxy-2-methylbutanoate (RR-5) (6 g, 41.7

mmol), triphenylphosphine (14.2 g, 54.2 mmol), and 4-nitro-

benzoic acid (9.4 g, 56.3 mmol) in THF (100 mL). After being

stirred at room temperature for 12 h, the reaction mixture was

concentrated. Flash column chromatography on silica gel

(hexane:ethyl acetate 6:1) gave 4-nitrobenzoic acid (1S,2R)-2-

ethoxycarbonyl-1-methylpropyl ester SR-9 as a yellow oil (8.55

g, 70%). [R]_D+17.7 (c 0.57, CHCl₃); ¹H NMR (CDCl₃) δ 8.31-

8.27 (m, 2H), 8.21-8.17 (m, 2H), 5.47 (dq, J ) 5.5, 6.4 Hz,

1H), 4.22-4.08 (m, 2H), 2.80 (dq, J ) 5.6, 7.1 Hz, 1H), 1.42

(d, J ) 6.4 Hz, 3H), 1.30 (d, J ) 7.1 Hz, 3H), 1.22 (t, J ) 7.1

Hz, 3H); ¹³C NMR (CDCl₃) δ 173.3, 163.9, 150.5, 135.7, 130.7,

123.5, 72.9, 60.8, 44.4, 17.5, 14.2, 12.2; IR (thin film) 2254,

1727, 1277 cm^-1; LRMS 295 (M⁺, 12%), 279 (11%), 150 (100%),

104 (36%), 83 (52%), 75 (100%); HRMS calculated 295.1063,

found 295.1056.

4-NitrobenzoicAcid(1R,2S)-2-Ethoxycarbonyl-1-methyl-

propyl Ester (RS-9). Synthesized by General Procedure

2. Yield 79%; yellow liquid; [R]_D-19.4 (c 0.51, CHCl₃); ¹H NMR

(CDCl₃) δ 8.32-8.28 (m, 2H), 8.21-8.17 (m, 2H), 5.47 (dq, J

) 5.6, 6.4 Hz, 1H), 4.23-4.08 (m, 2H), 2.80 (dq, J ) 5.6, 7.1

Hz, 1H), 1.42 (d, J ) 6.4 Hz, 3H), 1.30 (d, J ) 7.1 Hz, 3H),

1.23 (t, J ) 7.1 Hz, 3H); ¹³C NMR (CDCl₃) δ 173.1, 163.8, 150.6,

135.8, 130.6, 123.4, 72.8, 60.6, 44.4, 17.4, 14.1, 12.1; IR (thin

film) 2254, 1731, 1275 cm^-1; LRMS 295 (M⁺, 12%), 251 (17%),

150 (100%); HRMS calculated 295.1056, found 295.1059.

(2R,3R)-2-Methylbutane-1,3-diol (RR-6). A solution of

DIBAL in hexanes (1 M, 125 mL, 125 mmol) was slowly added

to a solution of 4-nitrobenzoic acid (1R,2S)-2-ethoxycarbonyl-

1-methylpropyl ester (RS-9) in dicholoromethane (120 mL) at

-65 °C. The reaction mixture was warmed to -25 °C and

stirred at that temperature for 5 h. After warming to room

temperature, the reaction mixture was quenched by the

addition of ethyl acetate (5 mL), water (10 mL), and 3 M NaOH

solution (15 mL). The reaction mixture was extracted with

refluxing ethyl acetate (5 × 200 mL), and the layers were

separated. The organic layers were combined, dried with

magnesium sulfate, and concentrated. Flash column chroma-

tography on silica gel (3:1 hexane:ethyl acetate) gave (2R,3R)-

2-methylbutane-1,3-diol (RR-6) as a viscous oil (2.86 g, 88%).

Experimental Section

Pre-Mix Stage. General Procedure 1. Reduction of

â-Hydroxy Ester to Diol. (2R,3S)-2-Methylbutane-1,3-diol

(RS-6). A solution of lithium aluminum hydride in ether (1

M, 23 mL, 23 mmol) was slowly added to a solution of ethyl

(2R,3R)-3-hydroxy-2-methylbutanoate RR-5 at 0 °C. After the

addition, the reaction mixture was stirred at room temperature

for 3 h and quenched with ethyl acetate (10 mL) and methanol

(1 mL). Water (8.4 mL), 30% NaOH (8.4 mL), and water (17

mL) were added and stirred for 30 min. The solution was then

decanted from the white crystalline precipitate and separated

using a separatory funnel. The aqueous layer was added to

the white crystalline precipitate and extracted with ethyl

1

[R]_D-10.2 (c 0.51, CHCl₃); H NMR (CDCl₃) δ 4.06 (dq, J )

2.9, 7.0 Hz, 1H), 3.77-3.68 (m, 2H), 1.89-1.77 (m, 1H), 1.21

(d, J ) 6.5 Hz, 3H), 0.92 (d, J ) 7.1 Hz, 3H); ¹³C NMR (CDCl₃)

δ 69.7, 65.7, 40.1, 19.2, 10.6; IR (thin film) 3354 (b), 2971, 1459,

1027 cm^-1; LRMS 89 ((M - Me)⁺, 6%), 73 (100%), 61 (96%);

HRMS calculated for (M - Me)⁺89.0603, found 89.0604.

9456 J. Org. Chem., Vol. 70, No. 23, 2005

Stereoisomers of Pinesaw Fly Sex Pheromones

(2S,3S)-2-Methylbutane-1,3-diol (SS-6). A solution of

lithium borohydride in THF (2 M, 35.7 mL, 71.5 mmol) was

slowly added to a solution of 4-nitro-benzoic acid (1S,2R)-2-

ethoxycarbonyl-1-methylpropyl ester (SR-9) (5.24 g, 17.87

mmol) in THF (60 mL) and stirred at room temperature for 1

d. The reaction was then quenched by slow addition of

saturated NH₄Cl solution (20 mL) and stirred at room tem-

perature for 1 h. The crude reaction mixture was then

extracted with refluxing ethyl acetate (5 × 100 mL). The

organic layers were then combined, dried, and concentrated.

Most of the p-nitrobenzyl alcohol was removed by recrys-

tallization from aqueous ethanol, and the remainder of the

crude product was subjected to column chromatography. After

flash column chromatography on silica gel (1:1 hexane:ethyl

acetate), (2S,3S)-2-methylbutane-1,3-diol (SS-6) was isolated

as a colorless viscous oil (1.42 g, 77%); [R]_D+11.4 (c 0.51,

4.14-4.00 (m, 5H), 2.43-2.19 (m, 2H), 2.17-2.05 (m, 2H),

1.53-1.45 (m, 1H), 1.23 (d, J ) 6.6 Hz, 3H), 1.21 (d, J ) 7.8

Hz, 3H); ¹³C NMR (CDCl₃) δ 158.9, 131.9, 127.4, 121-114 (m),

114.2, 101.8, 75.6, 73.8, 66.3, 32.9, 27.7 (t, J ) 22.2 Hz), 20.5

(t, J ) 3.5 Hz), 18.8, 10.9; ¹⁹F NMR (CDCl₃) -81.5 (3F), -115.0

(2F), -124.9 (2F), -126.5 (2F); IR (thin film) 2981, 1265, 1238

cm^-1; LRMS 467 ((M - H)⁺, 18%), 382 (45%), 121 (100%);

HRMS calculated 467.1269, found 467.1264.

(4S,5R)-4,5-Dimethyl-2-[4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-

pentadecafluorodecyloxy)-phenyl]-[1,3]dioxane (SR-8c).

This compound was synthesized by general procedure 3. Yield

82% (two steps); white solid mp 89-90 °C; [R]_D-1 (c 0.50,

CHCl₃); ¹H NMR (CDCl₃) δ 7.46-7.38 (m, 2H), 6.91-6.86 (m,

2H), 5.46 (s, 1H), 4.09 (dd, J ) 6.6, 11.2 Hz, 1H), 4.04 (t, J )

5.9 Hz, 2H), 3.59-3.45 (m, 2H), 2.40-2.18 (m, 2H), 2.13-2.05

(m, 2H), 1.80-1.77 (m, 1H), 1.32 (d, J ) 6.2 Hz, 3H), 0.80 (d,

J ) 6.7 Hz, 3H); ¹³C NMR (CDCl₃) δ 158.8, 131.7, 127.5, 121-

115 (m), 114.2, 101.1, 79.5, 73.0, 66.3, 35.8, 27.9 (t, J ) 22.1

Hz), 20.5, 19.1, 12.5; ¹⁹F NMR (CDCl₃) -81.2 (3F), -114.9 (2F),

-122.2 (2F), -122.6 (2F), -123.2 (2F), -123.9 (2F), -126.6

(2F); IR (thin film) 2985, 1265, 1242 cm^-1; LRMS 617 ((M -

H)⁺, 24%), 532 (28%), 121 (100%); HRMS calculated 617.1173,

found 617.1174.

(4R,5R)-2-[4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Hepta-

decafluoroundecyloxy)-phenyl]-4,5-dimethyl-[1,3]diox-

ane (RR-8d). Yield 86% (two steps); mp 106-107 °C; [R]_D-3.2

(c 0.53, CHCl₃); ¹H NMR (CDCl₃) δ 7.46-7.39 (m, 2H), 6.91-

6.86 (m, 2H), 5.47 (s, 1H), 4.11 (dd, J ) 2.4, 6.5 Hz, 1H), 4.08-

3.99 (m, 4H), 2.80-2.45 (m, 2H), 2.31-2.10 (m, 2H), 1.53-

1.49 (m, 1H), 1.23 (d, J ) 6.5 Hz, 3H), 1.21 (d, J ) 7.8 Hz,

3H); ¹³C NMR (CDCl₃) δ 158.9, 131.9, 127.5, 121.5-106.0 (m),

114.2, 101.8, 75.6, 73.8, 66.3, 32.9, 27.9 (t, J ) 22.1 Hz), 20.4

(t. J ) 3.4 Hz), 18.7, 10.8; ¹⁹F NMR (CDCl₃) -81.2 (3F), -114.8

(2F), -122.1 (2F), -122.4 (6F), -123.2 (2F), -123.9 (2F),

-126.6 (2F); IR (thin film) 2985, 1265, 1243 cm^-1; LRMS 667

((M - H)⁺, 25%), 582 (45%), 121 (100%); HRMS calculated

667.1141, found 667.1111.

Syntheses of Intermediates 10-13 and General Pro-

cedure 4, Determination of ee of Alcohol 13, Are De-

scribed in the Supporting Information. (3R)-2-[4-(tert-

Butyldimethylsilanyloxy)-3-methylbutane-1-sulfonyl]-

benzothiazole (R-3-BT). Diethylazodicarboxylate (0.16 mL,

1.0 mmol) was added to a solution of (3R)-4-(tert-butyldi-

methylsilanyloxy)-3-methylbutan-1-ol (R-13) (145 mg, 0.67

mmol), triphenylphosphine (262 mg, 1 mmol), and benzo-

thiazole-2-thiol (167 mg, 1.0 mmol) in THF (10 mL) at 0 °C.

After being stirred at room temperature for 2 d, the reaction

mixture was quenched by the addition of saturated sodium

bicarbonate solution (30 mL). The reaction mixture was

extracted with ethyl acetate (3 × 30 mL). The organic layers

were combined, washed with brine, dried with magnesium

sulfate, and concentrated. After flash column chromatography

on silica gel (20:1 hexane:ethyl acetate), (3R)-2-[4-(tert-

butyldimethylsilanyloxy)-3-methyl-butylsulfanyl]benzothi-

azole was isolated as a colorless liquid (213 mg, 88%). ¹H NMR

(CDCl₃) δ 7.87 (d, J ) 8.1 Hz, 1H), 7.76 (d, J ) 8.0 Hz, 1H),

7.42 (dd, J ) 7.4, 7.4 Hz, 1H), 7.30 (dd, J ) 7.7, 7.7 Hz, 1H),

3.53-3.32 (m, 4H), 2.02-1.93 (m, 1H), 1.89-1.76 (m, 1H),

1.69-1.57 (m, 1H), 0.97 (d, J ) 6.7 Hz, 3H), 0.89 (s, 9H), 0.05

(s, 6H).

1

CHCl₃); H NMR δ 4.05 (dq, J ) 3.1, 6.5 Hz, 1H), 3.77-3.67

(m, 2H), 1.89-1.77 (m, 1H), 1.21 (d, J ) 6.4 Hz, 3H), 0.92 (d,

J ) 7.1 Hz, 3H); ¹³C NMR (CDCl₃) δ 69.7, 65.7, 40.1, 19.2,

10.6; IR (thin film) 3362 (b), 2971, 1459, 1027 cm^-1; LRMS 89

((M - Me)⁺, 17%), 71 (100%), 59 (92%); HRMS calculated (M

- Me)⁺89.0603, found 89.0605.

General Procedure 3. Noyori Ketalization. (4R,5S)-

(4,5-Dimethyl-2-[4-(4,4,5,5,6,6,7,7,8,8,9,9,9-trideca-

fluorononyloxy)phenyl]-[1,3]dioxane (RS-8b). (2R,3S)-2-

Methylbutane-1,3-diol RS-6 (1.1 g, 10.6 mmol) was dissolved

in THF (100 mL) and cooled to 0 °C using an ice-bath.

Triethylamine (11.8 mL, 84.6 mmol) was added. Chlorotri-

methylsilane (10.7 mL, 84.6 mmol) was slowly added, and the

reaction mixture was warmed to room temperature. After 16

h at room temperature, the reaction was quenched with

saturated sodium bicarbonate solution (50 mL) and the layers

were separated. The aqueous layer was extracted with ether

(2 × 50 mL). The organic layers were combined, washed with

brine, and concentrated. A fast flash column chromatography

on silica gel (hexane:ethyl acetate:triethylamine ) 20:1:0.1)

gave (2R,3S)-2-methyl-1,3-bis(trimethylsilanyloxy)butane (2.20

g, 84%), which was used in the next step without characteriza-

tion.

Trimethylsilyltriflate (60 µL, 0.33 mmol) was added to

dichloromethane (75 mL) and cooled to -78 °C. A solution of

(2R,3S)-2-methyl-1,3-bis(trimethylsilanyloxy)butane (1.98 g,

7.97 mmol) in dichloromethane (15 mL) was added. A solution

of 4-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyloxy)benzalde-

hyde 7b (3.2 g, 6.64 mmol) in dichloromethane (30 mL) was

then slowly added. After beingstirred at -78 °C for 12 h, the

reaction was quenched by adding pyridine (0.3 mL) and

warmed to room temperature. Ethyl acetate (100 mL) and

saturated sodium bicarbonate (100 mL) were added and stirred

for 10 min. The phases were separated, and the aqueous layer

was extracted with ether (3 × 25 mL). The organic layers were

combined, washed with brine, dried with magnesium sulfate,

and concentrated. Flash column chromatography on silica gel

(20:1 hexane:ethyl acetate) gave (4R,5S)-(4,5-dimethyl-2-[4-

(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyloxy)phenyl ]-[1,3]di-

oxane (RS-8b) as a white solid (3.06 g, 81%). mp 84-85 °C;

1

[R]_D+2.1 (c 0.53, CHCl₃); H NMR (CDCl₃) δ 7.46-7.38 (m,

2H), 6.93-6.88 (m, 2H), 5.46 (s, 1H), 4.1 (dd, J ) 4.7, 11.4 Hz,

1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.59-3.45 (m, 2H), 2.40-2.19

(m, 2H), 2.14-2.05 (m, 2H), 1.86-1.71 (m, 1H), 1.32 (d, J )

6.2 Hz, 3H), 0.81 (d, J ) 6.7 Hz, 3H); ¹³C NMR (CDCl₃) δ 158.8,

131.7, 127.5, 121.5-106.0 (m), 114.2, 101.1, 79.5, 73.0, 66.3,

35.8, 27.9 (t, J ) 22.1 Hz), 20.5, 19.1, 12.4; ¹⁹F NMR (CDCl₃)

-81.3 (3F), -114.9 (2F), -122.4 (2F), -123.4 (2F), -124.0 (2F),

-126.7 (2F); IR (thin film) 2985, 1265, 1241 cm^-1; LRMS 567

((M - H)⁺, 12%), 482 (22%), 121 (100%); HRMS calculated

568.1283, found 568.1262.

m-Chloroperbenzoicacid (284 mg, 1.64 mmol) was added to

a solution of (3R)-2-[4-(tert-butyldimethylsilanyloxy)-3-meth-

ylbutylsulfanyl]benzo-thiazole (213 mg, 0.66 mmol) in di-

chloromethane (20 mL) at 0 °C. After being stirred at room

temperature for 36 h, the reaction mixture was quenched with

saturated sodium bicarbonate solution (20 mL). The phases

were separated, and the aqueous layer was extracted with

ethyl acetate (3 × 30 mL). The organic layers were combined,

washed with brine, dried with magnesium sulfate, and con-

centrated. Flash column chromatography on silica gel (5:1

hexane:ethyl acetate) gave (3R)-2-[4-(tert-butyldimethyl-

silanyloxy)-3-methylbutane-1-sulfonyl]benzo-thiazole (R-3-BT)

(4S,5S)-(4,5-Dimethyl-2-[4-(4,4,5,5,6,6,7,7,7-nona-

fluorononyloxy)phenyl]-[1,3]dioxane (SS-8a). This com-

pound was synthesized by general procedure 3. Yield 86% (two

steps); white solid mp 77 °C; [R]_D+5.1 (c 0.51, CHCl₃); ¹H NMR

(CDCl₃) δ 7.46-7.41 (m, 2H), 6.90-6.86 (m, 2H), 5.50 (s, 1H),

J. Org. Chem, Vol. 70, No. 23, 2005 9457

Dandapani et al.

as a white solid (206 mg, 89%). mp 39-40 °C; [R]_D+4.6 (c 0.26,

CHCl₃); ¹H NMR (CDCl₃) 8.24-8.16 (m, 1H), 8.04-8.00 (m,

1H), 7.65-7.55 (m, 2H), 3.61-3.54 (m, 2H), 3.48 (dd, J ) 4.0,

8.3 Hz, 1H), 3.35 (dd, J ) 6.3, 10.0 Hz, 1H), 2.05-1.89 (m,

1H), 1.82-1.68 (m, 2H), 0.88 (d, J ) 6.5 Hz, 3H), 0.80 (s, 9H),

0.03 (s, 6H); ¹³C NMR (CDCl₃) δ 165.7, 152.7, 136.8, 127.9,

127.6, 125.5, 122.3, 67.4, 53.1, 34.7, 26.1, 25.7, 18.1, 16.3, -5.5,

-5.6; IR (thin film) 2955, 2856, 1329, 1148, 1089 cm^-1; LRMS

384 (M - Me)⁺(10%), 342 (100%), 256 (46%); HRMS calculated

384.11123, found 384.1114.

General Procedure 6. Dess-Martin Oxidation. 3-

(Fluorous-4-methoxybenzyloxy)-2-methylbutyralde-

hyde (M-4a-d). Dess-Martin periodinane (5.6 g, 13.2 mmol)

was added to a solution of M-14a-d (6.42 g, 11.0 mmol) in

dichloromethane (300 mL). After being stirred at room tem-

perature for 3 h, the reaction mixture was quenched by the

addition of saturated sodium bicarbonate solution (200 mL)

and sodium thiosulfate solution (200 mL) and stirred for 30

min. The phases were separated, and the aqueous layer was

extracted with ether (3 × 100 mL). The organic layers were

combined, washed with brine, dried with magnesium sulfate,

and concentrated. Flash column chromatography on silica gel

(7:3 hexane:ethyl acetate) gave aldehyde M-4a-d (5.98 g,

94%). LC-MS (APCI) for M-4a-d: 4a m/z 467 (M - 1)⁺, 4b

m/z 567 (M - 1)⁺, 4c m/z 617 (M - 1)⁺, 4d m/z 667 (M - 1)⁺.

General Procedure 7. Julia Olefination. tert-Butyl-[7-

(fluorous-4-methoxybenzyloxy)-2,6-dimethyloct-4-enyloxy]-

dimethyl-silane MS-16. A solution of sodiumhexamethyl-

disilazide in THF (1 M, 6.1 mL, 6.1 mmol) was slowly added

to a solution of sulfone S-3-PT (2.71 g, 6.62 mmol) in THF (100

mL) at -78 °C. After the mixture was stirred at -78 °C for 30

min, a solution of M-4 (2.83 g, 4.87 mmol) in THF (20 mL)

was slowly added via a syringe. After being stirred at -78 °C

for 2 h, the reaction mixture was quenched with saturated

ammonium chloride (100 mL), water (100 mL), and warmed

to room temperature. The reaction mixture was extracted with

ether (5 × 100 mL). The organic layers were combined, washed

with brine, dried with magnesium sulfate, and concentrated.

Flash column chromatography on silica gel (10:1 hexane:ethyl

acetate) gave alkene MS-16 (3.505 g, 94%). LC-MS (APCI)

for MS-16: S-16a m/z 653 (M - 1)⁺, S-16b m/z 753 (M - 1)⁺,

S-16c m/z 803 (M - 1)⁺, S-16d m/z 853 (M - 1)⁺.

General Procedure 5. Synthesis of PT-Sulfones. (3R)-

5-[4-(tert-Butyldimethylsilanyloxy)-3-methylbutane-1-

sulfonyl]-1-phenyl-1H-tetrazole (R-3-PT). Diisopropylazo-

dicarboxylate (3.8 mL) was added via a syringe to a solution

of (3R)-4-(tert-butyldimethylsilanyloxy)-3-methylbutan-1-ol (R-

13) (3.47 g, 15.9 mmol), triphenylphosphine 8 (5.0 g, 19.1

mmol), and 1-phenyl-1H-tetrazole-5-thiol (3.4 g, 19.1 mmol)

in THF (120 mL). After being stirred at room temperature for

3 h, the reaction mixture was diluted with ethanol (120 mL)

and cooled to 0 °C. (NH₄)₆Mo₇O₂‚4H₂O (2.97 g, 2.4 mmol) and

30% hydrogen peroxide (24.2 mL, 237 mmol) were added, and

the reaction mixture was warmed to room temperature. After

the mixture was stirred at room temperature for 14 h, water

(200 mL) was added and the reaction mixture was extracted

with dichloromethane (5 × 70 mL). The organic layers were

combined, washed with brine, dried with magnesium sulfate,

and concentrated. After flash column chromatography on silica

gel (5:1 hexane:ethyl acetate), (3R)-5-[4-(tert-butyldimethyl-

silanyloxy)-3-methylbutane-1-sulfonyl]-1-phenyl-1H-tetra-

zole (R-3-PT) was isolated as a colorless oil (5.28 g, 81%). [R]_D

+8.7 (c 0.61, CHCl₃); ¹H NMR (CDCl₃) 7.71-7.51 (m, 5H),

3.86-3.81 (m, 2H), 3.56 (dd, J ) 4.6, 10.0 Hz, 1H), 3.43 (dd, J

) 6.4, 10.0 Hz, 1H), 2.12-2.04 (m, 1H), 1.91-1.76 (m, 2H),

0.95 (d, J ) 6.4 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); ¹³C NMR

(CDCl₃) 153.4, 133.0, 131.4, 129.6, 125.0, 67.5, 54.4, 34.6, 25.8,

18.2, 16.3, -5.5; IR (thin film) 2956, 2857, 1343, 1153, 1095

tert-Butyl-[7-(fluorous-4-methoxybenzyloxy)-2,6-di-

methyloct-4-enyloxy]dimethylsilane MR-16. Synthesized

by General Procedure 7. Yield 3.753 g, 93%. LC-MS (APCI)

for MR-16: R-16a m/z 653 (M - 1)⁺, R-16b m/z 753 (M - 1)⁺,

R-16c m/z 803 (M - 1)⁺, R-16d m/z 853 (M - 1)⁺.

t

cm^-1; LRMS 353 (M - Bu)⁺(18%), 175 (95%), 117 (100%);

HRMS calculated 353.1104, found 353.1120.

General Procedure 8. TBS Deprotection. 7-(Fluorous-

4-methoxybenzyloxy)-2,6-dimethyloct-4-en-1-ol MS-18. A

solution of TBAF in THF (1 M, 9 mL, 9.0 mmol) was slowly

added to a solution of MS-16 (3.437 g, 4.49 mmol) in THF (120

mL). After the mixture was stirred at room temperature for 3

h, brine (100 mL) was added and the reaction mixture was

extracted with ether (5 × 100 mL). The organic layers were

combined, washed with brine, dried with magnesium sulfate,

and concentrated. Flash column chromatography on silica gel

(3:1 hexane:ethyl acetate) gave alcohol MS-18 (2.90 g, 100%).

LC-MS (APCI) for MS-18: S-18a m/z 537 (M - 1)⁺, S-18b

m/z 637 (M - 1)⁺, S-18c m/z 687 (M - 1)⁺, S-18d m/z 737 (M

- 1)⁺.

7-(Fluorous-4-methoxybenzyloxy)-2,6-dimethyloct-4-

en-1-ol MR-18. This mixture was synthesized by general

procedure 8. Yield 3.09 g, 99%. LC-MS (APCI) for MR-18:

R-18a m/z 537 (M - 1)⁺, R-18b m/z 637 (M - 1)⁺, R-18c m/z

687 (M - 1)⁺, R-18d m/z 737 (M - 1)⁺.

7-(Fluorous-4-methoxybenzyloxy)-2,6-dimethyloct-4-

enal MS-19. This mixture was synthesized by general proce-

dure 6. Yield 2.32 g, 82%. LC-MS (APCI) for MS-19:

S-19a m/z 367 (C₄F₉(CH₂)₃O-p-C₆H₄CH₂)⁺, S-19b m/z 467

(C₆F₁₃(CH₂)₃O-p-C₆H₄CH₂)⁺, S-19c m/z 517 (C₇F₁₅(CH₂)₃O-p-

C₆H₄CH₂)⁺, S-19d m/z 567 (C₈F₁₇(CH₂)₃O-p-C₆H₄CH₂)⁺.

7-(Fluorous-4-methoxybenzyloxy)-2,6-dimethyloct-4-

enal MR-19. This mixture was synthesized by general pro-

cedure 6. Yield 2.62 g, 81%. LC-MS (APCI) for MR-19: R-19a

m/z 367 (C₄F₉(CH₂)₃O-p-C₆H₄CH₂)⁺, R-19b m/z 467 (C₆F₁₃-

(CH₂)₃O-p-C₆H₄CH₂)⁺, R-19c m/z 517 (C₇F₁₅(CH₂)₃O-p-C₆H₄-

CH₂)⁺, R-19d m/z 567 (C₈F₁₇(CH₂)₃O-p-C₆H₄CH₂)⁺.

tert-Butyl-[11-(fluorous-4-methoxybenzyloxy)-2,6,10-

trimethyldodeca-4,8-dienyloxy]dimethylsilane MSS-20.

This mixture was synthesized by general procedure 7. Yield

923 mg, 92%; 485 mg, 92%. LC-MS (APCI) for MSS-20: SS-

(3S)-5-[4-(tert-Butyldimethylsilanyloxy)-3-methyl-

butane-1-sulfonyl]-1-phenyl-1H-tetrazole (S-3-PT). This

compound was synthesized by general procedure 5. Yield 3.76

g, 84%; [R]_D-8.5 (c 0.62, CHCl₃); ¹H NMR (CDCl₃) 7.71-7.51

(m, 5H), 3.87-3.81 (m, 2H), 3.56 (dd, J ) 4.7, 10.1 Hz, 1H),

3.43 (dd, J ) 6.4, 10 Hz, 1H), 2.12-2.01 (m, 1H), 1.91-1.76

(m, 2H), 0.95 (d, J ) 6.5 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); ¹³

C

NMR (CDCl₃) 153.4, 133.0, 131.4, 129.7, 125.1, 67.5, 54.5, 34.6,

25.8, 18.2, 16.3, -5.4; IR (thin film) 2956, 2857, 1343, 1153,

1095 cm^-1; LRMS 353 (M - ^tBu)⁺(20%), 175 (95%), 117

(100%); HRMS calculated 353.1104, found 353.1114.

Fluorous Mixture Synthesis Stage. Some of the steps

involved in the FMS were carried out on smaller and larger

scales. In those cases, yields from both of the runs are reported.

Mixing (M-8a-d). Mixture M-8a-d was generated by

mixing acetals SS-8a (1.30 g, 2.79 mmol), RS-8b (1.58 g, 2.79

mmol), SR-8c (1.72 g, 2.79 mmol), and RR-8d (1.86 g, 2.79

mmol).

3-(Fluorous-4-methoxybenzyloxy)-2-methylbutan-1-

ol (M-14a-d). A solution of DIBAL in hexanes (1 M, 33.4 mL,

33.4 mmol) was slowly added to a solution of M-8a-d (6.47 g,

11.14 mmol, calculated on the basis of average molecular

weight of the mixtures) in dichloromethane (340 mL) at 0 °C.

After being stirred at 0 °C for 3 h, the reaction mixture was

quenched by the addition of saturated ammonium chloride

solution (50 mL) and saturated sodium potassium tartarate

solution (300 mL), and the resulting suspension was vigorously

stirred for 1 h. The crude reaction mixture was extracted with

ether (4 × 100 mL). The organic layers were combined, washed

with brine, dried with magnesium sulfate, and concentrated.

Flash column chromatography on silica gel (3:1 hexane:ethyl

acetate) gave alcohol M-14a-d (6.45 g. 99%). LC-MS (APCI)

for M-14a-d: 14a m/z 469 (M - 1)⁺, 14b m/z 569 (M - 1)⁺,

14c m/z 619 (M - 1)⁺, 14d m/z 669 (M - 1)⁺.

9458 J. Org. Chem., Vol. 70, No. 23, 2005

Stereoisomers of Pinesaw Fly Sex Pheromones

20a m/z 721 (M - 1)⁺, SS-20b m/z 821 (M - 1)⁺, SS-20c m/z

871 (M - 1)⁺, SS-20d m/z 921 (M - 1)⁺.

with ether (5 × 50 mL). The organic layers were combined,

washed with brine, dried with magnesium sulfate, and con-

centrated. Flash column chromatography on silica gel (15:1

hexane:ethyl acetate), gave alkene MSS-2 (544 mg, 97%). LC-

MS (APCI) for MSS-2: MSS-2a m/z 367 (C₄F₉(CH₂)₃O-p-

C₆H₄CH₂)⁺, MSS-2b m/z 467 (C₆F₁₃(CH₂)₃O-p-C₆H₄CH₂)⁺, MSS-

2c m/z 517 (C₇F₁₅(CH₂)₃O-p-C₆H₄CH₂)⁺, MSS-2d m/z 567

(C₈F₁₇(CH₂)₃O-p-C₆H₄CH₂)⁺.

tert-Butyl-[11-(fluorous-4-methoxybenzyloxy)-2,6,10-

trimethyldodeca-4,8-dienyloxy]dimethylsilane MSR-20.

This mixture was synthesized by general procedure 7. Yield

747 mg, 92%; 475 mg, 91%. LC-MS (APCI) for MSR-20: SR-

20a m/z 721 (M - 1)⁺, SR-20b m/z 821 (M - 1)⁺, SR-20c m/z

871 (M - 1)⁺, SR-20d m/z 921 (M - 1)⁺.

1-Fluorous Methoxy-4-(1,2,6,10-tetramethyldodeca-

3,7,11-trienyloxymethyl)benzene MSR-2. This mixture was

synthesized by general procedure 9. Yield 520 mg (98%). LC-

MS (APCI) for MSR-2: SR-2a m/z 367 (C₄F₉(CH₂)₃O-p-

C₆H₄CH₂)⁺, SR-2b m/z 467 (C₆F₁₃(CH₂)₃O-p-C₆H₄CH₂)⁺, SR-

2c m/z 517 (C₇F₁₅(CH₂)₃O-p-C₆H₄CH₂)⁺, SR-2d m/z 567

(C₈F₁₇(CH₂)₃O-p-C₆H₄CH₂)⁺.

1-Fluorous Methoxy-4-(1,2,6,10-tetramethyldodeca-

3,7,11-trienyloxymethyl)benzene MRS-2. This mixture was

synthesized by general procedure 9. Yield 625 mg (97%). LC-

MS (APCI) for MRS-2: RS-2a m/z 367 (C₄F₉(CH₂)₃O-p-

C₆H₄CH₂)⁺, RS-2b m/z 467 (C₆F₁₃(CH₂)₃O-p-C₆H₄CH₂)⁺, RS-

2c m/z 517 (C₇F₁₅(CH₂)₃O-p-C₆H₄CH₂)⁺, RS-2d m/z 567

(C₈F₁₇(CH₂)₃O-p-C₆H₄CH₂)⁺.

1-Fluorous Methoxy-4-(1,2,6,10-tetramethyldodeca-

3,7,11-trienyloxymethyl)benzene MRR-2. This mixture

was synthesized by general procedure 10. Yield 612 mg (95%).

LC-MS (APCI) for MRR-2: RR-2a m/z 367 (C₄F₉(CH₂)₃O-p-

C₆H₄CH₂)⁺, RR-2b m/z 467 (C₆F₁₃(CH₂)₃O-p-C₆H₄CH₂)⁺, RR-

2c m/z 687 (C₇F₁₅(CH₂)₃O-p-C₆H₄CH₂)⁺, RR-2d m/z 737

(C₈F₁₇(CH₂)₃O-p-C₆H₄CH₂)⁺.

tert-Butyl-[11-(fluorous-4-methoxybenzyloxy)-2,6,10-

trimethyldodeca-4,8-dienyloxy]dimethylsilane MRS-20.

This mixture was synthesized by general procedure 7. Yield

1.57 g, 92%. LC-MS (APCI) for MRS-20: RS-20a m/z 721 (M

- 1)⁺, RS-20b m/z 821 (M - 1)⁺, RS-20c m/z 871 (M - 1)⁺,

RS-20d m/z 921 (M - 1)⁺.

tert-Butyl-[11-(fluorous-4-methoxybenzyloxy)-2,6,10-

trimethyldodeca-4,8-dienyloxy]dimethylsilane MRR-20.

This mixture was synthesized by general procedure 7. Yield

1.366 g, 93%. LC-MS (APCI) for MRR-20: RR-20a m/z 721

(M - 1)⁺, RR-20b m/z 821 (M - 1)⁺, RR-20c m/z 871 (M -

1)⁺, RR-20d m/z 921 (M - 1)⁺.

11-(Fluorous-4-methoxybenzyloxy)-2,6,10-trimethyl-

dodeca-4,8-dien-1-ol MSS-21. This mixture was synthesized

by general procedure 8. Yield 1.12 g 100%. LC-MS (APCI)

for MSS-21: SS-21a m/z 607 (M - 1)⁺, SS-21b m/z 707 (M -

1)⁺, SS-21c m/z 757 (M - 1)⁺, SS-21d m/z 807 (M - 1)⁺.

11-(Fluorous-4-methoxybenzyloxy)-2,6,10-trimethyl-

dodeca-4,8-dien-1-ol MSR-21. This mixture was synthesized

by general procedure 8. Yield 1.03 g (100%). LC-MS (APCI)

for MSR-21: SR-21a m/z 607 (M - 1)⁺, SR-21b m/z 707 (M -

1)⁺, SR-21c m/z 757 (M - 1)⁺, SR-21d m/z 807 (M - 1)⁺.

General Procedure 10. Diimide Reduction. 1-Fluorous

Methoxy-4-(1,2,6,10-tetramethyldodecyloxymethyl)-

benzene MRR-23. Anhydrous hydrazine (7.1 mL, 0.23 mol)

was added to a suspension of triene MSS-2 (544 mg, 0.76

mmol) and copper sulfate (5.66 g, 22.67 mmol) in ethanol (10

mL). After being stirred at room temperature for 15 min, the

reaction mixture was warmed to 70 °C. (These reaction

conditions sometimes resulted in incomplete reduction of

starting triene. In those cases, the crude product was resub-

jected to the same reaction conditions. Bubbling air through

the reaction mixture also helped improve conversion.) After

being stirred at 70 °C for 20 h, the reaction was cooled to room

temperature. Water (50 mL) was added, and the reaction

mixture was extracted with ether (5 × 50 mL). The organic

layers were combined, washed with brine, dried with magne-

sium sulfate, and concentrated. Flash column chromatography

on silica gel (10:1 hexane:ethyl acetate) gave MRR-23 (514 mg,

94%). LC-MS (APCI) for MRR-23: RR-23a m/z 367 (C₄F₉-

(CH₂)₃O-p-C₆H₄CH₂)⁺, RR-23b m/z 467 (C₆F₁₃(CH₂)₃O-p-

C₆H₄CH₂)⁺, RR-23c m/z 517 (C₇F₁₅(CH₂)₃O-p-C₆H₄CH₂)⁺, RR-

23d m/z 567 (C₈F₁₇(CH₂)₃O-p-C₆H₄CH₂)⁺.

11-(Fluorous-4-methoxybenzyloxy)-2,6,10-trimethyl-

dodeca-4,8-dien-1-ol MRS-21. This mixture was synthesized

by general procedure 8. Yield 1.33 g (100%). LC-MS (APCI)

for MRS-21: RS-21a m/z 607 (M - 1)⁺, RS-21b m/z 707 (M -

1)⁺, RS-21c m/z 757 (M - 1)⁺, RS-21d m/z 807 (M - 1)⁺.

11-(Fluorous-4-methoxybenzyloxy)-2,6,10-trimethyl-

dodeca-4,8-dien-1-ol MRR-21. This mixture was synthesized

by general procedure 8. Yield 1.09 g (100%). LC-MS (APCI)

for MRR-21: RR-21a m/z 607 (M - 1)⁺, RR-21b m/z 707 (M -

1)⁺, RR-21c m/z 757 (M - 1)⁺, RR-21d m/z 807 (M - 1)⁺.

11-(Fluorous-4-methoxy-benzyloxy)-2,6,10-trimethyl-

dodeca-4,8-dienal MSS-22. This mixture was synthesized by

general procedure 6. Yield 908 mg, 81%. LC-MS (APCI) for

MSS-22: SS-22a m/z 605 (M - 1)⁺, SS-22b m/z 705 (M - 1)⁺,

SS-22c m/z 755 (M - 1)⁺, SS-22d m/z 805 (M - 1)⁺.

11-(Fluorous-4-methoxy-benzyloxy)-2,6,10-trimethyl-

dodeca-4,8-dienal MSR-22. This mixture was synthesized

by general procedure 6. Yield 833 mg (84%). LC-MS (APCI)

for MSR-22: SR-22a m/z 605 (M - 1)⁺, SR-22b m/z 705 (M -

1)⁺, SR-22c m/z 755 (M - 1)⁺, SR-22d m/z 805 (M - 1)⁺.

1-Fluorous Methoxy-4-(1,2,6,10-tetramethyldodecyl-

oxymethyl)benzene MRS-23. This mixture was synthesized

by general procedure 10. Yield 473 mg (90%). LC-MS (APCI)

for MRS-23: RS-23a m/z 367 (C₄F₉(CH₂)₃O-p-C₆H₄CH₂)⁺, RS-

23b m/z 467 (C₆F₁₃(CH₂)₃O-p-C₆H₄CH₂)⁺, RS-23c m/z 517

(C₇F₁₅(CH₂)₃O-p-C₆H₄CH₂)⁺, RS-23d m/z 567 (C₈F₁₇(CH₂)₃O-

p-C₆H₄CH₂)⁺.

1-Fluorous Methoxy-4-(1,2,6,10-tetramethyldodecyl-

oxymethyl)benzene MSR-23. This mixture was synthesized

by general procedure 10. Yield 432 mg (95%). LC-MS (APCI)

for MSR-23: SR-23a m/z 367 (C₄F₉(CH₂)₃O-p-C₆H₄CH₂)⁺, SR-

23b m/z 467 (C₆F₁₃(CH₂)₃O-p-C₆H₄CH₂)⁺, SR-23c m/z 517

(C₇F₁₅(CH₂)₃O-p-C₆H₄CH₂)⁺, SR-23d m/z 567 (C₈F₁₇(CH₂)₃O-

p-C₆H₄CH₂)⁺.

1-Fluorous Methoxy-4-(1,2,6,10-tetramethyldodecyl-

oxymethyl)benzene MSS-23. This mixture was synthesized

by general procedure 10. Yield 460 mg (96%). LC-MS (APCI)

for MSS-23: SS-23a m/z 367 (C₄F₉(CH₂)₃O-p-C₆H₄CH₂)⁺, SS-

23b m/z 467 (C₆F₁₃(CH₂)₃O-p-C₆H₄CH₂)⁺, SS-23c m/z 517

(C₇F₁₅(CH₂)₃O-p-C₆H₄CH₂)⁺, SS-23d m/z 567 (C₈F₁₇(CH₂)₃O-

p-C₆H₄CH₂)⁺.

11-(Fluorous-4-methoxy-benzyloxy)-2,6,10-trimethyl-

dodeca-4,8-dienal MRS-22. This mixture was synthesized

by general procedure 6. Yield 1.11 g (86%). LC-MS (APCI)

for MRS-22: RS-22a m/z 605 (M - 1)⁺, RS-22b m/z 705 (M -

1)⁺, RS-22c m/z 755 (M - 1)⁺, RS-22d m/z 805 (M - 1)⁺.

11-(Fluorous-4-methoxy-benzyloxy)-2,6,10-trimethyl-

dodeca-4,8-dienal MRR-22. This mixture was synthesized

by general procedure 6. Yield 858 mg (82%). LC-MS (APCI)

for MRR-22: RR-22a m/z 605 (M - 1)⁺, RR-22b m/z 705 (M +

1)⁺, RR-22c m/z 755 (M - 1)⁺, RR-22d m/z 805 (M - 1)⁺.

General Procedure 9. Wittig Reaction. 1-Fluorous

Methoxy-4-(1,2,6,10-tetramethyldodeca-3,7,11-trienyl-

oxymethyl)benzene MSS-2. A solution of sodiumhexa-

methyldisilazide (1 M, 2.3 mL, 2.3 mmol) was added to a

suspension of methyl triphenylphosphonium iodide (1.56 g,

3.85 mmol) in THF (10 mL) at -78 °C. After the mixture was

stirred at -78 °C for 30 min, a solution of MSS-22 (555 mg,

0.77 mmol) in THF (10 mL) was added. After being stirred at

-78 °C for 2 h, the reaction mixture was warmed to room

temperature over a period of 3 h and quenched with brine (30

mL) and water (50 mL). The reaction mixture was extracted

J. Org. Chem, Vol. 70, No. 23, 2005 9459

Dandapani et al.

General Procedure 11. Demixing. Demixing MRR-23.

The separation conditions were as follows: FluoroFlash HPLC

column (20 mm × 250 mm), gradient 95:5 acetonitrile:water

to 100% acetonitrile in 30 min, then isocratic acetonitrile to

50 min with a flow rate of 12 mL/min. UV detector (230 nm)

was used to manually identify peaks. A mixture of MRR-23

(476 mg, 0.66 mmol), acetonitrile (9 mL), and THF (2 mL) was

sonicated for about 15 s and filtered through a Wattman filter

paper (0.45 µm pore size). Five separations using 2 mL (86

mg of MRR-23) each and two separations using 1 mL (43 mg

of MRR-23) each were carried out to give SSRR-23a (96 mg,

0.16 mmol), RSRR-23b (113 mg, 0.16 mmol), SRRR-23c (120

mg, 0.16 mmol), and RRRR-23d (128 mg, 0.16 mmol).

11.4; ¹⁹F NMR (CDCl₃) -81.2 (3F), -114.8 (2F), -122.2 to

-122.4 (6F), -123.2 (2F), -123.9 (2F), -126.6 (2F); IR (thin

film) 2928, 1241 cm^-1; LRMS 808 (M⁺, 3%), 764 (10%),

567 (60%), 121 (100%); HRMS calculated 808.3148, found

808.3112.

Demixing of MRS-23. Mixture MRS-23 (460 mg, 0.64

mmol) was demixed by general procedure 11 to give com-

pounds SSRS-23a (81 mg, 0.13 mmol), RSRS-23b (103 mg,

0.15 mmol), SRRS-23c (108 mg, 0.14 mmol), and RRRS-23d

(117 mg, 0.15 mmol).

(1S,2S,6R,10S)-1-(4,4,5,5,6,6,7,7,7-Nonafluoroheptyloxy)-

4-(1,2,6,10-tetramethyldodecyloxymethyl)benzene SSRS-

1

23a. H NMR (CDCl₃, 600 MHz) δ 7.30-7.28 (m, 2H), 6.89-

(1S,2S,6R,10R)-1-(4,4,5,5,6,6,7,7,7-Nonafluoroheptyloxy)-

6.87 (m, 2H), 4.52 (d, J ) 11.5 Hz, 1H), 4.40 (d, J ) 11.5 Hz,

1H), 4.05 (t, J ) 6.0 Hz, 2H), 3.38 (dq, J ) 4.9, 6.3 Hz, 1H),

2.37-2.28 (m, 2H), 2.13-2.08 (m, 2H), 1.63-1.60 (m, 1H),

1.48-1.10 (m, 16H), 1.14 (d, J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.8

Hz, 3H), 0.88 (t, J ) 7.2 Hz, 3H), 0.87 (d, J ) 6.4 Hz, 3H),

0.86 (d, J ) 6.6 Hz, 3H); ¹³C NMR (CDCl₃, 151 MHz) 157.9,

132.0, 129.1, 114.3, 125-105 (m), 78.3, 70.2, 66.3, 38.0, 37.5,

37.4, 37.0, 34.4, 32.8, 32.4, 29.6, 27.9 (t, J ) 22.1 Hz), 24.8,

24.5, 20.6, 19.6, 19.2, 16.1, 15.3, 11.4; ¹⁹F NMR (CDCl₃) -81.5

(3F), -115.1 (2F), -124.9 (2F), -126.6 (2F); IR (thin film) 2928,

1242 cm^-1; LRMS 608 (M⁺, 10%), 564 (15%), 367 (100%);

HRMS calculated 608.3276, found 608.3291.

4-(1,2,6,10-tetramethyldodecyloxymethyl)benzene SSRR-

1

23a. H NMR (CDCl₃, 600 MHz) δ 7.30-7.28 (m, 2H), 6.89-

6.86 (m, 2H), 4.52 (d, J ) 11.5 Hz, 1H), 4.40 (d, J ) 11.5 Hz,

1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.38 (dq, J ) 4.9, 6.2 Hz, 1H),

2.37-2.28 (m, 2H), 2.13-2.09 (m, 2H), 1.64-1.58 (m, 1H),

1.46-1.07 (m, 16H), 1.14 (d, J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.8

Hz, 3H), 0.88 (t, J ) 7.2 Hz, 3H), 0.87 (d, J ) 6.5 Hz, 3H),

0.86 (d, J ) 6.6 Hz, 3H); ¹³C NMR (CDCl₃, 151 MHz) 157.9,

132.0, 129.1, 114.2, 121-105 (m), 78.3, 70.2, 66.3, 38.0, 37.6,

37.3, 37.0, 34.4, 32.8, 32.4, 29.5, 27.8 (t, J ) 21.9 Hz), 24.8,

24.5, 20.6, 19.7, 19.2, 16.1, 15.2, 11.3; ¹⁹F NMR (CDCl₃) -81.5

(3F), -115.1 (2F), -124.9 (2F), -126.6 (2F); IR (thin film) 2928,

1238 cm^-1; LRMS 608 (M⁺, 5%), 564 (15%), 367 (100%); HRMS

calculated 608.3276, found 608.3291.

(1R,2S,6R,10S)-1-(1,2,6,10-Tetramethyldodecyloxy-

methyl)-4-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyloxy)-

benzene RSRS-23b. ¹H NMR (CDCl₃, 600 MHz) δ 7.30-7.28

(m, 2H), 6.89-6.87 (m, 2H), 4.49 (d, J ) 11.5 Hz, 1H), 4.42 (d,

J ) 11.4 Hz, 1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.38 (dq, J ) 5.4,

6.2 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-2.09 (m, 2H), 1.74-1.71

(m, 1H), 1.41-1.09 (m, 16H), 1.11 (d, J ) 6.3 Hz, 3H), 0.89 (d,

J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.2 Hz, 3H), 0.87 (d, J ) 6.5 Hz,

3H), 0.86 (d, J ) 6.6 Hz, 3H); ¹³C NMR (CDCl₃, 151 MHz)

158.0, 131.9, 129.1, 114.3, 125-105 (m), 78.4, 70.0, 66.3, 37.5,

37.4, 37.3, 37.0, 34.4, 33.4, 32.8, 29.6, 27.8 (t, J ) 22.1 Hz),

24.8, 24.5, 20.6, 19.6, 19.2, 15.3, 14.3, 11.4; ¹⁹F NMR (CDCl₃)

-81.3 (3F), -114.9 (2F), -122.4 (2F), -123.4 (2F), -124.0 (2F),

-126.7 (2F); IR (thin film) 2928, 1241 cm^-1; LRMS 708 (M⁺,

4%), 664 (10%), 467 (100%); HRMS calculated 708.3212, found

708.3185.

(1S,2R,6R,10S)-1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Penta-

decafluorodecyloxy)-4-(1,2,6,10-tetramethyldodecyloxy-

methyl)benzene SRRS-23c. ¹H NMR (CDCl₃, 600 MHz) δ

7.30-7.28 (m, 2H), 6.88-6.86 (m, 2H), 4.49 (d, J ) 11.3 Hz,

1H), 4.42 (d, J ) 11.4 Hz, 1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.38

(dq, J ) 6.7, 6.7 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-2.09 (m,

2H), 1.73-1.71 (m, 1H), 1.41-1.07 (m, 16H), 1.11 (d, J ) 6.2

Hz, 3H), 0.89 (d, J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.0 Hz, 3H),

0.86 (d, J ) 6.4 Hz, 3H), 0.86 (d, J ) 6.2 Hz, 3H); ¹³C NMR

(CDCl₃, 151 MHz) 158.0, 131.9, 129.1, 114.3, 125-105 (m),

78.3, 70.0, 66.4, 37.5, 37.4, 37.3, 37.0, 34.4, 33.4, 32.8, 29.6,

28.0 (t, J ) 22.4 Hz), 24.8, 24.5, 20.6, 19.7, 19.2, 15.2, 14.3,

11.4; ¹⁹F NMR (CDCl₃) -81.3 (3F), -114.9 (2F), -122.2 (2F),

-122.6 (2F), -123.2 (2F), -123.9 (2F), -126.6 (2F); IR (thin

film) 2928, 1241 cm^-1; LRMS 758 (M⁺, 6%), 714 (10%), 517

(100%); HRMS calculated 758.3180, found 758.3143.

(1R,2R,6R,10S)-1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-

Heptadecafluoroundecyloxy)-4-(1,2,6,10-tetramethyldo-

decyloxymethyl)benzene RRRS-23d. ¹H NMR (CDCl₃, 600

MHz) δ 7.29-7.28 (m, 2H), 6.88-6.87 (m, 2H), 4.52 (d, J )

11.6 Hz, 1H), 4.40 (d, J ) 11.5 Hz, 1H), 4.04 (t, J ) 5.9 Hz,

2H), 3.38 (dq, J ) 6.1, 6.1 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-

2.09 (m, 2H), 1.63-1.59 (m, 1H), 1.51-1.09 (m, 16H), 1.14 (d,

J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.1 Hz,

3H), 0.87 (d, J ) 5.6 Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H); ¹³C

NMR (CDCl₃, 151 MHz) 158.0, 132.0, 129.1, 114.3, 125-105

(m), 78.3, 70.2, 66.4, 38.1, 37.5, 37.3, 37.0, 34.4, 32.8, 32.5, 29.6,

28.0 (t, J ) 22.5 Hz), 24.8, 24.5, 20.6, 19.7, 19.2, 16.1, 15.3,

11.4; ¹⁹F NMR (CDCl₃) -81.2 (3F), -114.8 (2F), -122.2 to

-122.4 (6F), -123.2 (2F), -123.9 (2F), -126.6 (2F); IR (thin

(1R,2S,6R,10R)-1-(1,2,6,10-Tetramethyldodecyloxy-

methyl)-4-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyloxy)-

benzene RSRR-23b. ¹H NMR (CDCl₃, 600 MHz) δ 7.29-7.28

(m, 2H), 6.89-6.87 (m, 2H), 4.50 (d, J ) 11.4 Hz, 1H), 4.42 (d,

J ) 11.4 Hz, 1H), 4.05 (t, J ) 5.9 Hz, 2H), 3.38 (dq, J ) 6.2,

6.2 Hz, 1H), 2.37-2.29 (m, 2H), 2.13-2.08 (m, 2H), 1.75-1.71

(m, 1H), 1.40-1.08 (m, 16H), 1.12 (d, J ) 6.2 Hz, 3H), 0.90 (d,

J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.1 Hz, 3H), 0.87 (d, J ) 6.4 Hz,

3H), 0.87 (d, J ) 6.6 Hz, 3H); ¹³C NMR (CDCl₃, 151 MHz)

158.0, 131.9, 129.1, 114.3, 121-105 (m), 78.3, 70.0, 66.4, 37.5,

37.3 (2C), 37.0, 34.5, 33.4, 32.7, 29.6, 28.0 (t, J ) 22.5 Hz),

24.8, 24.5, 20.6, 19.7, 19.2, 15.3, 14.3, 11.4; ¹⁹F NMR (CDCl₃)

-81.3 (3F), -114.9 (2F), -122.4 (2F), -123.4 (2F), -124.0 (2F),

-126.7 (2F); IR (thin film) 2928, 1241 cm^-1; LRMS 708 (M⁺,

10%), 664 (15%), 467 (100%); HRMS calculated 708.3212,

found 708.3222.

(1S,2R,6R,10R)-1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Penta-

decafluorodecyloxy)-4-(1,2,6,10-tetramethyldodecyloxy-

1

methyl)benzene SRRR-23c. H NMR (CDCl₃, 600 MHz) δ

7.30-7.28 (m, 2H), 6.89-6.87 (m, 2H), 4.50 (d, J ) 11.4 Hz,

1H), 4.42 (d, J ) 11.4 Hz, 1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.38

(dq, J ) 5.4, 5.4 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-2.09 (m,

2H), 1.75-1.71 (m, 1H), 1.41-1.05 (m, 16H), 1.11 (d, J ) 6.3

Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H), 0.88 (t, J ) 6.7 Hz, 3H),

0.87 (d, J ) 6.5 Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H); ¹³C NMR

(CDCl₃, 151 MHz) 158.0, 131.9, 129.1, 114.3, 125-105 (m),

78.3, 70.0, 66.4, 37.4 (2C), 37.3, 37.0, 34.4, 33.5, 32.8, 29.5,

28.0 (t, J ) 26.1 Hz), 24.8, 24.5, 20.6, 19.8, 19.2, 15.2, 14.3,

11.4; ¹⁹F NMR (CDCl₃) -81.3 (3F), -114.9 (2F), -122.2 (2F),

-122.6 (2F), -123.2 (2F), -123.9 (2F), -126.6 (2F); IR (thin

film) 2928, 1241 cm^-1; LRMS 758 (M⁺, 5%), 714 (15%), 517

(100%); HRMS calculated 758.3180, found 758.3193.

(1R,2R,6R,10R)-1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-

Heptadecafluoroundecyl-oxy)-4-(1,2,6,10-tetramethyl-

1

dodecyloxymethyl)benzene RRRR-23d. H NMR (CDCl₃,

600 MHz) δ 7.29-7.28 (m, 2H), 6.88-6.87 (m, 2H), 4.52 (d, J

) 11.5 Hz, 1H), 4.40 (d, J ) 11.5 Hz, 1H), 4.04 (t, J ) 5.9 Hz,

2H), 3.38 (dq, J ) 4.8, 6.2 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-

2.09 (m, 2H), 1.63-1.58 (m, 1H), 1.50-1.06 (m, 16H), 1.14 (d,

J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.2 Hz,

3H), 0.87 (d, J ) 5.5 Hz, 3H), 0.86 (d, J ) 6.4 Hz, 3H); ¹³C

NMR (CDCl₃, 151 MHz) 158.0, 132.0, 129.1, 114.3, 125-105

(m), 78.3, 70.2, 66.4, 38.1, 37.4, 37.4, 37.0, 34.4, 32.8, 32.5, 29.5,

28.0 (t, J ) 22.3 Hz), 24.8, 24.5, 20.6, 19.8, 19.2, 16.1, 15.3,

9460 J. Org. Chem., Vol. 70, No. 23, 2005

Stereoisomers of Pinesaw Fly Sex Pheromones

film) 2928, 1242 cm^-1; LRMS 808 (M⁺, 3%), 764 (10%),

567 (45%), 91(100%); HRMS calculated 808.3148, found

808.3172.

Demixing of MSR-23. Mixture MSR-23 (471 mg, 0.65

mmol) was demixed by general procedure 11 to give com-

pounds SSSR-23a (92 mg, 0.15 mmol), RSSR-23b (106 mg,

0.15 mmol), SRSR-23c (111 mg, 0.15 mmol), and RRSR-23d

(119 mg, 0.15 mmol).

Demixing of MSS-23. Mixture MSS-23 (451 mg, 0.62

mmol) was demixed by general procedure 11 to give com-

pounds SSSS-23a (86 mg, 0.14 mmol), RSSS-23b (103 mg, 0.15

mmol), SRSS-23c (108 mg, 0.14 mmol), and RRSS-23d (113

mg, 0.14 mmol).

(1S,2S,6S,10S)-1-(4,4,5,5,6,6,7,7,7-Nonafluoroheptyloxy)-

4-(1,2,6,10-tetramethyldodecyloxymethyl)benzene SSSS-

1

23a. H NMR (CDCl₃, 600 MHz) δ 7.29-7.28 (m, 2H), 6.88-

6.87 (m, 2H), 4.52 (d, J ) 11.6 Hz, 1H), 4.40 (d, J ) 11.5 Hz,

1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.38 (dq, J ) 4.8, 6.2 Hz, 1H),

2.37-2.28 (m, 2H), 2.13-2.09 (m, 2H), 1.63-1.59 (m, 1H),

1.51-1.08 (m, 16H), 1.14 (d, J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.8

Hz, 3H), 0.88 (t, J ) 7.2 Hz, 3H), 0.87 (d, J ) 5.3 Hz, 3H),

0.87 (d, J ) 6.6 Hz, 3H); ¹³C NMR (CDCl₃, 151 MHz) 158.0,

132.0, 129.2, 114.3, 125-105 (m), 78.4, 70.3, 66.4, 38.1, 37.5,

37.5, 37.1, 34.5, 32.9, 32.5, 29.6, 28.0 (t, J ) 22.4 Hz), 24.9,

24.6, 20.7, 19.9, 19.3, 16.2, 15.4, 11.5; ¹⁹F NMR (CDCl₃) -81.5

(3F), -115.1 (2F), -124.9 (2F), -126.6 (2F); IR (thin film) 2928,

1242 cm^-1; LRMS 608 (M⁺, 5%), 564 (10%), 367 (100%); HRMS

calculated 608.3276, found 608.3283.

(1R,2S,6S,10S)-1-(1,2,6,10-Tetramethyldodecyloxy-

methyl)-4-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyloxy)-

benzene RSSS-23b. ¹H NMR (CDCl₃, 600 MHz) δ 7.29-7.28

(m, 2H), 6.89-6.87 (m, 2H), 4.50 (d, J ) 11.4 Hz, 1H), 4.42 (d,

J ) 11.4 Hz, 1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.38 (dq, J ) 5.5,

6.2 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-2.09 (m, 2H), 1.75-1.70

(m, 1H), 1.42-1.07 (m, 16H), 1.11 (d, J ) 6.3 Hz, 3H), 0.89 (d,

J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.0 Hz, 3H), 0.87 (d, J ) 6.4 Hz,

3H), 0.87 (d, J ) 6.6 Hz, 3H); ¹³C NMR (CDCl₃, 151 MHz)

158.1, 132.0, 129.2, 114.4, 125-105 (m), 78.3, 70.1, 66.4, 37.5

(2C), 37.4, 37.1, 34.5, 33.5, 32.9, 29.6, 28.1 (t, J ) 22.5 Hz),

24.8, 24.6, 20.7, 19.8, 19.3, 15.3, 14.4, 11.4; ¹⁹F NMR (CDCl₃)

-81.3 (3F), -114.9 (2F), -122.4 (2F), -123.4 (2F), -124.0 (2F),

-126.7 (2F); IR (thin film) 2928, 1241 cm^-1; LRMS 708 (M⁺,

6%), 567 (3%), 467 (100%); HRMS calculated 708.3212, found

708.3218.

(1S,2R,6S,10S)-1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Penta-

decafluorodecyloxy)-4-(1,2,6,10-tetramethyldodecyloxy-

methyl)benzene SRSS-23c. ¹H NMR (CDCl₃, 600 MHz) δ

7.29-7.28 (m, 2H), 6.89-6.87 (m, 2H), 4.49 (d, J ) 11.4 Hz,

1H), 4.42 (d, J ) 11.4 Hz, 1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.37

(dq, J ) 5.5, 6.2 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-2.09 (m,

2H), 1.74-1.69 (m, 1H), 1.41-1.06 (m, 16H), 1.11 (d, J ) 6.3

Hz, 3H), 0.89 (d, J ) 6.8 Hz, 3H), 0.87 (t, J ) 7.1 Hz, 3H),

0.86 (d, J ) 6.5 Hz, 3H), 0.86 (d, J ) 6.6 Hz, 3H); ¹³C NMR

(CDCl₃, 151 MHz) 158.1, 132.0, 129.2, 114.3, 125-105 (m),

78.5, 70.1, 66.5, 37.6, 37.4, 37.4, 37.1, 34.5, 33.5, 32.9, 29.6,

28.1 (t, J ) 22.3 Hz), 24.8, 24.6, 20.7, 19.8, 19.3, 15.4, 14.4,

11.5; ¹⁹F NMR (CDCl₃) -81.2 (3F), -114.9 (2F), -122.2 (2F),

-122.6 (2F), -123.2 (2F), -123.9 (2F), -126.6 (2F); IR (thin

film) 2928, 1241 cm^-1; LRMS 758 (M⁺, 9%), 714 (15%), 517

(100%); HRMS calculated 758.3180, found 758.3183.

(1R,2R,6S,10S)-1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-

Heptadecafluoroundecyloxy)-4-(1,2,6,10-tetramethyldo-

decyloxymethyl)benzene RRSS-23d. ¹H NMR (CDCl₃, 600

MHz) δ 7.29-7.28 (m, 2H), 6.88-6.87 (m, 2H), 4.52 (d, J )

11.5 Hz, 1H), 4.40 (d, J ) 11.5 Hz, 1H), 4.04 (t, J ) 5.9 Hz,

2H), 3.38 (dq, J ) 4.8, 6.2 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-

2.09 (m, 2H), 1.63-1.59 (m, 1H), 1.49-1.09 (m, 16H), 1.14 (d,

J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.2 Hz,

3H), 0.87 (d, J ) 6.5 Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H); ¹³C

NMR (CDCl₃, 151 MHz) 158.0, 132.1, 129.2, 114.3, 125-105

(m), 78.4, 70.3, 66.4, 38.1, 37.7, 37.4, 37.1, 34.5, 32.9, 32.5, 29.6,

28.1 (t, J ) 22.3 Hz), 24.9, 24.6, 20.7, 19.7, 19.3, 16.2, 15.4,

11.4; ¹⁹F NMR (CDCl₃) -81.2 (3F), -114.9 (2F), -122.2 to

-122.4 (6F), -123.2 (2F), -123.9 (2F), -126.6 (2F); IR (thin

film) 2928, 1242 cm^-1; LRMS 808 (M⁺, 6%), 764 (15%), 567

(100%); HRMS calculated 808.3148, found 808.3122.

(1S,2S,6S,10R)-1-(4,4,5,5,6,6,7,7,7-Nonafluoroheptyloxy)-

4-(1,2,6,10-tetramethyldodecyloxymethyl)benzene SSSR-

1

23a. H NMR (CDCl₃, 600 MHz) δ 7.28-7.27 (m, 2H), 6.87-

6.86 (m, 2H), 4.51 (d, J ) 11.5 Hz, 1H), 4.39 (d, J ) 11.5 Hz,

1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.37 (dq, J ) 6.2, 6.2 Hz, 1H),

2.36-2.27 (m, 2H), 2.12-2.08 (m, 2H), 1.62-1.58 (m, 1H),

1.50-1.05 (m, 16H), 1.13 (d, J ) 6.3 Hz, 3H), 0.91 (d, J ) 6.8

Hz, 3H), 0.87 (t, J ) 7.2 Hz, 3H), 0.85 (d, J ) 6.4 Hz, 3H),

0.85 (d, J ) 6.5 Hz, 3H); ¹³C NMR (CDCl₃, 151 MHz) 157.9,

132.0, 129.1, 114.3, 125-105 (m), 78.3, 70.2, 66.3, 38.0, 37.5,

37.3, 36.9, 34.4, 32.8, 32.4, 29.6, 27.9 (t, J ) 23.2 Hz), 24.8,

24.5, 20.6, 19.7, 19.2, 16.2, 15.3, 11.4; ¹⁹F NMR (CDCl₃) -81.5

(3F), -115.1 (2F), -124.9 (2F), -126.5 (2F); IR (thin film) 2928,

1242 cm^-1; LRMS 608 (M⁺, 6%), 564 (10%), 367 (100%); HRMS

calculated 608.3276, found 608.3284.

(1R,2S,6S,10R)-1-(1,2,6,10-Tetramethyldodecyloxy-

methyl)-4-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyloxy)-

benzene RSSR-23b. ¹H NMR (CDCl₃, 600 MHz) δ 7.29-7.27

(m, 2H), 6.87-6.86 (m, 2H), 4.48 (d, J ) 11.4 Hz, 1H), 4.41 (d,

J ) 11.5 Hz, 1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.37 (dq, J ) 6.2,

6.2 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-2.08 (m, 2H), 1.73-1.69

(m, 1H), 1.40-1.06 (m, 16H), 1.10 (d, J ) 6.3 Hz, 3H), 0.88 (d,

J ) 6.8 Hz, 3H), 0.87 (t, J ) 7.1 Hz, 3H), 0.85 (d, J ) 6.5 Hz,

3H), 0.85 (d, J ) 6.5 Hz, 3H); ¹³C NMR (CDCl₃, 151 MHz)

157.9, 131.9, 129.1, 114.3, 125-105 (m), 78.2, 70.0, 66.4, 37.5,

37.3, 37.3, 36.9, 34.4, 33.4, 32.8, 29.6, 28.0 (t, J ) 22.8 Hz),

24.8, 24.5, 20.6, 19.7, 19.2, 15.2, 14.3, 11.4; ¹⁹F NMR (CDCl₃)

-81.3 (3F), -114.9 (2F), -122.4 (2F), -123.4 (2F), -124.0 (2F),

-126.6 (2F); IR (thin film) 2928, 1242 cm^-1; LRMS 708 (M⁺,

6%), 664 (10%), 467 (100%); HRMS calculated 708.3212, found

708.3215.

(1S,2R,6S,10R)-1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Penta-

decafluorodecyloxy)-4-(1,2,6,10-tetramethyldodecyloxy-

methyl)benzene SRSR-23c. ¹H NMR (CDCl₃, 600 MHz) δ

7.29-7.27 (m, 2H), 6.88-6.86 (m, 2H), 4.48 (d, J ) 11.4 Hz,

1H), 4.41 (d, J ) 11.4 Hz, 1H), 4.04 (t, J ) 5.9 Hz, 2H), 3.37

(dq, J ) 6.2, 6.2 Hz, 1H), 2.37-2.28 (m, 2H), 2.13-2.08 (m,

2H), 1.73-1.68 (m, 1H), 1.38-1.08 (m, 16H), 1.10 (d, J ) 6.3

Hz, 3H), 0.88 (d, J ) 6.8 Hz, 3H), 0.87 (t, J ) 7.2 Hz, 3H),

0.85 (d, J ) 6.5 Hz, 3H), 0.85 (d, J ) 6.5 Hz, 3H); ¹³C NMR

(CDCl₃, 151 MHz) 157.9, 131.9, 129.1, 114.3, 125-105 (m),

78.4, 70.0, 66.4, 37.5, 37.4, 37.3, 36.9, 34.4, 33.4, 32.8, 29.6,

28.0 (t, J ) 22.2 Hz), 24.8, 24.5, 20.6, 19.6, 19.2, 15.3, 14.3,

11.4; ¹⁹F NMR (CDCl₃) -81.2 (3F), -114.9 (2F), -122.2 (2F),

-122.6 (2F), -123.2 (2F), -123.9 (2F), -126.6 (2F); IR (thin

film) 2928, 1241 cm^-1; LRMS 758 (M⁺, 8%), 714 (15%), 517

(100%); HRMS calculated 758.3180, found 758.3155.

(1R,2R,6S,10R)-1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-

Heptadecafluoroundecyloxy)-4-(1,2,6,10-tetramethyldo-

decyloxymethyl)benzene RRSR-23d. ¹H NMR (CDCl₃, 600

MHz) δ 7.28-7.27 (m, 2H), 6.88-6.86 (m, 2H), 4.51 (d, J )

11.5 Hz, 1H), 4.39 (d, J ) 11.5 Hz, 1H), 4.04 (t, J ) 5.9 Hz,

2H), 3.37 (dq, J ) 4.8, 6.2 Hz, 1H), 2.36-2.28 (m, 2H), 2.13-

2.08 (m, 2H), 1.63-1.57 (m, 1H), 1.40-1.05 (m, 16H), 1.13 (d,

J ) 6.3 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H), 0.87 (t, J ) 7.2 Hz,

3H), 0.85 (d, J ) 6.5 Hz, 3H), 0.85 (d, J ) 6.7 Hz, 3H); ¹³C

NMR (CDCl₃, 151 MHz) 157.9, 132.0, 129.1, 114.2, 125-105

(m), 78.3, 70.2, 68.3, 38.0, 37.5, 37.4, 37.0, 34.4, 32.8, 32.3, 29.6,

28.0 (t, J ) 22.2 Hz), 24.8, 24.5, 20.6, 19.6, 19.2, 16.2, 15.3,

11.4; ¹⁹F NMR (CDCl₃) -81.2 (3F), -114.8 (2F), -122.2 to

-122.4 (6F), -123.2 (2F), -123.9 (2F), -126.6 (2F); IR (thin

film) 2928, 1242 cm^-1; LRMS 808 (M⁺, 10%), 764 (15%), 567

(100%); HRMS calculated 808.3148, found 808.3144.

Post-Mix Stage. General Procedure 12. Detagging.

(2S,3S,7R,11R)-3,7,11-Trimethyltridecan-2-ol SSRR-24.

(1S,2S,6R,10R)-1-(4,4,5,5,6,6,7,7,7-Nonafluoroheptyloxy)-4-

(1,2,6,10-tetramethyl-dodecyloxymethyl)-benzene SSRR-23a

J. Org. Chem, Vol. 70, No. 23, 2005 9461

Dandapani et al.

(76 mg, 0.125 mmol) and Pd/C (10 wt %) (10 mg) was taken

up in ethanol (2 mL) and water (0.2 mL). The reaction flask

was degassed using aspirator and filled with hydrogen from a

balloon. After being stirred at room temperature for 12 h, the

reaction mixture was filtered through Celite. After flash

column chromatography on silica gel (10:1 hexane:ethyl acetate

to remove fluorous toluene and then 2:1 hexane:ethyl acetate

to remove the product), (2S,3S,7R,11R)-3,7,11-trimethyl-

tridecan-2-ol SSRR-24 was isolated as a colorless oil (30 mg,

97%).

General Procedure 13. Propionylation. (1S,2S,6R,10R)-

Propionic Acid 1,2,6,10-Tetramethyldodecyl Ester SSRR-

1. Propionyl chloride (49 µL, 0.56 mmol) was added to a

solution of (2S,3S,7R,11R)-3,7,11-trimethyltridecan-2-ol SSRR-

24 (16 mg, 0.07 mmol) in dichloromethane (3 mL). After the

mixture was stirred at room temperature for 12 h, PS-

trisamine (4.11 mmol/g, 476 mg, 1.96 mmol) was added. After

gentle stirring at room temperature for 4 h, the reaction mix-

ture was filtered, concentrated, and dried to get (1S,2S,6R,10R)-

propionic acid 1,2,6,10-tetramethyldodecyl ester SSRR-1 as a

colorless oil (20 mg, 100%).

All of the other 15 fluorous PMB ethers of 23 were detagged

by general procedure 12. The yields of all 15 reactions are as

follows: (2R,3S,7R,11R)-3,7,11-trimethyltridecan-2-ol RSRR-

24 (31 mg, 89%), (2S,3R,7R,11R)-3,7,11-trimethyltridecan-2-

ol SRRR-24 (33 mg, 96%), (2R,3R,7R,11R)-3,7,11-trimethyl-

tridecan-2-ol RRRR-24 (29 mg, 87%), (2S,3S,7R,11S)-

3,7,11-trimethyltridecan-2-ol SSRS-24 (28 mg, 98%), (2R,3S,

7R,11S)-3,7,11-trimethyltridecan-2-ol RSRS-24 (24 mg, 80%),

(2S,3R,7R,11S)-3,7,11-trimethyltridecan-2-ol SRRS-24 (30 mg,

97%), (2R,3R,7R,11S)-3,7,11-trimethyltridecan-2-ol RRRS-24

(26 mg, 85%), (2S,3S,7S,11R)-3,7,11-trimethyltridecan-2-ol

SSSR-24 (36 mg, 96%), (2R,3S,7S,11R)-3,7,11-trimethyltri-

decan-2-ol RSSR-24 (35 mg, 99%), (2S,3R,7S,11R)-3,7,11-

trimethyltridecan-2-ol SRSR-24 (35 mg, 99%), (2R,3R,7S,11R)-

3,7,11-trimethyltridecan-2-ol RRSR-24 (35 mg, 99%), (2S,3S,7S,

11S)-3,7,11-trimethyltridecan-2-ol SSSS-24 (31 mg, 94%),

(2R,3S,7S,11S)-3,7,11-trimethyltridecan-2-ol RSSS-24 (27 mg,

78%), (2S,3R,7S,11S)-3,7,11-trimethyltridecan-2-ol SRSS-24

(32 mg, 99%), (2R,3SR,7S,11S)-3,7,11-trimethyltridecan-2-ol

RRSS-24 (28 mg, 87%).

All of the other 15 stereoisomers of 24 were propionylated

by general procedure 13. The yields of all 15 reactions are as

follows: (1R,2S,6R,10R)-propionic acid 1,2,6,10-tetramethyl-

dodecyl ester RSRR-1 (18 mg, 98%), (1S,2R,6R,10R)-propionic

acid 1,2,6,10-tetramethyldodecyl ester SRRR-1 (18 mg, 98%),

(1R,2R,6R,10R)-propionic acid 1,2,6,10-tetramethyldodecyl es-

ter RRRR-1 (20 mg, 96%), (1S,2S,6R,10S)-propionic acid

1,2,6,10-tetramethyldodecyl ester SSRS-1 (18 mg, 97%),

(1R,2S,6R,10S)-propionic acid 1,2,6,10-tetramethyldodecyl es-

ter RSRS-1 (17 mg, 99%), (1S,2R,6R,10S)-propionic acid

1,2,6,10-tetramethyldodecyl ester SRRS-1 (16 mg, 93%),

(1R,2R,6R,10S)-propionic acid 1,2,6,10-tetramethyldodecyl es-

ter RRRS-1 (17 mg, 99%), (1S,2S,6S,10R)-propionic acid

1,2,6,10-tetramethyldodecyl ester SSSR-1 (23 mg, 98%),

(1R,2S,6S,10R)-propionic acid 1,2,6,10-tetramethyldodecyl es-

ter RSSR-1 (23 mg, 98%), (1S,2R,6S,10R)-propionic acid

1,2,6,10-tetramethyldodecyl ester SRSR-1 (21 mg, 90%),

(1R,2R,6S,10R)-propionic acid 1,2,6,10-tetramethyldodecyl es-

ter RRSR-1 (19 mg, 91%), (1S,2S,6S,10S)-propionic acid

1,2,6,10-tetramethyldodecyl ester SSSS-1 (18 mg, 91%),

(1R,2S,6S,10S)-propionic acid 1,2,6,10-tetramethyldodecyl

ester RSSS-1 (18 mg, 91%), (1S,2R,6S,10S)-propionic acid

1,2,6,10-tetramethyldodecyl ester SRSS-1 (18 mg, 91%),

(1R,2R,6S,10S)-propionic acid 1,2,6,10-tetramethyldodecyl es-

ter RRSS-1 (18 mg, 91%).

The structures and yields of all of the stereoisomers of 24

obtained by the detagging reactions are shown below.

¹H and ¹³C NMR data for all 16 stereoisomers of 1 are given

in Appendix 3 of the Supporting Information. Copies of the

¹H and ¹³C NMR spectra of the eight different diastereomers

of 1 are reproduced in Appendix 5 of the Supporting Informa-

tion.

Acknowledgment. We thank the National Insti-

tutes of Health for funding this work. M.J. thanks the

Humboldt Foundation for a postdoctoral fellowship. We

thank Dr. F.-M. Lin for recording the LC-NMR spectra.

Supporting Information Available: Additional experi-

mental and characterization details for all of the intermediates

described in the paper. This material is available free of charge

via the Internet at http://pubs.acs.org.

¹H and ¹³C NMR data for all 16 isomers of 24 are given in

1

Appendix 1 of the Supporting Information. Copies of the H

and ¹³C NMR spectra of the eight different diastereomers of

24 are reproduced in Appendix 4 of the Supporting Informa-

tion.

JO051526A

9462 J. Org. Chem., Vol. 70, No. 23, 2005

Article Doi

Synthesis of all 16 stereoisomers of pinesaw fly sex pheromones - Tools and tactics for solving problems in fluorous mixture synthesis

DOI: 10.1021/jo051526a

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