Application of stereoselective ether transfer to the synthesis of isotactic polyethers

Article abstract of DOI:10.1021/jo100094d

An efficient, convergent synthetic strategy has been developed which enables the synthesis of a series of naturally occurring isotactic polymethoxy compounds. Ether transfer followed by a hydride workup enables simultaneous, diastereoselective production of two methoxy centers in a single step. High yields and diastereoselectivity are observed even in stereochemically rich, polyoxygenated systems. Direct generation of bis-methyl ether moieties from methoxymethyl ethers minimizes the need for typical protective group strategies and the use of expensive methyl transfer reagents. Moreover, the simultaneous generation of a terminal primary iodide serves as a coupling partner for the generation of higher order congeners.

Full text of DOI:10.1021/jo100094d

pubs.acs.org/joc
Application of Stereoselective Ether Transfer to the Synthesis of
Isotactic Polyethers
Kai Liu, Joseph W. Arico, and Richard E. Taylor*
Department of Chemistry and Biochemistry and the Walther Cancer Research Center,
University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, Indiana 46556-5670.
taylor.61@nd.edu
Received January 22, 2010
An efficient, convergent synthetic strategy has been developed which enables the synthesis of a series
of naturally occurring isotactic polymethoxy compounds. Ether transfer followed by a hydride
workup enables simultaneous, diastereoselective production of two methoxy centers in a single step.
High yields and diastereoselectivity are observed even in stereochemically rich, polyoxygenated
systems. Direct generation of bis-methyl ether moieties from methoxymethyl ethers minimizes the
need for typical protective group strategies and the use of expensive methyl transfer reagents.
Moreover, the simultaneous generation of a terminal primary iodide serves as a coupling partner for
the generation of higher order congeners.
Introduction
Recently, we described a fundamentally new method of syn-
thesizing 1,3-syn-diol, 1,3-syn-diol monoethers, and orthogo-
nally protected 1,3-syn-diether derivatives from homoallylic
alkoxymethyl ethers.3 As shown in Scheme 1, activation with
iodine monochloride initiates stereoselective ether transfer
and provides an intermediate chloromethyl ether which
can be reduced in situ to provide access to 1,3-syn-diethers.
We envisioned the product, a primary iodide, as a synthetic
handle for the convergent construction of more complex
polyketide fragments. Herein, we report application of ether
transfer for the efficient assembly of isotactic polyether
structures.
Isotactic polymethoxy-1-alkenes constitute a family of natu-
ral products that have been found in terrestrial, tolytoxin-
producing blue-green algae.1 A combination of NMR and
mass spectra analyses provide the gross structure and relative
stereochemistry of these compounds shown in Figure 1. The
all-syn, repetitive pattern attracted many synthetic attempts
with a common strategy: classic methods applicable to poly-
ketide polyols, both convergent and linear, followed by protec-
ting group manipulation and global methyl ether formation
using a methyl transfer source.2
SCHEME 1. Ether Transfer and in Situ Hydride Reduction
FIGURE 1. Tolypothrix polyethers.
(1) (a) Desikachary, T. V. Cyanophyta 1959, 503. (b) Mynderse, J. S.;
Moore, R. E. Phytochemistry 1979, 18, 1181.
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Deschenes, D. J. Am. Chem. Soc. 1992, 114, 1090. (c) Carmeli, S.; Moore,
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Y.; Noguchi, H.; Suzuki, M. Tetrahedron 1991, 47, 4889. (e) Mori, Y.;
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Ota, T.; Suzuki, M. Tetrahedron Lett. 1990, 31, 2915. (g) Nakata, T.;
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J. Org. Chem. 2010, 75, 3953–3957 3953
DOI: 10.1021/jo100094d
r
Published on Web 05/19/2010
2010 American Chemical Society

Liu et al.
SCHEME 2. Synthesis of the Common Intermediate from
L-Malic Acid
JOCFeatured Article
FIGURE 2. Divergent-convergent strategy for modular assembly.
SCHEME 3. Alternative Route to the Common Intermediate via
Kinetic Resolution
Instead of a linear approach, a divergent-convergent stra-
tegy was designed, as shown in Figure 2, using epoxide 5 as
the common intermediate. The epoxide can be conveniently
converted to dithiane 7 and act as the right half of the target.
One the other hand, 5 is also the precursor for the MOM-
protected homoallylic alcohol (not shown here), which under
ICl treatment followed by reductive workup would then
afford primary iodide 6 as the left portion.
Results and Discussion
The synthesis of the common intermediate 5 started with
L-malic acid. Esterification4 followed by chelation-controlled
reduction5 produced a diol, which was then protected as the
acetonide. The methyl ester was then reduced under carefully
controlled conditions (1 equiv of DIBAL-H, -78 °C) to afford
aldehyde 8. Considering the lack of stability6 of the aldehyde,
it was used immediately for the subsequent allylation step.
Although an enantioselective allylation could be used, a dia-
stereorandom method proved to be more practical. Reaction
with allylmagnesium bromide produced a 1:1 mixture of dia-
stereomers which were separable by flash column chromato-
graphy. The anti-product 9b was successfully converted to
the syn-homoallylic alcohol 9a by an oxidation/reduction7
sequence. Protection with chloromethyl methyl ether (MOMCl)
and hydrolysis of the acetonide restored the diol without
harm to the MOM group. One-pot conversion8 of the 1,2-
diol to the epoxide completed the synthesis of the common
intermediate 5 in eight steps (Scheme 2).
SCHEME 4. Coupling Partners Prepared from a Common
Intermediate
iodine-induced carbonate cyclization9,11 to produce iodo-
carbonate rac-11 with excellent diastereoselectivity (dr 15:1
by 1H NMR). Solvolysis of the carbonate led to the corres-
ponding epoxide. The efficiency of this particular route was
further enhanced by performing both operations in a single
pot process. The secondary alcohol was then protected as a
MOM ether (rac-5). Hydrolytic kinetic resolution12 using
Jacobsen’s cobalt-salen complex finished the alternative
synthesis of common intermediate 5 with >99% ee in just
four steps (Scheme 3).
Alternatively, 5 can also be efficiently made by a simple
sequence through asymmetric resolution.9 Commercially avail-
able hepta-1,6-dien-4-ol10 (10) was desymmetrized using
(4) Gaunt, M. J.; Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook, D. F.;
Ley, S. V. Org. Lett. 2003, 5, 4819.
For the construction of the left-hand portion, epoxide 5
was reacted with lithium dibutyl cuprate13 and the resulting
secondary alcohol was subsequently converted to its methyl
ether. ICl-induced methyl ether transfer with reductive workup
demonstrated satisfactory efficiency, producing iodide 6 as a
single diastereomer (Scheme 4). In a complementary fashion,
epoxide 5 was opened by 2-lithio-1,3-dithiane to afford
alcohol 13, which was converted to 7 (Scheme 4).
(5) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetra-
hedron 1992, 48, 4067.
(6) Kocienski, P. J.; Yeates, C.; Street, S. D. A.; Campbell, S. F. J. Chem.
Soc., Perkin Trans. 1 1987, 2183.
(7) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett.
1988, 29, 5419.
(8) (a) Murthy, V. S.; Gaitonde, A. S.; Rao, S. P. Synth. Commun. 1993,
23, 285. (b) Rao, A. V. R.; Murthy, V. S.; Sharma, G. V. M. Tetrahedron Lett.
1995, 36, 139.
(9) Kim, Y.-J.; Tae, J. Synlett 2006, 61.
(10) Parks, B. W.; Gilbertson, R. D.; Domaille, D. W.; Hutchison, J. E.
J. Org. Chem. 2006, 71, 9622.
(11) (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.;
Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013–4018. (b) Butler, D. E.; Deering,
C. F.; Millar, A.; Nanninga, T. N.; Roth, B. D. (Warner-Lambert Co.) US Patent
(12) 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.
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5,245,047. (c) Radl, S.; Stach, J.; Hajicek, J. Tetrahedron Lett. 2002, 43, 2087.
(13) Mori, Y.; Kohchi, Y.; Suzuki, M. J. Org. Chem. 1991, 56, 631.
3954 J. Org. Chem. Vol. 75, No. 12, 2010

Liu et al.
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SCHEME 5. Dithiane-Based Fragment Assembly and Completion of the Hexaether
SCHEME 6. Efficient Late-Stage Ether Transfer and Terminal Functionalization
Deprotonation14 of dithiane 7 was not effective with tra-
ditional bases. However, the Schlosser-type base developed
by Lipshutz15 induced full deprotonation (evidenced by
quantitative methylation with MeI), and the coupling reac-
tion with iodide 6 gave adduct 14 in 50% yield as shown in
Scheme 5. Sequential deprotection of the dithiane and the
PMB ether followed by diastereoselective reduction16 of
β-hydroxyketone 15 and methylation provided pentamethyl
ether 16. This compound was readily converted to Tolypothrix
hexaether by acidic removal of the MOM group and sub-
sequent methylation.
Compared to the homoallylic methoxymethyl ether that
led to 6, compound 16 contains four additional methoxy
groups. Successful ether transfer within 16 would be the key
to our synthetic strategy toward more complex congeners.
We were delighted to find that the reaction occurred with
high yields, and iodide 17 was isolated as a single diastereo-
mer in 87% yield (Scheme 6). This example provided further
evidence17 that the ether transfer method can be efficient
even when performed in a polyoxygenated environment.
We fully expected a simple vinylation of 17 would com-
plete the synthesis of the heptaether (n=5). Disappointingly,
a variety of conditions failed to affect the desired coupling.
Classic Cu(I)-promoted Grignard18 or a higher order cuprate19
provided only trace amounts of the natural product, while
Negishi coupling under the conditions of Fu20 or Knochel21
resulted in dehalogenation or no reaction, respectively. A two-
step ethynylation-Lindlar reduction approach to the natu-
ral product was also unsuccessful: the use of sodium acety-
lide, CuI-promoted (trimethylsilyl)acetylene coupling22 or
lithium trimethylsilylacetylide (either with23 or without Pd
catalysis) to displace the terminal iodide resulted only in de-
composition. Despite the failure in homologating 17 to the
terminal alkene in reasonable yield, the primary iodide is ex-
pected to exhibit excellent electrophilicity toward dithiane-
based nucleophiles for further elongation (i.e., 17þ7, Scheme 5).
However, it was also found that iodide 17 underwent quanti-
tative elimination24 with n-BuLi to afford an alternative route
to the Tolypothrix hexaether.
Conclusions
In summary, we have successfully utilized our ICl-induced
methyl ether transfer for the construction of isotactic poly-
methoxy structural units. In situ reduction of an intermedi-
ate chloromethyl ether provided stereospecific formation of
bis-methyl ether with a 1,3-syn relationship. The resulting
primary iodide proved to be a good coupling partner for
dithiane-based nucleophiles providing a strategy for the
generation of higher order congeners of the Tolypothrix
polyethers. Additional applications of the ether transfer
(14) Deprotonation of 2-substituted-1,3-dithianes are often substrate-
specific. For summaries and related studies, see: (a) Smith, A. B., III;
Adams, D. M. Acc. Chem. Res. 2004, 37, 365. (b) Ide, M.; Yasuda, M.;
Nakata, M. Synlett 1998, 936. (c) Ide, M.; Nakata, M. Bull. Chem. Soc. Jpn.
1999, 72, 2491.
(15) Lipshutz, B. H.; Garcia, E. Tetrahedron Lett. 1990, 31, 7261.
(16) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
(19) (a) Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. J. Am. Chem. Soc.
1981, 103, 7672. (b) Lipshutz, B. H.; Kozlowski, J. A.; Wilhelm, R. S. J. Am.
Chem. Soc. 1982, 104, 2305.
ꢁ
Repic, O.; Shapiro, M. J. Chem. Lett. 1987, 16, 1923.
(17) For previous examples that used an ether-transfer method toward
syntheses of complex molecules, see: (a) Kartika, R.; Taylor, R. E. Angew.
Chem., Int. Ed. 2007, 46, 6874. (b) Kartika, R.; Gruffi, T. R.; Taylor, R. E.
Org. Lett. 2008, 10, 5047.
(20) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527.
(21) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
(22) Inack-Ngi, S.; Rahmani, R.; Commeiras, L.; Chouraqui, G.; Thibonnet,
^
J.; Duchene, A.; Abarbri, M.; Parrain, J.-L. Adv. Synth. Catal. 2009, 351, 779.
(18) Derguini-Boumechal, F.; Linstrumelle, G. Tetrahedron Lett. 1976,
36, 3225.
(23) Yang, L.-M.; Huang, L.-F.; Luh, T.-Y. Org. Lett. 2004, 6 (9), 1461.
(24) Maeda, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1996, 61, 6770.
J. Org. Chem. Vol. 75, No. 12, 2010 3955

Liu et al.
JOCFeatured Article
reaction are currently under exploration in our laboratory
and will be reported in due course.
CHCl3); 1H NMR (500 MHz, CDCl3) δH 0.89 (3H, t, J=6.82 Hz),
1.25-1.35 (8H), 1.40-1.59 (2H, m), 1.80-1.90 (2H, m), 3.10-
3.22 (1H, m), 3.25-3.50 (4H) 3.38 (3H, s), 3.39 (3H, s), 3.40 (3H,
s); 13C NMR (125 MHz, CDCl3) δC 10.9, 14.3, 22.9, 24.8, 32.3,
33.5, 37.8, 38.5, 56.5, 56.7, 56.8, 75.3, 76.4, 78.0; HRMS calcd
for C14H29IO3 [M þ H]þ 373.1248, found 373.1234.
Experimental Section
1
General Experimental Methods. H NMR spectra were col-
lected at 300 or 500 MHz, and 13C NMR spectra were collected
at 75 or 126 MHz. Chemical shifts for 1H and 13C NMR spectra
are reported in parts per million (ppm) relative to residual chloro-
form (7.27, 77.23 ppm) in CDCl3, and coupling constants are
reported in hertz (Hz). Mass spectra were obtained employing
the fast atom bombardment (FAB) ionization method. Optical
rotation was measured on a polarimeter in a 1 dm cell. Reagents
were purchased commercially and used without further puri-
fication. Reactions were performed under nitrogen atmo-
sphere. Solvents were purified by standard procedures. Column
chromatography was performed using silica gel (230-400 mesh).
Thin-layer chromatography was performed on aluminum-backed
silica gel plates (250 μm thickness), and spots were visualized
with UV light (254 nm), p-anisaldehyde, or potassium perman-
ganate stain.
(2S,4S)-1-(1,3-Dithian-2-yl)-4-(methoxymethoxy)hept-6-en-2-ol
(13). To a stirred solution of 1,3-dithiane (635 mg, 5.28 mmol) in
THF (10 mL) at 0 °C under N2 atmosphere was added n-BuLi
(2.1 M in hexanes, 2.3 mL, 4.88 mmol) dropwise. After 20 min,
epoxide 5 (700 mg, 4.06 mmol) in THF (5 mL) was added drop-
wise. TLC analysis indicated complete reaction after 2 h, and
satd NH4Cl (20 mL) was added to quench the reaction. Diethyl
ether was used to extract twice (2 ꢀ 50 mL), and the combined
organic layers were washed with NaHCO3 and brine, dried with
MgSO4, and filtered. The solvent was removed under reduced
pressure, and flash column chromatography (20f30% EtOAc
in hexanes) yielded 13 as a colorless liquid (926 mg, 3.17 mmol,
78%): [R]20 = þ31.5 (c 1.0, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δH 1.52-1.70 (2H, m), 1.72-1.90 (3H), 2.02-2.12 (1H,
m), 2.27-2.33 (2H, m), 2.72-2.93 (4H), 3.25 (1H, dd, J = 2.73,
0.57 Hz), 3.35 (3H, s), 3.77-3.87 (1H, m), 3.99-4.09 (1H, m),
4.24 (1H, dd, J=9.47, 4.95 Hz), 4.61 (2H, d, J=6.85 Hz), 4.69
(2H, d, J=6.85 Hz), 5.01-5.08 (2H, m), 5.66-5.80 (1H, m); 13C
NMR (125 MHz, CDCl3) δC 26.0, 30.0, 30.5, 39.0, 41.4, 43.1,
43.8, 56.0, 67.2, 76.6, 95.4, 117.9, 133.8; HRMS calcd for C13H24-
NaO3S2 [M þNa]þ 315.1059, found 315.1058
(2R,4R,6R)-1-Iodo-2,4,6-trimethoxyundecane (6). To a stirred
diethyl ether suspension (50 mL) containing CuI (2.59 g, 13.6
mmol) was added n-BuLi (2.5 M in hexanes, 10.9 mL, 27.2 mmol)
at -20 °C. The solution turned black immediately. A solution of
5 (1.56 g, 9.06 mmol) in 10 mL of diethyl ether was then added
dropwise. After 10 min, TLC indicated complete reaction, and
cold water was added. Minimum amount of saturated ammo-
nium hydroxide was used to achieve clear separation of the two
phases, and the aqueous phase was extracted with diethyl ether
for a second time. The combined organic layers were then
washed with NaHCO3 and dried with MgSO4. After removal
of the solvents at reduced pressure and flash column chromato-
graphy, (4S,6R)-4-(methoxymethoxy)undec-1-en-6-ol (2.00 g,
8.70 mmol, 96%) was isolated as a colorless oil. This alcohol was
then dissolved in THF (40 mL) in a 100 mL round-bottomed
flask equipped with a condenser. Under nitrogen gas environ-
ment and with magnetic stirring, NaH (418 mg, 17.4 mmol) was
added in several batches over 1 min. After 20 min, MeI (1 mL)
was added, and the solution was gently heated to maintain a
mild reflux. TLC analysis indicated complete methylation after
4 h. The flask was allowed to cool to room temperature, and cold
water was added very carefully along the side of the flask into the
stirred solution until all of the hydride was destroyed. More
water (20 mL) was added to dissolve the inorganic byproduct
and to achieve clear phase separation. The organic layer was sepa-
rated, and the aqueous layer was extracted with diethyl ether
for a second time. The combined organic layers were washed
with brine, dried with MgSO4, filtered, and concentrated under
reduced pressure. After flash column chromatography, (4S,6R)-
4-(methoxymethoxy)-6-methoxyundec-1-ene (1.83 g, 8.00 mmol,
92%) was obtained as a colorless oil. This alkene was dissolved
in toluene (100 mL), and the stirred solution was cooled to -78 °C.
ICl (1 M in dichloromethane, 8.8 mL, 8.8 mmol) was added
dropwise. After an additional 15 min of stirring, LiBH4 (2 M
solution in THF, 8.8 mL, 17.6 mmol) was added dropwise, and
gentle foaming was observed while the red-brown color of the
solution quickly disappeared. Aqueous NH4Cl (about 10 mL)
was added, and the mixture was stirred at room temperature.
The whole content in the flask was then poured into a 250 mL
separatory funnel. When gas evolution stopped, the organic
layer was collected, and the aqueous layer was extracted with
diethyl ether for a second time. The combined organic layers were
washed with saturated NaHCO3 and brine, dried with MgSO4,
filtered, and concentrated under reduced pressure. After flash
column chromatography on silica gel (5% EtOAc/hexane), iodide
6 (1.54 g, 4.06 mmol, 51%, 75% based on recovered starting
material) was isolated as a colorless oil: [R]20D =-14.61 (c 2.3,
2-((2S,4S)-2-(4-Methoxybenzyloxy)-4-(methoxymethoxy)hept-
6-enyl)-1,3-dithiane (7). To a stirred solution of 13 (330 mg, 1.13
mmol) in THF (5 mL) was added NaH (54 mg, 2.3 mmol) at 0 °C.
After 30 min, PMBCl (0.28 mL, 2.03 mmol) was added drop-
wise, and a few crystals of tetrabutylammonium iodide were
added. The solution was heated to reflux for 16 h before TLC
analysis indicated complete reaction. Saturated NaHCO3 solu-
tion was added to quench the reaction, and diethyl ether was
used to extract the product twice. The combined organic layers
were washed with brine, dried with MgSO4, and filtered. Remo-
val of solvent under reduced pressure followed by flash column
chromatography gave 7 as a colorless, viscous oil (420 mg, 1.02
mmol,90%):[R]20D=þ19.76 (c0.85, CHCl3);1HNMR(500MHz,
CDCl3) δH 1.59-1.67 (1H, m), 1.78-1.98 (4H), 2.04-2.14 (1H,
m), 2.25-2.34 (2H, m), 2.75-2.89 (4H), 3.38 (3H, s), 3.65-3.73
(1H, m), 3.79 (3H, s), 3.80-3.88 (1H, m), 4.17 (1H, dd, J=6.20,
8.27 Hz), 4.43 (2H, d, J = 10.99), 4.49 (2H, d, J = 10.99), 4.64
(2H, d, J = 6.91), 4.67 (2H, d, J = 6.91), 5.04-5.12 (2H, m),
5.72-5.87 (1H, m); 13C NMR (125 MHz, CDCl3) δC 26.1, 30.1,
30.4, 38.9, 39.2, 40.4, 44.0, 55.3, 55.9, 70.8, 72.5, 74.0, 95.7, 113.8,
117.6, 129.6, 130.8, 134.3, 159.2; HRMS calcd for C21H32O4S2
[M þ Na]þ 435.1615, found 435.1634.
2-((2S,4S)-2-(4-Methoxybenzyloxy)-4-(methoxymethoxy)hept-
6-enyl)-2-((2R,4R,6R)-2,4,6-trimethoxyundecyl)-1,3-dithiane (14).
An oven-dried flask containing finely powdered t-BuONa (197 mg,
2.05 mmol) under Ar atmosphere was charged with hexanes
(4 mL) and n-BuLi (2.0 M in hexanes, 0.96 mL, 1.92 mmol) at 0 °C.
After 30 min, the flask was cooled to -78 °C, and 7 (690 mg, 1.67
mmol) in THF (4 mL) was added via syringe. The solution turned
orange immediately. After 2 min, 6 (478 mg, 1.28 mmol) in THF
(4 mL) was added by syringe and the mixture allowed to stir for
another 10 min. Saturated NH4Cl (20 mL) was added to quench
the reaction, and ether (2ꢀ30 mL) was used to extract. The com-
bined organic layers were washed with satd NaHCO3 and brine,
dried with MgSO4, and filtered. Removal of solvent under redu-
ced pressure followed by column chromatography (5%f25%
EtOAc in hexanes) yielded 14 as a colorless oil (410 mg, 50%).
Unreacted 7 (174 mg) and 6 (180 mg, 37%) were also recovered:
1H NMR (500 MHz, CDCl3) δH 0.90 (3H, t, J = 6.80 Hz),
1.28-1.36 (6H, m), 1.47-1.54 (3H, m), 1.57-1.64 (1H, m),
1.75-1.95 (6H, m), 2.11-2.24 (3H, m), 2.27-2.43 (3H, m),
3956 J. Org. Chem. Vol. 75, No. 12, 2010

Liu et al.
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2.77-2.82 (2H, m), 2.78-2.90 (2H, m), 3.21-3.27 (1H, m), 3.30
(3H, s), 3.31 (3H, s), 3.32 (3H, s), 3.35-2.39 (1H, m), 3.40 (3H, s),
3.66-3.71 (1H, m), 3.73-3.78 (1H, m), 3.79 (3H, s), 3.83-3.90
(1H, m), 4.42 (2H, d, J=10.40 Hz), 4.50 (2H, d, J=10.40 Hz),
4.69 (2H, d, J=6.85 Hz), 4.73 (2H, d, J=6.85 Hz), 5.06-5.13
(2H, m), 5.78-5.88 (1H, m), 6.83-6.87 (2H, m), 7.27-7.32 (2H,
m); 13C NMR (125 MHz, CDCl3) δC 14.3, 22.86, 24.9, 25.2, 26.5,
26.9, 32.2, 33.7, 38.0, 38.9, 39.8, 40.1, 44.9, 45.4, 52.5, 55.5, 55.9,
56.1, 56.4, 56.5, 70.4, 74.3, 75.5, 76.0, 78.1, 96.2, 113.8, 117.6,
129.8, 131.1, 134.8, 159.2; HRMS calcd for C35H60O7S2Na [Mþ
Na]þ 679.3673, found 679.3682.
(4S,6S,10R,12R,14R)-6-Hydroxy-10,12,14-trimethoxy-4-
(methoxymethoxy)nonadec-1-en-8-one (15). To a stirred solution
of 14 (174 mg, 0.27 mmol) in CH3CN (8 mL) at room tempera-
ture were added H2O (2 mL), MeI (3 mL) and CaCO3 (358 mg).
The suspension was allowed to stir for 12 h and filtered through
a pad of Celite. The solvent was removed under reduced pressure
to afford a colorless liquid. The liquid was then dissolved in
CH2Cl2 (20 mL). To this solution were added DDQ (67.3 mg,
0.30 mol) and H2O (1 mL) at 0 °C. After 1 h, saturated Na2S2O3
(5 mL) was added, and diethyl ether (2 ꢀ 20 mL) was used to
extract. The combined organic layers were washed with NaH-
CO3, dried with MgSO4, and filtered. Removal of solvent under
reduced pressure followed by flash column chromatography
(40% EtOAc in hexanes) afforded ketone 15 as a colorless oil
(95 mg, 0.21 mmol, 80% two steps): 1H NMR (500 MHz, CDCl3)
134.7; HRMS calcd for C26H52O7Na [M þNa]þ 499.3598, found
499.3605.
(2R,4R,6R,8R,10R,12R,14R)-1-Iodo-2,4,6,8,10,12,14-hepta-
methoxynonadecane (17). To a stirred solution of 16 (19 mg, 0.04
mol) in toluene at -78 °C was added ICl (1 M in dichloromethane,
0.06 mL, 0.06 mmol) dropwise. After 20 min, LiBH4 (2 M solu-
tion in THF, 0.04 mL, 0.08 mmol) was added, and the solution
turned colorless upon completion. The dry ice bath was removed,
and the reaction was allowed to warm to room temperature over
15 min. HCl (1 M, 10 mL) was used to quench the extra hydride,
and diethyl ether (2 ꢀ 20 mL) was used to extract the product
twice. The combined organic layers were washed with NaHCO3
and brine, dried with MgSO4, and filtered. Removal of the sol-
vent under reduced pressure followed by flash column chromato-
graphy (2% MeOH in dichloromethane) afforded 17 as colorless
liquid (21 mg, 0.0347 mmol, 87%): [R]20D=-5.33 (c1.05, CHCl3);
1H NMR (500 MHz, CDCl3) δH 0.89 (3H, t, J = 6.82 Hz),
1.25-1.35 (8H), 1.46-1.66 (6H), 1.75-1.86 (6H), 3.25-3.45
(7H), 3.31 (3 H, s), 3.32 (12H, s), 3.33 (3H, s), 3.36 (3H, s),
3.36-3.45 (2H, m); 13C NMR (125 MHz, CDCl3) δC 10.7, 14.3,
22.9, 24.8, 32.3, 33.6, 38.08, 38.09, 38.10, 38.30, 38.35, 38.5,
56.46, 56.47, 56.49, 56.52, 56.53, 56.6, 56.9, 75.2, 75.40, 75.41,
75.5, 75.6, 76.4, 78.1; HRMS calcd for C26H53IO7 [M þ H]þ
605.2914, found 605.2910.
(4S,6S,8S,10R,12R,14R)-4,6,8,10,12,14-Hexamethoxynonadec-
1-ene. To a stirred solution of 17 (7.1 mg, 0.01 mmol) in hexanes
at -30 °C was added 0.1 mL of n-BuLi (2.2 M in hexanes). TLC
analysis indicated immediate reaction, and H2O was added to
quench. The organic layer was washed with brine, dried with
MgSO4, filtered, and concentrated under reduced pressure to
afford Tolypothrix hexaether (5.2 mg, 0.01 mmol, 99%) as a
colorless oil without further purification.
Alternatively, the hexaether was produced by the following
two-step sequence. To a stirred solution of 16 (8.0 mg, 0.02 mmol)
in MeOH (2 mL) were added two drops of concd HCl. The
reaction was stirred at 50 °C for 15 min, and TLC analysis indi-
cated complete reaction. All volatile components were removed
under reduced pressure. The crude product was subjected to
methylation conditions similar to those used in the preparation
of 16. The reaction was finished in 12 h of reflux for this sub-
strate. Column chromatography (2% MeOH in CH2Cl2) pro-
duced Tolypothrix hexaether as a colorless oil (7.0 mg, 0.02 mmol,
93% two steps): [R]20D =þ3.33 (c 0.39, CHCl3); 1H NMR (500
MHz, CDCl3) δH 0.89 (3H, t, J = 6.82 Hz), 1.25-1.35 (6H),
1.46-1.66 (6H), 1.75-1.85 (6H), 2.27-2.43 (2H, m), 3.25-3.45
(6H), 3.31 (12H, s), 3.32 (3H, s), 3.35 (3H, s), 5.07-5.14 (2H, m),
5.79-5.87 (1H, m); 13C NMR (125 MHz, CDCl3) δC 32.3, 33.6,
37.8, 37.9, 38.1, 38.3, 38.38, 38.40, 56.42, 56.44, 56.47, 56.48,
56.52, 56.6, 75.49, 75.51, 75.52, 75.7, 77.5, 78.1, 117.5, 134.6;
HRMS calcd for C25H50O6 [MþH]þ 447.3686, found 447.3695.
δ
H 0.90 (3H, t, J=6.86 Hz), 1.28-1.38 (6H), 1.46-1.55 (2H, m),
1.59-1.68 (3H), 1.72-1.85 (3H), 2.32-2.40 (2H), 2.57-2.75
(4H), 3.22-3.28 (1H, m), 3.30 (3H, s), 3.31 (3H, s), 3.31 (3H, s),
3.37-3.41 (1H, m), 3.39 (3H, s), 3.49 (2H, br. d, J = 2.31 Hz),
3.81-3.85 (1H, s), 3.85-3.91 (1H, s), 4.20-4.27 (1H, s), 4.66
(1H, d, J=6.89 Hz), 4.72 (1H, d, J=6.89 Hz), 5.07-5.12 (2H,
m), 5.75-5.85 (1H, s); 13C NMR (125 MHz, CDCl3) δC 14.3, 22.9,
24.8, 32.2, 33.6, 37.7, 37.7, 37.8, 38.9, 40.8, 48.3, 50.8, 56.0, 56.3, 56.4,
57.0, 66.4, 74.8, 75.3, 75.8, 78.0, 95.5, 117.9, 134.2, 210.1; HRMS
calcd for C24H46NaO7 [MþNa]þ 469.3136, found 469.3131.
(4S,6R,8R,10R,12R,14R)-6,8,10,12,14-Pentamethoxy-4-(meth-
oxymethoxy)nonadec-1-ene (16). A stirred solution of 15 (90.0 mg,
0.20 mmol) in THF (5 mL) and MeOH (1 mL) was cooled to -78 °C
before Et2BOMe (1.0 M in THF, 0.81 mL, 0.81 mmol) was added
dropwise. After 15 min, sodium borohydride (15.2 mg, 0.40 mmol)
was added in one batch. TLC analysis after 10 min indicated com-
plete reaction. The solution was allowed to warm to room tem-
perature, and 1 mL of AcOH was added to quench the reaction,
followed by addition of H2O. Ethyl acetate was used to extract the
product (2 ꢀ 15 mL). The combined organic layers were washed
with NaHCO3 and brine, dried with MgSO4, filtered, and concen-
trated under reduced pressure. The crude product (89 mg) was a
colorless oil and contained only one diastereomer by NMR analy-
sis. To a stirred solution of the crude diol (38 mg, 0.085 mmol) in
THF (3 mL) were added NaH (100 mg, excess) and MeI (3 mL).
The solution was then heated to reflux for 48 h. Water was added
very carefully to destroy extra NaH, and diethyl ether was used to
extract the product. The organic layer was then dried with MgSO4
and filtered. Removal of the solvent under reduced pressure follo-
wed by flash column chromatography (2% MeOH in CH2Cl2)
afforded 16 as a colorless liquid (94.9 mg, 0.20 mmol, 99% two
steps): [R]20D=þ1.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
δH 0.89 (3H, t, J = 6.82 Hz), 1.25-1.35 (6H), 1.46-1.66 (6H),
1.75-1.85 (6H), 2.27-2.43 (2H, m), 3.25-3.45 (5H, m), 3.29 (3H,
s), 3.30 (9H), 3.31 (3H, s), 3.38 (3H, s), 3.73-3.78 (1H, s), 4.65 (1H,
d, J = 6.89 Hz), 4.67 (1H, d, J = 6.89 Hz), 5.07-5.14 (2H, m),
5.79-5.88 (1H, m); 13C NMR (125 MHz, CDCl3) δC 14.3, 22.9,
24.8, 32.3, 33.6, 38.1, 38.2, 38.3, 38.4, 38.6, 39.2, 55.8, 56.3, 56.42,
56.44, 56.47, 56.48, 74.5, 75.36, 75.38, 75.5, 75.6, 78.1, 95.8, 117.6,
Acknowledgment. The Department of Chemistry & Bio-
chemistry at University of Notre Dame is acknowledged for
support of this work through a Reilly Fellowship (K.L.).
Partial support provided by funds from the National Insti-
tutes of Health, National Institute of General Medical
Sciences (GM084922). J.W.A. thanks the Walther Cancer
Research Center (Notre Dame) for fellowship support.
Supporting Information Available: Full experimental and
characterization data for compounds 10, 11, and rac-5, (S)-5, as
well as proton and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 3957