Synthesis of plakortethers F and G

Article abstract of DOI:10.1021/jo901203s

(Chemical Equation Presented) Synthesis of plakortethers F and G has been performed by taking advantage of the symmetry in the structure. The structures of the prepared compounds have been confirmed by COSY, 1D NOE, and chemical transformation studies. Th

Full text of DOI:10.1021/jo901203s

pubs.acs.org/joc
Synthesis of Plakortethers F and G
Jinu P. John, Joshua Jost, and Alexei V. Novikov*
University of North Dakota, Chemistry Department, 151 Cornell Street, Stop 9024, Grand Forks,
North Dakota 58202
anovikov@chem.und.edu
Received June 7, 2009
Synthesis of plakortethers F and G has been performed by taking advantage of the symmetry in the
structure. The structures of the prepared compounds have been confirmed by COSY, 1D NOE, and
chemical transformation studies. The synthetic plakortether F was found to match the natural
product by all physical data. The synthetic plakortether G exhibited several disagreements in 13C
NMR data with the reported values. However, on the basis of an extremely close match in appearance
1
1
of its H NMR spectrum to the obtained H NMR spectrum of the natural product, as well as
matching optical rotations, the two compounds are believed to be identical.
Introduction
Recently, a set of unusual secondary metabolites of pla-
kortin1 have been isolated from Plakortis simplex and have
shown a selective cytotoxic activity against the RAW 264-6
cell line.6 These new compounds, named plakortethers A-G,
possessed the parent plakortin carbon skeleton but featured
additional functionality, most notably an unusual highly
substituted tetrahydrofuran fragment. Later, a related alkaloid
simplakidine A was isolated from the same source, addition-
ally containing a pyridine ring (Figure 1).7 While generally
tetrahydrofurans are very commonly encountered in natural
products, tetrahydrofurans with this density of substitution
(2,2,4,5-tetrasubstituted) are much more rare.
Sponges of the genus Plakortis have served as the source of
a number of related natural products. These natural pro-
ducts have exhibited several interesting types of biological
activity, such as antimalarial,1 antibacterial,2 and antitu-
mor.3 Structurally, these are poliketides (often butyrate
derived) that have been known to contain cyclic peroxide
and lactone functionalities, as well as, in some cases, an all-
carbon bicyclic framework, evidently resulting from bio-
synthetic intramolecular Diels-Alder reaction.4 These
compounds enjoyed significant attention as targets for total
synthesis.5
No synthesis of plakortethers A-G has been reported to
date. The following report describes a preparation of the
proposed structures of plakortethers F and G by taking
advantage of the symmetry in the structure.
(1) Higgs, M. D.; Faulkner, D. J. J. Org. Chem. 1978, 43, 3454.
(2) Fattorusso, E.; Parapini, S.; Campagnuolo, C.; Basilico, N.;
Taglialatela-Scafati, O.; Taramelli, D. J. Antimicrob. Chemother. 2002, 50, 883.
(3) Pettit, G. R.; Nogawa, T.; Knight, J. C.; Doubek, D. L.; Hooper,
J. N. A. J. Nat. Prod. 2004, 67, 1611.
(4) Huang, X.; Soest, R. V.; Roberge, M.; Andersen, R. J. Org. Lett. 2004,
6, 75.
Results and Discussion
(5) Total syntheses reported: (a) Kirkham, J. E. D.; Lee, A. V.; Baldwin,
J. E. Chem. Commun. 2006, 2863. (b) Mehta, G.; Kundu, U. K. Org. Lett.
2005, 7, 5569. (c) Akiyama, M.; Isoda, Y.; Nishimoto, M.; Narazaki, M.;
Oka, H. Tetrahedron Lett. 2006, 47, 2287. (d) Yao, G.; Steliou, K. Org. Lett.
2002, 4, 485. (e) Paddon-jones, G. C.; Hungerford, N. L.; Hayes, P.;
Kitching, W. Org. Lett. 1999, 1, 1905. (f ) Kowashi, S.; Ogamino, T.; Kamei,
J.; Ishikawa, Y.; Nishiyama, S. Tetrahedron Lett. 2004, 45, 4393. (g)
Akiyama, M.; Isoda, Y.; Nishimoto, M.; Kobayashi, A.; Togawa, D.; Hirao,
N.; Kuboki, A.; Ohira, S. Tetrahedron Lett. 2005, 46, 7483.
Our approach to plakortethers F and G (1a and 1b,
Scheme 1) stemmed from the recognition of the partial
(6) Campagnuolo, C.; Fattorusso, E.; Taglialatela-Scafati, O.; Ianaro,
A.; Pisano, B. Eur. J. Org. Chem. 2002, 61.
(7) Campagnuolo, C.; Fattorusso, C.; Fattorusso, E.; Ianaro, A.; Pisano,
B.; Taglialatela-Scafati, O. Org. Lett. 2003, 5, 673.
DOI: 10.1021/jo901203s
r
Published on Web 07/17/2009
J. Org. Chem. 2009, 74, 6083–6091 6083
2009 American Chemical Society

John et al.
JOCArticle
SCHEME 1. Retrosynthetic Analysis of Plakortethers F and G
TABLE 1. Optimization of the Alkylation Step
FIGURE 1. Plakortethers and related compounds.
symmetry in the structures of these compounds. The dis-
connection of the 3-hydroxyester via acetate aldol and the
tetrahydrofuran ring via iodocyclization leads to a comple-
tely C2-symmetric intermediate that can be assembled via a
bis-alkylation of a conveniently allylic dihalide by a chiral
auxiliary modified butyrate (Scheme 1).
The synthesis was initiated via a bis-alkylation of 3-iodo-
2-(iodomethyl)prop-1-ene, 3 (X = I), obtained from the
commercial 3-chloro-2-(chloromethyl)prop-1-ene,8 by the
enolate of oxazalidinone 2 (Table 1). In the initial experi-
ments, low yields and poor reproducibility were observed,
producing only small amounts, if at all, of the desired bis-
alkylated product, 4, either with lithium or sodium enolates.
Isolation of the monoalkylated product 5, along with the
unsubstituted 4-benzyloxazolidin-2-one, 6, suggested a com-
petitive decomposition of the enolate, possibly by the ketene
pathway.9 Maintaining a low temperature (at or below
-50 °C) throughout the course of the reaction resolved this
problem (Table 1, entry 4). Isolation of small amounts of
unsubstituted 4-benzyloxazolidin-2-one, 6, indicated that
the enolate decomposition was still taking place, although
apparently at a slow enough rate to permit the target alkyla-
tion to happen. Under optimized conditions, the bis-alkyla-
tion product was cleanly obtained in 75% yield with no
detectable amount of undesired diastereomers.
The resulting C2-symmetric intermediate 4 was subjected
to iodolactonization using the standard conditions (I2-
NaHCO3-H2O-CH3CN).10 Slow formation of iodolac-
tones 8a,b was observed, along with several unidentified
byproducts. It was found that the use of I2 in THF-H2O,
followed by treatment with silica gel, provided a cleaner
reaction and superior yields. Under the latter conditions the
initial product that formed appeared to be acyclic iodohy-
drin 7.11 It could be observed in the crude reaction mixture,
but would very easily cyclize to lactones 8a,b, particularly in
the course of flash chromatography. Thus, it was converted
to the iodolactones by treatment with silica gel, and the
iodolactones were isolated. Under both conditions, iodolac-
tones 8a and 8b formed as a separable mixture of diastere-
omers in an approximately 1.5:1 ratio (Scheme 2).
yield (%)
entry X
conditionsa
4
5
6
1
2
3
4
Br NaHMDS, THF -78 f -25 °C, 8 hb
I
I
I
3
NDc 10
NaHMDS, THF -78 f -25 °C, 8-16 hb 0-2 50-60 10-15
LDA, THF -78 f -25 °C, 8 hb
NaHMDS, THF -55 °C, 16 h
0
75
20
0
6
5
aIn all cases, the reaction was carried out by addition of 3 to 2.5 equiv
of the enolate of 2 in THF. bAfter addition of 3 to the enolate at -78 °C,
the mixture was gradually (over ∼1.5 h) warmed to -25 °C and kept at
c
-25 °C for the remainder of the reaction time. Not determined. The
monoalkylated product appeared to form in substantial quantities but
could not be separated from unreacted 2 and characterized.
The major diastereomer 8a was hydrogenolyzed and then
reduced by sodium borohydride to provide the alcohol,
which was assigned configuration 10b on the basis of the
observed NOE correlation (Scheme 3).
Despite our hopes, the influence of the chiral auxiliary did
not bring the diastereoselectivity of iodocyclization to a
useful level. The possibility to improve the diastereoselec-
tivity via the change of the chiral auxiliary was briefly
explored but was not pursued any further due to a poor
availability of the chiral auxiliaries that are potentially
effective for this transformation.12 Instead, we decided to
exploit the symmetry of the structure. Since both diastereo-
mers of the alcohol (10a and 10b, Scheme 4) could be utilized,
thanks to their nearly symmetric nature, the diastereoselec-
tivity control was not necessary, as long as the diastereomers
could be separated.
Thus, starting with 4, the chiral auxiliaries were removed
by peroxide-assisted hydrolysis,13 producing diacid 11 that
readily and cleanly cyclized upon treatment with trifluoroa-
cetic acid at room temperature for 8 h. The resulting diaster-
eomeric lactonic acids 12a and 12b were obtained as a
mixture with the same ratio of approximately 1.5:1. This
ease of the cyclization of the diacid is notable, since, in
(8) Purchased from Acros Organics, product code 277070050.
(9) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(10) Silva, F. M. D.; Junior, J. J.; Mattos, M. C. D. Curr. Org. Synth.
2005, 2, 393.
(11) Curiously, the opposite trend was observed in iodocyclization of
amides: basic conditions tended to produce iodohydrins, while acidic pro-
duce lactones: Maligres, P. E.; Weissman, S. A.; Upadhyay, V.; Cianciosi,
S. J.; Reamer, R. A.; Purick, R. M.; Sager, J.; Rossen, K.; Eng, K. K.; Askin,
D.; Volante, R. P.; Reider, P. J. Tetrahedron 1996, 52, 3327.
(12) Moon, H.; Eisenberg, S. W. E.; Wilson, M. E.; Schore, N. E.; Kurth,
M. J. J. Org. Chem. 1994, 59, 6504.
(13) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28,
6141.
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John et al.
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SCHEME 2. Idocyclization of 4
SCHEME 3. Determination of Stereoselectivity in the Iodocy-
clization
SCHEME 5. Preparation of the Key Intermediates 16a and 16b
SCHEME 4. Simplification of the Sequence
involves formation of the mixed anhydride followed by its
reduction with sodium borohydride.15
Comparison of the NMR data confirmed that the ob-
served major diastereomer was equivalent to 10b, indicating
that the stereoselectivity of the cyclization was the same as in
the iodocyclization. Both alcohol 10a and its diastereomer
10b were then independently converted to the desired key
intermediates 16a and 16b (Scheme 5).
The major diastereomer of the alcohol 10b was oxidized to
the aldehyde and treated with p-toluenesulfonic acid in
methanol. Initially formed dimethyl acetal 14, which could
be observed in the reaction mixture and isolated from the
reaction mixture at incomplete conversions, upon longer
exposure to the reaction conditions was converted to cyclic
acetals 15a,b, apparently via an opening of the lactone and a
subsequent closing of the cyclic acetal ring. The acetal was
formed as an approximately 1.5:1 mixture of diastereomers
at the acetal center, corresponding to the configuration of
plakortethers F (15a) and G (15b), respectively. The mixture
was separable. The separation, however, was found to be
more convenient at the next step. Lithium aluminum hydride
reduction of 15a,b provided alcohols 16a and 16b.
comparison, 4 was inert to trifluoroacetic acid or HClO4 in
THF-H2O, probably due to added steric hindrance from the
presence of the two auxiliaries. Separation of the diastereo-
mers of the lactonic acids was possible by flash chromatog-
raphy via a careful choice of chromatographic system
(2-propanol-hexanes proved effective). It was later found
that separation of alcohols 10a and 10b, obtained after the
reduction, was more convenient. The reduction could be
performed using borane-dimethyl sulfide complex in
THF,14 although noticeable overreduction was observed.
Superior results were obtained using the method that
The minor diastereomer of the alcohol 10a, in turn, was
converted to the same key intermediates 16a and 16b by a
sequence of a reduction with DIBALH and treatment with
p-toluenesulfonic acid in methanol (16a and 16b were
(14) Examples of the reduction of carboxylic acids in presense of a
butyrolactone in BH3 in THF: (a) White, J. D.; Sheldon, B. G. J. Org. Chem.
1981, 46, 2273–2273. (b) Fuji, K.; Node, M.; Terada, S.; Murata, M.;
Nagasawa, H.; Taga, T.; Machida, K. J. Am. Chem. Soc. 1985, 107, 6404.
(c) Janssen, A. J. M.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron 1991,
47, 5513.
(15) An example of the reduction of a carboxylic acid in presense of a
butyrolactone: Burke, S. D.; Shankaran, K.; Helber, M. J. Tetrahedron Lett.
1991, 32, 4655.
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SCHEME 6. Completion of the Synthesis of 1a
FIGURE 2. NOE confirmation of the stereochemistry of 16b.
obtained as a 1:1 mixture in this case). 1D NOE study
showed that the more polar isomer 16b had the configuration
corresponding to plakortether G while also confirming the
expected configuration around the acetal ring (Figure 2).
After separation, diastereomers 16a and 16b were indepen-
dently converted to target 1a and 1b. Swern oxidation of
alcohol 16a provided the aldehyde, which was unstable and
had to be immediately used (storage for 8 h at -15 °C resulted
in significant decomposition of the material). It was subjected
to samarium(II) iodide mediated Reformatsky reaction using
bromoacetylated Evans oxazalidinone16 to provide aldol
adduct 17a as the major diastereomer (formation of small
amounts of the minor diastereomer was also observed, but it
could be separated by flash chromatography).
TABLE 2. Differences in the NMR Data for 1b
Hydrogen peroxide assisted hydrolysis, followed by a
careful acidification (decreasing pH below 3 tended to lead
to transformations of the acetal moiety) provided the
free carboxylic acid, which was immediately converted to
methyl ester using the trimethylsilyldiazomethane method
(Scheme 6).17 Compound 1a, thus obtained, was a satisfactory
match to the natural plakortether F by 1H, 13C, and HRMS
data as well as by the value and sign of specific rotation.
The same sequence of aldol condensation, peroxide-as-
sisted hydrolysis and methylation, performed on alcohol 16b
provided 1b (Scheme 7). In this case, however, while the sign
and value of specific rotation matched, the NMR data
showed significant deviations from those reported for pla-
kortether G. While a good match was observed in 1H NMR
chemical shifts, certain disagreements in the coupling con-
stants were seen. The J values for the acetal hydrogen (H9,
numbering as shown in Table 2) noticeably differed, as did
the coupling constants for the proton in the CH2 on the
acetal ring (H7b). The latter discrepancy appears to indicate
a typo in the original report, as no common J value is listed
between the reportedly interacting protons H7a and H7b.
The most significant differences, however, were observed in
the 13C chemical shifts. The signal for the acetal carbon (C9)
was displaced by 5.6 ppm in 13C NMR, the alcohol carbon
(C3) by 1.9 ppm, acetal methoxy (C15) by 2.6 ppm, C7 by 2.1
ppm, and C10 by 2.6 ppm. Smaller differences are observed
for other carbons (Table 2).
entry
signal
reported
obsd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H9
H7b
C1
C2
C3
C4
C5
C6
C7
4.65 (d, J=3.2 Hz)
1.48 (dd, J=1.5, 2 Hz)
4.66 (d, J=5 Hz)
1.49 (dd, J=12, 10 Hz)
173.6
173.9
37.6
71.4
42.2
42.1
83.8
43.6
107.1
21.9
26.9
27.1
54.8
38.1
69.5
41.5
41.3
84.5
45.7
112.7
24.5
26.8
26.0
57.4
C9
C10
C12
C13
C15
SCHEME 7. Completion of the Synthesis of 1b
To confirm the structure of the prepared compound,
additional NMR studies were performed. COSY confirmed
the 1H NMR peak assignments, coinciding with the assign-
ments in the original report. Observed NOE correlations
confirmed the proposed configuration of the acetal center in
both 1a and 1b, as well as the relative configuration of
substituents around the acetal ring in 1b (Figure 3).
bicyclic acetal, 18, confirming the identical configuration of
both compounds with the exception of the acetal center
(Scheme 8).
NOE correlations, obtained in 18, were also consistent
with the assigned stereochemistry (Figure 4).
Furthermore, treatment of both 1a and 1b with pyridi-
nium tosylate in chloroform at 45 °C produced the same
To clarify the matter, we have contacted the authors of the
original paper. Dr. Taglialatela-Scafati graciously provided
1
us with a copy of the H NMR spectrum of the natural
(16) Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. J. Org. Chem. 2000,
65, 1702.
(17) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981, 29,
1475.
plakortether G (included in the Supporting Information) as
well as a confirmation that the reported odd J values are a
6086 J. Org. Chem. Vol. 74, No. 16, 2009

John et al.
JOCArticle
FIGURE 3. NOE correlations in the synthetic 1a and 1b.
SCHEME 8. Conversion of 1a and 1b to Rigid Bicycle 18
FIGURE 4. NOE correlations in 18.
(3 ꢀ 40 mL). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated. Chromatography
(EtOAc/hexanes, 0:1 to 3:7) provided 797 mg (75%) of bis-
oxazalidinone 4 as a pale yellow oil.
(4S,40S)-3,30-((2R,6R)-1,7-Dioxo-2,6-diethyl-4-methylene-
1,7-heptanediyl)bis(4-benzyl)-2-oxazolidinone (4): pale yel-
low oil; Rf 0.6 (3:7 EtOAc/hexanes); [R]20D = þ33 (0.147,
CHCl3); 1H NMR (CDCl3, 500 MHz): δ 7.18-7.35 (m, 10H),
4.87 (s, 2H), 4.66-4.73 (m, 2H), 4.06-4.19 (m, 6H), 3.33 (dd,
J=13, 3 Hz, 2H), 2.69 (dd, J=13, 10.5 Hz, 2H), 2.60 (dd, J=
14.5, 8 Hz, 2H), 2.27 (dd, J=14, 6 Hz, 2H), 1.68-1.1.79 (m,
2H), 1.57-1.66 (m, 2H), 0.94 (t, J=7.5 Hz, 6H); 13C NMR
(CDCl3, 125 MHz): δ 176.4 (C), 153.4 (C), 144.6 (C), 135.8
(C), 129.6 (CH), 129.0 (CH), 127.3 (CH), 113.5 (CH2), 66.0
(CH2), 55.7 (CH), 42.3 (CH), 38.7 (CH2), 38.1 (CH2), 25.5
(CH2), 11.8 (CH3); HRMS (ESI) calcd for C32H38N2O6Na
[MþNa] 569.2622, found 569.2625.
recording error, with the actual J values matching our
findings. A nearly photographic match in the appearance
of the key regions of the spectra leads us to believe the two
compounds are identical. The nature of the differences in the
13C NMR data, however, is still unclear.
Conclusion
Thus, synthesis of plakortethers F and G was achieved by
taking advantage of the symmetry of the structure. The
structure of the obtained compounds was confirmed by the
COSY and 1D NOE NMR data, as well as by chemical
transformations. The synthetic plakortether F matched the
natural counterpart by 1H, 13C NMR, and optical rotation
data. The synthetic plakortether G exhibited several inex-
plicable differences in 13C NMR data with the reported
values, but it is also believed to match the natural counter-
part on the basis of optical rotation, 1H NMR data, and the
identical appearance of the 1H NMR spectrum. Further
synthetic studies to confirm the structure of plakortethers
are being performed and will be reported in due course.
Also isolated during the initial experimentation, at incom-
plete conversion:
(S)-3-((R)-2-Ethyl-4-(iodomethyl)pent-4-enoyl)-4-benzyloxazo-
lidin-2-one (5): pale yellow oil, darkens on standing; Rf 0.35 (1:4
EtOAc/hexanes); [R]20D=þ24 (0.183, CHCl3); 1H NMR(CDCl3,
500 MHz) δ 7.32-7.36 (m, 2H), 7.29 (d, J=7 Hz, 1H), 7.22 (d, J=
7 Hz, 2H), 5.31 (s, 1H), 5.00 (s, 1H), 4.66-4.73 (m, 1H), 4.13-
4.20 (m, 2H), 4.03-4.09 (m, 2H), 3.99 (d, J=9.5 Hz, 1H), 3.27
(dd, J=13, 3 Hz, 1H), 2.64-2.72 (m, 2H), 2.52 (dd, J=14.5, 5.5
Hz, 1H), 1.70-1.79 (m, 1H), 1.56-1.66 (m, 1H), 0.96 (t, J=7.5
Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 176.0 (C), 153.4 (C),
144.5 (C), 135.4 (C), 129.6 (CH), 129.1 (CH), 127.5 (CH), 115.9
(CH2), 66.1 (CH2), 55.7 (CH), 42.4 (CH), 38.2 (CH2), 36.7
(CH2), 25.8 (CH2), 11.7 (CH3), 10.5 (CH2); HRMS (ESI) calcd
for C18H23NO3I [MþH]þ 428.0717, found 428.0715.
Experimental Section
Iodocyclization of (4S,40S)-3,30-((2R,6R)-1,7-Dioxo-2,6-di-
ethyl-4-methylene-1,7-heptanediyl)bis(4-benzyl)-2-oxazolidinone
(4). To the solution of bis-oxazalidinone 4 (50 mg, 0.092 mmol)
in THF (0.5 mL) and water (0.1 mL) was added iodine (116 mg,
0.46 mmol). The mixture was stirred at rt for 36 h while being
monitored by TLC. Upon disappearance of the starting materi-
al, the solution was diluted with EtOAc (20 mL) and washed
with saturated solution of Na2SO3 (20 mL). The organic layer
was washed with brine, dried, and concentrated. The crude
iodohydrin was dissolved in methylene chloride (5 mL) and
stirred with silica gel (200 mg) for 10 h. The reaction mixture was
filtered, the silica gel was washed with ethyl acetate (2 ꢀ 30 mL),
and the combined organic washings were concentrated. Chroma-
tography (EtOAc/hexanes, 0:1 to 3:7) afforded the two diastere-
omers of the product, 8a (23 mg, 49%) and 8b (15 mg, 32%).
(S)-3-((R)-2-(((2S,4R)-4-Ethyltetrahydro-2-(iodomethyl)-5-oxo-
furan-2-yl)methyl)butanoyl)-4-benzyloxazolidin-2-one (8a): pale
yellow oil; Rf 0.5 (1:4 EtOAc/hexanes); [R]20D = þ22 (0.027,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.25-7.36 (m, 5H),
4.60-4.68 (m, 1H), 4.06-4.23 (m, 3H), 3.59 (dd, J=13.5, 3 Hz,
1H), 3.34 (s, 2H), 2.89 (dd, J=13.5, 11.5 Hz, 1H), 2.66-2.74 (m,
1H), 2.63 (dd, J = 14.5, 11 Hz, 1H), 2.53 (dd, J=13, 9.5 Hz, 1H),
1.95-2.07 (m, 3H), 1.69-1.76 (m, 1H), 1.52-1.65 (m, 2H, over-
lapped with water peak), 1.03 (t, J=7.5 Hz, 3H), 0.96 (t, J=7.5 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 177.6 (C), 176.3 (C), 153.7
Preparation of 3-Iodo-2-(iodomethyl)prop-1-ene. To the solu-
tion of 3-chloro-2-(chloromethyl)prop-1-ene (3 g, 24 mmol,
purchased from Acros Organics) in acetone (50 mL) was added
sodium iodide (10.8 g, 72 mmol), and the reaction mixture was
refluxed for 10 h. Then, the reaction mixture was cooled and
vapped almost to dryness, and the residue was treated with
hexanes (70 mL) and water (70 mL). After shaking and separa-
tion of layers, the organic layer was washed with saturated
Na2SO3 (10 mL) and brine, dried, and carefully concentrated.
The product was obtained as a white solid, 7.01 g (95%).
Preparation of (4S,40S)-3,30-((2R,6R)-1,7-Dioxo-2,6-diethyl-
4-methylene-1,7-heptanediyl)bis(4-benzyl)-2-oxazolidinone (4)
by Alkylation. Butyryl oxazalidinone 2 (1.2 g, 4.86 mmol) was
dissolved in THF (7 mL) and cooled to -55 °C (using a
recirculative cooler). A solution of sodium hexamethyldisilazide
(2.5 mL, 2 M in THF, purchased from Acros Organics, 5 mmol)
was added dropwise. After the miture was stirred for 40 min at -
55 °C, a solution of 3-iodo-2-(iodomethyl)prop-1-ene (598 mg,
1.95 mmol, prepared as described above, immediately before use
dissolved in hexanes, filtered through basic Al2O3, and
evaporated) in THF (3 mL) was added. The reaction mixture
was stirred at -55 °C for 16 h and then quenched with saturated
NH4Cl. After being warmed to rt, the reaction mixture was
diluted with water (50 mL) and extracted with ethyl acetate
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John et al.
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(C), 136.7 (C), 129.6 (CH), 129.0 (CH), 127.1 (CH), 82.7 (C), 66.2
(CH2), 56.4 (CH), 42.0 (CH2), 41.8 (CH), 38.7 (CH), 37.3 (CH2),
35.8 (CH2), 27.4 (CH2), 23.8 (CH2), 12.7 (CH2), 12.4 (CH3), 11.5
(CH3); HRMS (ESI) calcd for C22H29NO5I [Mþ H] 514.1085,
found 514.1092.
(20 mL) and extracted with CH2Cl2 (3 ꢀ 20 mL). The methylene
chloride layer was concentrated to recover the auxiliary. To the
aqueous layer a saturated solution of NaH2PO4 was added
(15 mL), followed by acidification by 1 N HCl to pH of a 2-3
and extraction with EtOAc (3ꢀ 30 mL). The organic layer was
dried and concentrated. The resulting diacid was used without
further purification. 195 mg (90%).
+(2R,6R)-2,6-Diethyl-4-methyleneheptanedioic acid (11):
white crystals; mp 93-94 °C; Rf 0.3 (1:9 2-propanol/hexanes);
[R]20D=-5 (0.06, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 11.12
(br s, 2H), 4.82 (s, 2H), 2.58-2.65 (m, 2H), 2.41 (dd, J=15, 11
Hz, 2H), 2.04 (dd, J=15, 3.5, 2H), 1.62-1.73 (m, 2H), 1.51-1.61
(m, 2H), 0.99 (t, J=7.5 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ
182.6 (C), 144.0 (C), 112.9 (CH2), 45.6 (CH), 38.1 (CH2), 25.6
(CH2), 11.8 (CH3); HRMS (ESI) calcd for C12H19O4 [M - H]-
227.1288, found 227.1293.
Acidic Cyclization of (2R,6R)-2,6-Diethyl-4-methylenehepta-
nedioic acid (11). Diacid 11 (150 mg, 0.65 mmol) was dissolved in
TFA (1 mL) and stirred overnight at rt. Removal of TFA in
vacuo (followed by dilution with CHCl3 and repeated
concentration) afforded the diastereomeric mixture of acid
lactones that was used without further purification. For analy-
tical purposes, the diastereomers were separated using flash
chromatography (hexanes/2-propanol 4:1).
(S)-3-((R)-2-(((2R,4R)-4-Ethyltetrahydro-2-(iodomethyl)-5-oxo-
furan-2-yl)methyl)butanoyl)-4-benzyloxazolidin-2-one (8b): pale
yellow oil; Rf 0.45 (1:4 EtOAc/hexanes); [R]20D = þ33 (0.07,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.29-7.34 (m, 2H),
7.21-7.28 (m, 3H), 4.60-4.67 (m, 1H), 4.17 (dd, J=9, 2.5 Hz,
1H), 4.14 (d, J=7 Hz, 1H), 4.02-4.11 (m, 1H), 3.71(d, J=10.5 Hz,
1H), 3.56 (dd, J=13.5, 3 Hz, 1H), 3.39 (dd, J=10.5, 1.5 Hz, 1H),
2.72-2.81 (m, 2H), 2.57 (dd, J=14, 11.5 Hz, 1H), 2.33 (dd, J=13, 9
Hz, 1H), 2.19 (dd, J=15, 1.5 Hz, 1H), 1.87-1.95 (m, 1H), 1.84 (dd,
J=13, 12 Hz, 1H), 1.64-1.74 (m, 1H), 1.47-1.57 (m, 2H), 0.99 (m,
J=7.5 Hz, 6H); 13C NMR (CDCl3, 125 MHz): δ 177.1 (C), 176.1
(C), 153.7 (C), 136.4 (C), 129.7 (CH), 129.0 (CH), 127.1 (CH), 83.0
(C), 66.3 (CH2), 56.1 (CH), 41.7 (CH), 40.4 (CH2), 39.0 (CH), 37.7
(CH2), 37.5 (CH2), 27.5 (CH2), 23.5 (CH2), 12.7 (CH2), 11.8
(CH3), 11.7 (CH3); HRMS (ESI) calcd for C22H29NO5I [MþH]
514.1085, found 514.1082.
Hydrogenolysis of (S)-3-((R)-2-(((2S,4R)-4-Ethyltetrahydro-
2-(iodomethyl)-5-oxofuran-2-yl)methyl)butanoyl)-4-benzyloxazoli-
din-2-one (8a). Iodide 8a (10 mg, 0.026 mmol) was dissolved in
methanol (0.5 mL), sodium acetate (10 mg, 0.12 mmol) and Pd/C
(3 mg) were added, and the reaction mixture was stirred under an
atmosphere of hydrogen (hydrogen balloon) for 20 h. After
filtration through Celite, the solvent was removed, and the residue
was treated with water (10 mL) and ethyl acetate (20 mL). The
organic layer was washed with brine, dried over Na2SO4, and
concentrated. Chromatography (EtOAc/hexanes, 0:1 to 3:7) pro-
vided 9a as pale yellow oil: 7 mg (93%).
(S)-3-((R)-2-(((2S,4R)-4-Ethyltetrahydro-2-methyl-5-oxofuran-
2-yl)methyl)butanoyl)-4-benzyloxazolidin-2-one (9a): pale yellow
oil; Rf 0.6 (1:4 EtOAc/hexanes); [R]20D=þ10 (0.06, CHCl3); 1H
NMR (CDCl3, 500 MHz) δ 7.27-7.35 (m, 4H), 7.23-7.27 (m,
1H), 4.61-4.66 (m, 1H), 4.13-4.20 (m, 2H), 4.15 (dd, J=9, 2.5
Hz), 4.10 (ddd, J=9, 7.5, 1 Hz, 1H), 3.58 (dd, J=13.5, 3 Hz, 1H),
2.89 (dd, J=13.5, 11 Hz, 1H), 2.55-2.66 (m, 2H), 2.58 (dd, J=
14.5, 11 Hz), 2.03-2.11 (m, 2H), 1.93-2.03 (m, 1H), 1.68-1.75
(m, 2H), 1.50-1.62 (m, 2H, overlapped with water peak), 1.38 (s,
3H), 1.01 (t, J=7.5 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 178.4 (C), 177.0 (C), 153.8 (C), 136.8 (C),
129.8 (CH), 129.0 (CH), 127.1 (CH), 83.1 (C), 66.3 (CH2), 56.5
(CH), 43.5 (CH2), 41.9 (CH), 38.7 (CH), 38.0 (CH2), 37.4 (CH2),
27.5 (CH2), 27.0 (CH3), 23.4 (CH2), 12.5 (CH3), 11.6 (CH3);
HRMS (ESI) calcd for C22H29NO5Na [M þ Na] 410.1937, found
410.1938.
Borohydride Reduction of (S)-3-((R)-2-(((2S,4R)-4-Ethyltetra-
hydro-2-methyl-5-oxofuran-2-yl)methyl)butanoyl)-4-benzyloxazo-
lidin-2-one (9a). Compound 9a (7 mg, 0.018 mmol) was dissolved
in THF (0.3 mL), and water (0.2 mL) was added followed by
sodium borohydride (5 mg, 0.131 mmol). After the mixture was
stirred for 3 h, saturated NH4Cl (5 mL) was added, and the
reaction mixture was extracted with ethyl acetate (3ꢀ10 mL). The
organic layer was washed with brine, dried over Na2SO4, and
concentrated. Chromatography (EtOAc/hexanes, 0:1 to 1:1)
afforded alcohol 10b (2 mg, 50%).
(R)-2-(((2R,4R)-4-Ethyltetrahydro-2-methyl-5-oxofuran-2-yl)-
methyl)butanoic acid (12a): pale yellow oil; Rf 0.4 (3:7 2-
propanol/hexanes); [R]20 = þ21 (0.048, CHCl3); 1H NMR
D
(CDCl3, 500 MHz) δ 10.7 (br s, 1H), 2.65-2.73 (m, 1H), 2.36-
2.44 (m, 1H), 2.20-2.28 (m, 2H), 1.81-1.90 (m, 1H), 1.60-1.68
(m, 2H), 1.46-1.56 (m, 2H), 1.32-1.42 (m, 4H), 1.40 (s), 0.92 (t,
J=7.5 Hz, 3H), 0.91 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 181.4 (C), 178.4 (C), 83.3 (C), 42.7 (CH), 41.8 (CH), 41.6
(CH2), 40.0 (CH2), 27.1 (CH2), 27.0 (CH3), 24.0 (CH2), 11.7
(CH3), 11.6 (CH3); HRMS (ESI) calcd for C12H19O4 [M - H]
227.1283, found 227.1290.
(R)-2-(((2S,4R)-4-Ethyltetrahydro-2-methyl-5-oxofuran-2-yl)-
methyl)butanoic acid (12b): pale yellow oil; Rf 0.4 (3:7 2-
propanol/hexanes); [R]20 = -27 (0.097, CHCl3); 1H NMR
D
(CDCl3, 500 MHz) δ 11.06 (br s, 1H), 2.64-2.73 (m, 1H),
2.47-2.54 (m, 1H), 2.24 (dd, J=14.5, 10 Hz, 1H), 2.17 (dd, J=
12.5, 9 Hz, 1H), 1.85-1.95 (m, 1H), 1.63-1.83 (m, 3H), 1.55-
1.63 (m, 1H), 1.44-1.52 (m, 1H), 1.35 (s, 3H), 0.96 (t, J=7.5 Hz,
3H), 0.94 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
181.7 (C), 178.4 (C), 83.6 (C), 43.4 (CH2), 42.8 (CH), 41.6 (CH),
39.0 (CH2), 26.9 (CH2), 25.0 (CH3), 23.6 (CH2), 11.7 (CH3),
11.5 (CH3); HRMS (ESI) calcd for C12H19O4 [M - H] 227.1283,
found 227.1288.
Mixed Anhydride/Borohydride Reduction of (3R)-3-Ethyldi-
hydro-5-((R)-2-(hydroxymethyl)butyl)-5-methylfuran-2(3H)-one
(12a,b). The crude mixture of acids 12a and 12b (152 mg) was
dissolved in THF (5 mL) at 0 °C, and Et3N (100 μL, 0.79 mmol)
was added followed by dropwise addition of n-butyl chlorofor-
mate (107 mg, 0.79 mmol). After 30 min at rt, a solution of
NaBH4 in water (150 mg in 3 mL) was added, and the mixture
stirred at 0 °C for 5 h. The mixture was diluted with water (20
mL), and extracted with ethyl acetate (2ꢀ30 mL). The combi-
ned extracts were washed with brine, dried over Na2SO4, and
concentrated. Chromatography (hexanes/isopropanol 93:7)
qafforded 10a (40 mg, 29%) and 10b (58 mg, 42%).
Hydrolysis of (4S,40S)-3,30-((2R,6R)-1,7-Dioxo-2,6-diethyl-4-
methylene-1,7-heptanediyl)bis(4-benzyl)-2-oxazolidinone (4). To
the solution of bis-oxazalidinone 4 (520 mg, 0.95 mmol) in THF
(8 mL) at 0 °C was added sequentially H2O (4 mL), 30% H2O2
(3R,5R)-3-Ethyldihydro-5-((R)-2-(hydroxymethyl)butyl)-5-
methylfuran-2(3H)-one (10a): pale yellow oil; Rf 0.5 (1:4 2-
1
propanol/hexanes); [R]20D =-7.7 (0.039, CHCl3); H NMR
(CDCl3, 500 MHz) δ 3.59 (dd, J=10.5, 5 Hz, 1H), 3.52 (dd, J=
10.5, 5 Hz, 1H), 2.69 (ddd, J=9.5, 9.5, 4.5 Hz, 1H), 2.28 (dd,
J=12.5, 9.5 Hz, 1H), 2.15 (br s, 1H), 1.86-1.94 (m, 1H), 1.78
(dd, J=14.5, 7 Hz, 1H), 1.72 (dd, J=12.5, 10.5 Hz, 1H), 1.57-
1.63 (m, 1H), 1.45-1.53 (m, 3H), 1.44 (s, 3H), 1.25-1.34 (m,
1H), 0.96 (t, J=7.5 Hz, 3H), 0.9 (t, J=7.5 Hz, 3H); 13C NMR
(1 mL), and LiOH H2O (160 mg, 3.8 mmol). The reaction
3
mixture was stirred for 1.5 h at 0 °C (care should be taken to
keep the temperature low, as warming of the mixture appears to
degrade the yield), and then solid Na2SO3 (1.5 g) was added in
several portions (quick addition may cause excessive bubbl-
ing and foaming). The resulting mixture was diluted with H2O
6088 J. Org. Chem. Vol. 74, No. 16, 2009

John et al.
JOCArticle
(CDCl3, 125 MHz): δ 178.9 (C), 84.8 (C), 65.2 (CH2), 42.1
(CH), 41.5 (CH2), 41.0 (CH2), 38.4 (CH), 26.9 (CH3), 25.6
(CH2), 24.2 (CH2), 11.9 (CH3), 11.5 (CH3); HRMS (ESI)
calcd for C12H22O3Na [M þ Na] 237.1461, found 237.1456.
(3R,5S)-3-Ethyldihydro-5-((R)-2-(hydroxymethyl)butyl)-5-
methylfuran-2(3H)-one (10b): pale yellow oil; Rf 0.45 (1:4 2-
15a (105 mg, 0.41 mmol) was dissolved in THF (1.5 mL) and LAH
(31 mg, 0.81 mmol) was added. The reaction mixture was stirred at
rt overnight. Water (30 μL) was added with vigorous stirring. After
10 min, 15% NaOH (30 μL) was added, and then, after 15 min,
water again (30 μL). The resulting mixture was stirred until the
color of the suspended solids changed to white or pale gray and a
readily sedimenting precipitate formed. The mixture was filtered
through a pad of Celite, washed with EtOAc (2 ꢀ 10 mL), and
concentrated. Chromatography (ether/hexanes 1:4) provided pure
16a (89 mg, 95%).
(R)-2-(((2R,4R,5S)-4-Ethyltetrahydro-5-methoxy-2-methylfur-
an-2-yl)methyl)butan-1-ol (16a): pale yellow oil; Rf 0.45 (3:7 ether/
hexanes); [R]20D=þ69.3 (0.075, CHCl3); 1H NMR (CDCl3, 500
MHz) δ 4.78 (d, J=4.5 Hz, 1H), 4.10 (br s, 1H), 3.65 (d, J=10.5
Hz, 1H), 3.35 (d, J = 10.5 Hz, 1H), 3.31 (s, 3H), 2.09-2.19 (m,
1H), 1.87 (dd, J=12, 8 Hz, 1H), 1.64-1.77 (m, 2H), 1.47-1.64
(m, 3H, overlapped with water peak), 1.28-1.45 (m, 5H), 1.38 (s),
1.13-1.24 (m, 1H), 0.91 (t, J=7.5 Hz, 6H); 13C NMR (CDCl3,
125 MHz) δ 105.8 (CH), 84.2 (C), 67.6 (CH2), 54.6 (CH3), 47.0
(CH2), 46.3 (CH), 44.0 (CH2), 39.3 (CH), 28.0 (CH3), 26.9
(CH2), 21.7 (CH2), 13.0 (CH3), 11.9 (CH3); HRMS (ESI) calcd
for C13H26O3Na [MþNa] 253.1774, found 253.1768.
1
propanol/hexanes); [R]20D =-6.8 (0.118, CHCl3); H NMR
(CDCl3, 500 MHz) δ 3.51 (dd, J=10.5, 5.5 Hz, 1H), 3.47 (dd,
J=10.5, 5.5 Hz, 1H), 2.61-2.68 (m, 1H), 2.45 (br s, 1H), 2.13
(dd, J=12.5, 9 Hz, 1H), 1.83-1.91 (m, 1H), 1.72-1.83 (m,
2H), 1.50-1.58 (m, 2H), 1.38-1.48 (m, 3H), 1.33 (s, 3H), 0.93
(t, J=7.5 Hz, 3H), 0.86 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 178.7 (C), 84.6 (C), 65.5 (CH2), 42.4 (CH2), 41.6
(CH), 39.5 (CH2), 38.2 (CH), 26.0, 25.1, 23.8, 11.9 (CH3),
11.3 (CH3); HRMS (ESI) calcd for C12H22O3Na [M þ Na]
237.1461, found 237.1454.
Preparation of (R)-Methyl 2-(((2R,4R)-4-Ethyltetrahydro-5-meth-
oxy-2-methylfuran-2-yl)methyl)butanoate (15a,b) from (3R,5S)-3-
Ethyldihydro-5-((R)-2-(hydroxymethyl)butyl)-5-methylfuran-
2(3H)-one (10b). DMSO (77 μL, 85 mg, 1.1 mmol) was added
to the solution of oxalyl chloride (48 μL, 70 mg, 0.55 mmol)
in CH2Cl2 (2 mL) at -78 °C. After being stirred for 10 min, a
solution of alcohol 10b (108 mg, 0.5 mmol) in CH2Cl2 (3 mL)
was added and stirred for additional 30 min at -78 °C. Et3N
(348 μL, 252 mg, 2.5 mmol) was added, and the solution was
allowed to gradually warm to 0 °C over 30 min. After 5 min
at 0 °C (and when the slurry stopped getting thicker), 1 N
HCl (20 mL) was added. The solution was diluted with
CH2Cl2, and layers were separated. The organic layer was
washed with satd NaHCO3 (30 mL) and brine, dried over
Na2SO4, and concentrated. The crude aldehyde (100 mg)
was dissolved in methanol (1 mL) and p-toluenesulfonic acid
(80 mg, 0.47 mmol) was added. The solution was kept at rt
for 24 h. Upon completion, the reaction mixture was neu-
tralized with saturated NaHCO3 (5 mL) and extracted with
ethyl acetate (3 ꢀ 30). The organic layer was dried over
Na2SO4 and concentrated. The resulting crude diastereo-
meric mixture was directly used in the following step. For
purposes of analysis, the esters were separated using flash
chromatography (hexanes/ether, 0:1 to 4:1), providing 15a
(66 mg, 51%) and 15b (41 mg, 31%).
(R)-Methyl 2-(((2S,4R,5S)-4-ethyltetrahydro-5-methoxy-2-
methylfuran-2-yl)methyl)butanoate (15a): pale yellow oil; Rf 0.6
(1:4 ether/hexanes); [R]20D = þ50 (0.02, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 4.60 (d, J = 4.5 Hz, 1H), 3.66 (s, 3H),
3.27 (s, 3H), 2.39-2.46 (m, 1H), 2.07-2.15 (m, 1H), 2.04 (dd, J
= 14, 10.5 Hz, 1H), 1.80 (dd, J=12.5, 8 Hz, 1H), 1.41-1.62 (m,
5H), 1.32-1.39 (m, 1H), 1.29 (s, 3H), 0.89 (t, J = 7.5 Hz, 3H),
0.88 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.5
(C), 105.7 (CH), 82.9 (C), 54.4 (CH3), 51.5 (CH3), 46.4 (CH),
44.4 (CH2), 43.3 (CH), 41.8 (CH2), 28.9 (CH3), 27.6 (CH2), 21.7
(CH2), 13.1 (CH3), 11.9 (CH3); HRMS (ESI) calcd for
C14H26O4Na [MþNa] 281.1723, found 281.1721.
Similarly, by a reduction of 15b, or a mixture of 15a and 15b,
with a following separation, compound 16b was obtained.
(R)-2-(((2R,4R,5R)-4-Ethyltetrahydro-5-methoxy-2-methylfur-
an-2-yl)methyl)butan-1-ol (16b): pale yellow oil; Rf 0.4 (3:7 ether/
hexanes); [R]20D=þ12.5 (0.016, CHCl3); 1H NMR (CDCl3, 500
MHz) δ 4.67 (d, J=4 Hz, 1H), 3.95 (br s, 1H), 3.73 (d, J=10.5 Hz,
1H), 3.44 (d, J=4.5 Hz, 1H), 3.42 (s, 3H), 2.15-2.24 (m, 1H), 2.04
(dd, J=12.5, 8 Hz, 1H), 1.76 (dd, J=14, 10.5 Hz, 1H), 1.64-1.73
(m, 1H, overlapped with water peak), 1.45-1.62 (m, 3H), 1.28-
1.42 (m, 5H), 1.33 (s), 1.14-1.24 (m, 1H), 0.93 (t, J = 7.5 Hz, 3H),
0.91 (t, J = 7.5 Hz, 3H); 1H NMR (C6D6, 500 MHz) δ 4.49 (d, J=
4 Hz, 1H), 3.96 (d, J=10 Hz, 1H), 3.60-3.77 (m, 2H), 3.64 (dd, J=
11, 6 Hz), 3.25 (s, 3H), 2.06-2.15 (m, 1H), 1.80 (dd, J = 14, 10 Hz,
1H), 1.73 (dd, J=12.5, 8 Hz, 1H), 1.63-1.72 (m, 1H), 1.23-1.44
(m, 6H), 1.25 (s), 1.06-1.23 (m, 3H), 0.87 (t, J = 7.5Hz, 3H), 0.77
(t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 112.3 (CH),
84.8 (C), 66.1 (CH2), 56.7 (CH3), 47.8 (CH), 45.7 (CH2), 45.5
(CH2), 39.3 (CH), 26.8 (CH3), 26.6 (CH2), 26.1 (CH2), 12.8
(CH3), 12.0 (CH3); HRMS (ESI) calcd for C13H26O3Na [Mþ Na]
253.1774, found 253.1782.
Preparation of (R)-2-(((4R,5R)-4-Ethyltetrahydro-5-methoxy-
2-methylfuran-2-yl)methyl)butan-1-ol (16a,b) from (3R,5R)-3-
Ethyldihydro-5-((R)-2-(hydroxymethyl)butyl)-5-methylfuran-2(3H)-
one (10a). In a wide test tube equipped with a septum, submerged in
an acetone-dry ice bath, to a solution of alcohol 10a (43 mg, 0.2
mmol) at -78 °C in CH2Cl2 (0.5 mL) was added DIBALH (0.5 mL
1 M solution in hexanes, 0.5 mmol), letting each drop descend on the
cooled side of the test tube. Upon completion of the addition, the
mixture was stirred for 2 h at -78 °C. MeOH (1 mL) was added,
followed by a saturated Rochelle salt (sodium potassium tartrate)
solution (5 mL), and the mixture was allowed to warm to rt. After 1
h of vigorous stirring, two clear layers formed. The aqueous layer
was washed with CH2Cl2 (2 ꢀ 20 mL), and the combined organic
layers were dried over Na2SO4 and concentrated. The crude lactol
was dissolved in MeOH (2 mL), and pyridinium p-toluenesulfonate
(25 mg, 0.1 mmol) was added. The mixture was stirred at rt
overnight. Saturated NaHCO3 (1 mL) was added and the mixture
concentrated. Water (10 mL) and ethyl acetate (20 mL) were added,
the mixture was shaken, and the layers were separated. The organic
layer was washed with brine, dried over Na2SO4, and concentrated.
The diastereomeric mixture was separated by flash chromato-
graphy (ether/hexanes 1:4) to yield 21 mg of 16a (46%) and 20
mg of 16b (44%).
(R)-Methyl 2-(((2S,4R,5R)-4-ethyltetrahydro-5-methoxy-2-
methylfuran-2-yl)methyl)butanoate (15b): pale yellow oil; Rf 0.5
(1:4 ether/hexanes); [R]20D = -55 (0.107, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 4.63 (d, J=2.2 Hz, 1H), 3.69 (s, 3H), 3.34
(s, 3H), 2.37-2.44 (m, 1H), 2.15 (dd, J=14, 9.5 Hz, 1H), 2.03-
2.11 (m, 2H), 1.61-1.69 (m, 2H, overlapped with water peak),
1.46-1.59 (m, 2H), 1.37-1.44 (m, 1H), 1.28-1.37 (m, 1H), 1.25
(s, 3H) 0.92 (t, J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 177.3 (C), 111.1 (CH), 84.1 (C), 55.6
(CH3), 51.6 (CH3), 48.1 (CH), 45.1 (CH2), 44.0 (CH), 42.4
(CH2), 27.8 (CH2), 27.6 (CH3), 26.3 (CH2), 12.8 (CH3), 12.0
(CH3); HRMS (ESI) calcd for C14H26O4Na [M þ Na] 281.1723,
found 281.1715.
Preparation of (S)-3-((3R,4R)-4-(((2R,4R,5S)-4-Ethyltetrahy-
dro-5-methoxy-2-methylfuran-2-yl)methyl)-3-hydroxyhexanoyl)-4-
isopropyloxazolidin-2-one (17a). DMSO (18 mg, 0.23 mmol) was
Reduction of (R)-Methyl 2-(((2R,4R)-4-Ethyltetrahydro-5-
methoxy-2-methylfuran-2-yl)methyl)butanoate (15a,b). Compound
J. Org. Chem. Vol. 74, No. 16, 2009 6089

John et al.
JOCArticle
added to the solution of oxalyl chloride (6 μL, 0.11 mmol) in
CH2Cl2 (0.4 mL) at -78 °C. After being stirred for 10 min, a
solution of alcohol 13a (15 mg, 0.065 mmol) in CH2Cl2 (0.6 mL)
was added and the mixture stirred for 30 min at -78 °C. Et3N
(75 μL, 0.54 mmol) was added, and the solution was allowed to
gradually warm to 0 °C over 30 min. After 5 min at 0 °C (and when
the slurry stopped getting thicker), saturated NH4Cl (5 mL) was
added. The solution was diluted with CH2Cl2 (15 mL) and
extracted with water (20 mL). The organic layer was washed with
brine, dried over Na2SO4, and concentrated. The crude product
was dissolved in hexanes, filtered through a pad of cotton, and
immediately used. Storing of the aldehyde even at low temperatures
and short times was found to result results in significant decom-
position. To the crude aldehyde was added (S)-3-(2-bromoacetyl)-
4-isopropyloxazolidin-2-one (115 mg, 0.46 mmol), along with
anhydrous THF (1 mL). This mixture was canulated to a cooled
to -78 °C solution of samarium(II) iodide (10 mL of 0.1 M solution,
1 mmol, purchased from Aldrich), washing twice with more THF
(2ꢀ0.5 mL). After being stirred for 40 min, the reaction mixture was
quenched with pH 7 phosphate buffer (5 mL) at -78 °C. After
warming, the mixture was diluted with ethyl acetate (30 mL) and
water (10 mL). The layers were separated, and the organic layer was
washed with saturated Na2SO3 (10 mL) and brine, dried over
Na2SO4, and concentrated. Chromatography (EtOAc/hexanes
0:1 to 3:7) provided 15 mg (58%) of the aldol product 17a.
(1 mL) at 0 °C were added sequentially H2O (0.5 mL), 30%
H2O2 (0.125 mL), and LiOH H2O (2 mg, 0.048 mmol). The
3
reaction mixture was stirred for 1.5 h at 0 °C, and then solid
Na2SO3 (0.2 g) was added in several portions (quick addition
may cause excessive bubbling and foaming). The resulting
mixture was diluted with H2O (5 mL) and extracted with CH2Cl2
(2ꢀ10 mL). The methylene chloride layer was concentrated to
recover the auxiliary. To the aqueous layer saturated buffer with
pH 3 (NaH2PO4-H3PO4 in H2O, 20 mL) was added, and the
water layer was extracted with CH2Cl2 (3 ꢀ 20 mL). The organic
layer was dried and concentrated. The resulting crude acid was
dissolved in methanol (0.1 mL) and benzene (0.3 mL), and the
solution of TMSCHN2 (50 μL, 1 M solution, 0.05 mmol) was
added. The mixture was stirred at rt for 30 min and concen-
trated. Chromatography (EtOAc/hexanes 0:1 to 1:1) provided
1a, 6 mg (80%).
(3R,4R)-Methyl 4-(((2R,4R,5S)-4-ethyltetrahydro-5-methoxy-
2-methylfuran-2-yl)methyl)-3-hydroxyhexanoate (1a): pale yellow
oil; Rf 0.45 (3:7 EtOAc/hexanes); [R]20D=þ39 (0.02, CHCl3); 1H
NMR (CDCl3, 500 MHz) δ4.79(d, J=4.4 Hz, 1H), 4.39 (d, J=7.5
Hz, 1H), 4.15-4.21 (m, 1H), 3.72 (s, 3H), 3.31 (s, 3H), 2.36-2.39
(m, 2H), 2.08-2.16 (m, 1H), 1.86-1.91 (m, 2H), 1.88 (dd, J=11.5,
8 Hz), 1.65-1.74 (m, 2H), 1.50-1.56 (m, 1H, overlapped with
water peak), 1.29-1.44 (m, 6H), 1.37 (s), 1.32 (dd, J=14.5, 3.5
Hz), 1.15-1.22 (m, 1H), 0.95 (t, J=7.5 Hz, 3H), 0.92 (t, J=7.5 Hz,
3H); 13C NMR (CDCl3, 125 MHz): δ 173.5 (C), 105.8 (CH), 84.1
(C), 70.6 (CH), 54.6 (CH3), 51.9 (CH3), 46.6 (CH), 43.7 (CH2),
42.1 (CH2), 41.7 (CH), 37.9 (CH2), 28.1 (CH3), 26.5 (CH2), 21.7
(CH2), 13.0 (CH3), 12.5 (CH3); HRMS (ESI) calcd for C16H30-
O5Na (M þ Na)þ 325.1985, found 325.1977.
(S)-3-((3R,4R)-4-(((2R,4R,5S)-4-Ethyltetrahydro-5-methoxy-2-
methylfuran-2-yl)methyl)-3-hydroxyhexanoyl)-4-isopropyloxazoli-
din-2-one (17a): white needles; mp 95-96 °C; Rf 0.3 (3:7 EtOAc/
1
hexanes); [R]20D =þ74 (0.027, CHCl3); H NMR (CDCl3, 500
MHz) δ 4.82 (d, J=4.4 Hz, 1H), 4.65 (d, J = 8 Hz, 1H), 4.48-4.52
(m, 1H), 4.28 (br t, J = 8.5 Hz, 1H), 4.19-4.25 (m, 2H), 3.30 (s,
3H), 3.26 (dd, J=14.5, 10 Hz, 1H), 2.78 (dd, J = 14.5, 2 Hz, 1H),
2.36-2.43 (m, 1H), 2.15-2.23 (m, 1H), 1.90-1.97 (m, 1H), 1.89
(dd, J=11.5, 7.5 Hz, 1H), 1.79 (dd, J=14.5, 9 Hz, 1H), 1.68 (br t,
J=12 Hz, 1H), 1.49-1.57 (m, 1H), 1.32-1.46 (m, 6H), 1.37 (s),
Using the same procedure, (3R,4R)-methyl 4-(((2R,4R,5R)-4-
ethyltetrahydro-5-methoxy-2-methylfuran-2-yl)methyl)-3-hydro-
xyhexanoate (1b) was prepared from (S)-3-((3R,4R)-4-
(((2R,4R,5R)-4-ethyltetrahydro-5-methoxy-2-methylfuran-2-yl)-
methyl)-3-hydroxyhexanoyl)-4-isopropyloxazolidin-2-one (17b)
in 80% yield: pale yellow oil; Rf 0.45 (3:7 EtOAc/hexanes);
[R]20D = -14 (0.02, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
4.66 (d, J=5 Hz, 1H), 4.35-4.41 (m, 1H), 3.97 (d, J=7 Hz, 1H),
3.70 (s, 3H), 3.44 (s, 3H), 2.62 (dd, J=15, 10 Hz, 1H), 2.37 (dd, J=
15, 3.5 Hz, 1H), 2.16-2.24 (m, 1H), 2.05 (dd, J=12.5, 7.5 Hz, 1H),
1.86 (dd, J=14.5, 9.5 Hz, 1H), 1.74-1.80 (m, 1H), 1.54-1.61 (m,
1H, overlapped with water peak), 1.49 (dd, J=12, 10 Hz, 1H),
1.34-1.42 (m, 3H), 1.32 (s, 3H), 1.17-1.23 (m, 1H), 0.93 (t, J=
7.5, 3H), 0.92 (t, J=7.5 Hz, 3H); 1H NMR (C6D6, 500 MHz) δ
4.72-4.78(m,1H), 4.47(d, J= 4.7 Hz, 1H), 4.00 (d, J=7 Hz, 1H),
3.40 (s, 3H), 3.34 (s, 3H), 2.76 (dd, J=15, 10 Hz, 1H), 2.33 (dd, J=
15, 3.5 Hz, 1H), 2.05-2.12 (m, 1H), 1.86 (dd, J=14.5, 9.5 Hz, 1H),
1.72-1.79 (m, 1H), 1.68 (dd, J=12, 7.5 Hz, 1H), 1.30-1.38 (m,
2H), 1.25 (s, 3H), 1.15-1.24 (m, 3H), 1.07-1.15 (m, 1H), 0.84 (t,
J=7.5 Hz, 3H), 0.77 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 173.6 (C), 112.7 (CH), 84.5 (C), 69.5 (CH), 57.4 (CH3),
51.8 (CH3), 47.7 (CH), 45.7 (CH2), 41.5 (CH), 41.3 (CH2), 38.1
(CH2), 26.8 (CH3), 26.0 (CH2), 24.5 (CH2), 12.8 (CH3), 12.5
(CH3); HRMS (ESI) calcd for C16H30O5Na (MþNa)þ 325.1985,
found 325.1969.
1.14-1.21 (m, 1H), 0.96 (t, J=7.5 Hz, 3H), 0.88-0.94 (m, 9H); 13
C
NMR (CDCl3, 125 MHz) δ 172.8 (C), 154.5 (C), 105.9 (CH), 84.0
(C), 71.0 (CH), 63.5 (CH2), 58.7 (CH), 54.6 (CH3), 46.3 (CH),
43.8 (CH2), 42.21 (CH), 42.2 (CH2), 38.3 (CH2), 28.7 (CH), 28.0
(CH3), 26.7 (CH2), 21.7 (CH2), 18.2 (CH3), 14.9 (CH3), 13.0
(CH3), 12.6 (CH); HRMS (ESI) calcd for C21H37NO6Na (Mþ
Na)þ 422.2513, found 422.2503.
Using the same procedure, (S)-3-((3R,4R)-4-(((2R,4R,5R)-4-
ethyltetrahydro-5-methoxy-2-methylfuran-2-yl)methyl)-3-hydro-
xyhexanoyl)-4-isopropyloxazolidin-2-one (17b) was prepared
from (R)-2-(((2R,4R,5R)-4-ethyltetrahydro-5-methoxy-2-methyl-
furan-2-yl)methyl)butan-1-ol (15b) in 56% yield. A second chro-
matography (ether) was necessary in this case.
(S)-3-((3R,4R)-4-(((2R,4R,5R)-4-Ethyltetrahydro-5-methoxy-2-
methylfuran-2-yl)methyl)-3-hydroxyhexanoyl)-4-isopropyloxa-
zolidin-2-one (17b): pale yellow oil; Rf 0.3 (3:7 EtOAc/hexanes-
); [R]20D=þ23 (0.06, CHCl3); 1H (CDCl3, 500 MHz) δ 4.64 (d,
J=4.4 Hz, 1H), 4.45-4.55 (m, 2H), 4.27 (br t, J=8.5 Hz, 1H),
4.21 (dd, J=9, 3 Hz, 1H), 3.70 (d, J = 6.5 Hz, 1H), 3.43 (s, 3H),
3.13 (dd, J = 15.5, 10 Hz, 1H), 3.02 (dd, J = 15.5, 2.5 Hz,
1H), 2.35-2.43 (m, 1H), 2.17-2.25 (m, 1H), 2.05 (dd,
J =12, 8 Hz, 1H), 1.91 (dd, J= 14.5, 9 Hz, 1H), 1.73-1.79
(m, 1H), 1.53-1.62 (m, 1H, overlapped with water peak),
1.33-1.53 (m, 4H), 1.31 (s, 3H), 1.20-1.29 (m, 1H), 0.88-
0.96 (m, 12H); 13C NMR (CDCl3, 125 MHz) δ 172.5 (C), 154.4
(C), 112.6 (CH), 84.6 (C), 68.9 (CH), 63.6 (CH2), 58.6 (CH),
57.2 (CH3), 47.6 (CH), 45.6 (CH2), 41.8 (CH), 41.1 (CH2), 39.7
(CH2), 28.7 (CH), 26.9 (CH3), 26.0 (CH2), 23.9 (CH2), 18.2
(CH3), 14.9 (CH3), 12.8 (CH3), 12.5 (CH3); HRMS (ESI)
calcd for C21H37NO6Na (M þ Na)þ 422.2513, found 422.2514.
Preparation of (3R,4R)-methyl 4-(((2R,4R,5S)-4-ethyltetra-
hydro-5-methoxy-2-methylfuran-2-yl)methyl)-3-hydroxyhexano-
ate (1a). To the solution of 17a (10 mg, 0.02 mmol) in THF
Preparation of Methyl 2-((1S,3R,4R,6R,8R)-4,8-Diethyl-6-
methyl-2,9-dioxabicyclo[4.2.1]nonan-3-yl)acetate (18). 1a or 1b
(4 mg, 0.013 mmol) was dissolved in chloroform (0.5 mL), pyr-
idinium p-toluenesulfonate (3.3 mg, 0.013 mmol) was added, and
the reaction mixture was kept at 45 °C for 15 h (in the rotavap bath.
Initially, the reaction was carried out directly in the NMR tube,
1
monitoring by periodic H NMR spectra. Gradual emergence of
the product peaks was observed, along with decay of the starting
material peaks, with a small degree of equilibration of 1a to 1b, or
vice versa). Upon completion, the reaction mixture was diluted with
methylene chloride (5 mL), washed with satd NaHCO3 (5 mL) and
brine, dried over Na2SO4, and concentrated. Chromatography
(EtOAc/hexanes, 0:1 to 3:7) afforded pure 18 (3 mg, 84%).
6090 J. Org. Chem. Vol. 74, No. 16, 2009

John et al.
Methyl 2-((1S,3R,4R,6R,8R)-4,8-diethyl-6-methyl-2,9-dioxa-
bicyclo[4.2.1]nonan-3-yl)acetate (18): pale yellow oil; Rf 0.25 (1:9
JOCArticle
Acknowledgment. This work was supported by the Amer-
ican Chemical Society Petroleum Research Fund under
Grant No. PRF#46278-G1 and also the National Institutes
of Health under Grant No. GM085645. We thank Alena
Kubatova for HRMS analyses. The work on TOF MS was
supported by the National Foundation under Grant No.
CHE-0216038.
1
EtOAc/hexanes); [R]20D=þ25 (0.02, CHCl3); H NMR (C6D6,
500 MHz) δ 5.25 (s, 1H), 4.97 (ddd, J=9.5, 4.5, 1 Hz, 1H), 3.37 (s,
3H), 2.76 (dd, J=15.5, 9.5 Hz, 1H), 2.19 (dd, J=15.5, 4.5 Hz, 1H),
1.97-2.08 (m, 2H), 1.49-1.55 (m, 2H), 1.42-1.49 (m, 2H), 1.36-
1.41 (m, 1H), 1.24-1.32 (m, 4H), 1.25 (s), 1.00-1.09 (m, 2H), 0.79
(t, J=7.5 Hz, 3H), 0.72 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz): δ 172.6 (C), 104.9 (CH), 87.0 (C), 69.3 (CH), 51.8 (CH3),
51.4 (CH), 44.4 (CH), 40.5 (CH2), 39.3 (CH), 39.1 (CH2), 32.1
(CH3), 26.9 (CH2), 19.3 (CH2), 13.1 (CH3), 12.5 (CH3); HRMS
(ESI) calcd for C15H27O4 (MþH)þ 271.1904, found 271.1908.
Supporting Information Available: Copies of 1H, 13C,
COSY and 1D NOE difference spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6091