Stereoselective synthesis of both enantiomers of rugulactone

Article abstract of DOI:10.1021/jo2004583

The stereoselective total synthesis of both enantiomers of rugulactone 1 has been completed by applying enantioselective allyl additions as key steps. Two different strategies based on highly stable and enantiomerically pure α-substituted allylboronic esters 2 and 3 were performed starting from boronic ester 4.

Full text of DOI:10.1021/jo2004583

ARTICLE
pubs.acs.org/joc
Stereoselective Synthesis of Both Enantiomers of Rugulactone
Dietrich B€ose, Enrique Fernꢀandez, and J€org Pietruszka*
Institut f€ur Bioorganische Chemie der Heinrich-Heine-Universit€at D€usseldorf, Forschungszentrum J€ulich, Stetternicher Forst, Geb. 15.8,
52426 J€ulich, Germany
S Supporting Information
b
ABSTRACT: The stereoselective total synthesis of both enan-
tiomers of rugulactone 1 has been completed by applying
enantioselective allyl additions as key steps. Two different stra-
tegies based on highly stable and enantiomerically pure R-
substituted allylboronic esters 2 and 3 were performed starting
from boronic ester 4.
’ INTRODUCTION
reagents to aldehydes proved to be an excellent approach for the
construction of enantiomerically pure 1,5-ene-diols. The ease of
access of these reagents, their stability, high stereoselectivity, and
the mild conditions of the allyl additions make the use of this
method appropriate for multistep synthesis.
Rugulactone (1) is a naturally occurring dihydro-R-pyrone
isolated for the first time in 2009 from the plant Cryptocarya
rugulosa.1 Rugulactone (1) has proved to inhibit the nuclear
factor NF-kB activation pathway in lymphoma cell lines, which is
constitutively active in many types of cancers, and thus a
potential therapeutic target.2 Due to its remarkable inhibition
activity,1,3 some total syntheses have already been reported in the
literature.3,4 The published syntheses of rugulactone are based in
cross-coupling reactions or Horner-Wadworth-Emmons (HWE)
olefination for the construction of the internal E-olefin, and Still-
Gennari olefination or Ring-Closing-Metathesis (RCM) for the
synthesis of the Z-configured R,β-unsaturated lactone. The
chirality was induced through different ways: by using a chiral
pool,4c proline-catalyzed R-aminooxylation of aldehydes,3 enzy-
matic resolution of racemic homoallylic alcohols,4e Jacobseꢀns
’ RESULTS AND DISCUSSION
To prove the viability of our reagents we envisioned two
approaches for the enantioselective synthesis of rugulactone (1).
The first approach, which is summarized in Scheme 1, was based
on the synthesis of the open chain 1,5-ene-diol system (E-olefin)
by means of the allyl addition of allylboronic ester 2 to aldehyde 5
and the subsequent construction of the lactone using RCM after
functional group interconversion of acrylate 6.
The starting R-substituted allylboronic ester 2a was readily
available5e,f from methylsulfonate 4 after palladium-catalyzed
carbonyl allylation with SnCl2 (60% yield, Scheme 2). Subse-
quent TES protection of 2a furnished the protected allylboronic
ester 2b (95% yield). The addition of the resulting allylboronic
ester 2b to aldehyde 5 produced the corresponding 1,5-ene-diols
7b and 8b in moderate yield (53%) and with unfavorable
diastereomeric ratio (7b:8b = 40:60). Nevertheless, we were
able to separate the two diastereomers by means of MPLC. The
observed Z-selectivity was somehow expected, since we have
already shown that the presence of a protecting group in these
reagents results in an enhancement of the Z-product in the allyl
addition (transition states B versus A).5f Therefore, we
hydrolytic kinetic resolution of epoxides,4a or Kecks asymmetric
ꢀ
allylation.4b A close look at the structure of rugulactone (1)
shows two chiral 1,5-ene-diol systems, which can be considered
as the key targets for its successful enantioselective total
synthesis.
As a part of our ongoing project focused on the development
of efficient allylboron reagents5 for allyl additions to obtain
enantiopure homoallylic alcohols, we have recently developed
a family of new reagents for the stereocontrolled synthesis of 1,5-
ene-diols.5e,f We have shown that boronic ester 4 is a suitable
precursor for palladium-catalyzed allylation of carbonyl com-
pounds with SnCl2 via the formation of an π-allylpaladium(II)
complex. The reaction proceeds smoothly to give stereoselec-
tively R-substituted allylboronic esters. The addition of the new
Received: March 2, 2011
Published: March 24, 2011
r
2011 American Chemical Society
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|

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Scheme 1. First Retrosynthetic Approach for the Synthesis of
Rugulactone (1)
Scheme 3. Dead End of the First Approach Toward
Rugulactone (1)
Scheme 2. Synthesis of 1,5-Ene-Diols by Means of Allyl
Additions
Scheme 4. Second Retrosynthetic Approach for the
Synthesis of Rugulactone (1)
With alcohol 9 in hand, we were able to move on with our
strategy by esterification with acryloyl chloride (96% yield) and
the simultaneous deprotection of both TBS protected alcohols in
performed the allyl addition with unprotected allylboronic ester
2a, envisaging an improvement of the E-selectivity as well as the
yield. Indeed, the E-selectivity (7a:8a = 60:40) and the yield
(76%) were increased.
acrylate 10 with HF pyridine (88% yield). The next step was the
3
oxidation of both hydroxyl groups in diol 11 with DMP.
However, we were not able to isolate the desired keto-aldehyde
12. We observed decomposition, most likely by β-elimination,
leading to R,β-unsaturated aldehyde 13 (Scheme 3). As ex-
pected, aldehyde 12 proved to be very unstable under alkaline
conditions. To avoid this, we decided not to isolate the inter-
mediate 12, but to perform the Wittig-olefination in situ. Un-
fortunately, no formation of acrylate 14 was detected and
aldehyde 13 was again obtained almost quantitatively. The
uncontrolled reactivity of 12 and the low selectivity of the
original allyl addition led us to focus our efforts in a second
approach.
With the improved yield and selectivity, we faced the
problem of having two unprotected hydroxy groups in diol
7a. Consequently, we needed a strategy to distinguish between
the homoallylic alcohol and the allylic alcohol. Surprisingly,
attempts failed to selectively oxidize the allylic alcohol directly,
e.g. with γ-MnO2. Roush and co-workers showed that upon
treatment with imidazole and catalytic DMAP in 1:1
CH2Cl2ꢀDMF at ꢀ78 °C, silyl-protecting groups can mask
one of two hydroxyl groups in similar 1,5-diols chemoselec-
tively (>95:5).6 Although they described that the selective
protection works best with TESCl, in the present example
TBSCl proved to be superior: the desired allyl-protected
alcohol 9 was obtained in 43% yield [31% of starting material
(7a) was recovered (Scheme 3)]. Further efforts to increase the
yield of the reaction by adding additional equivalents of TBSCl
resulted in the doubly protected product.
The second route utilizes allylboronic ester 3 to achieve
enantioselectively the Z-configured R,β-unsaturated lactone of
rugulactone (1), and a HWE olefination for the synthesis of the
E-olefin (Scheme 4). We thought that an allyl addition of
allylboronic ester 3 to aldehyde 5, followed by oxidation of the
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Scheme 5. Synthesis of Rugulactone (1)
the optical rotation of the natural product 1 have been reported.
Values range from ꢀ46.5 (c 0.7, CHCl3)4e or ꢀ47.0 (c 0.3,
CHCl3)4c to ꢀ57.9 (c 0.7, CHCl3)3 or ꢀ61.9 (c 0.5, CHCl3).4b
Not surprisingly the values we received {[R]20 (1) ꢀ82.5
D
(c 1.03, CHCl3), [R]20 (ent-1) þ78.9 (c 0.53, CHCl3)} are
D
different from the ones mentioned before; however, to exclude a
systematic error in our investigation we rigorously proved the
analytical purity of the final natural product 1.
’ CONCLUSION
We have reported the enantioselective synthesis of both
enantiomers of rugulactone (1) employing highly stereoselective
allyl additions of allylboronic esters as the source of chirality. The
synthesis was short (five steps starting from 3), efficient (38%
overall yield), highly selective [98.4% ee for rugulactone (1) and
96.0% ee for ent-rugulactone (ent-1)], and provided the product
1 with unprecedented purity. The success of this total synthesis
shows the versatility and viability of the family of R-substituted
allylboronic esters. Further applications of these reagents in
natural product synthesis are currently under investigation in
our laboratories.
Scheme 6. Enantioselective Total Synthesis of Both
Enantiomers of Rugulactone Starting from Allylboronic
Esters 3a and 3b
’ EXPERIMENTAL SECTION
General Experimental Details. Unless otherwise specified the
reactions were carried out by using standard Schlenk techniques under
dry N2 with magnetic stirring. Glassware was oven-dried at 120 °C
overnight. Solvents were dried and purified by conventional methods
prior to use. All the reagents were used as purchased from commercial
suppliers without further purification. Common solvents for chroma-
tography (petroleum ether 40ꢀ60 °C, ethyl acetate) were distilled prior
to use. Flash column chromatographies were performed on silica gel 60,
0.040ꢀ0.063 mm (230ꢀ400 mesh). TLC (monitoring the course of the
reactions) was performed on precoated plastic sheets with detection by
UV (254 nm) and/or by coloration with cerium molybdenum solution
corresponding 1,5-ene-diol to form R,β-unsaturated lactone 15,7
should be more effective than our first synthetic approach. We
have previously reported that boronic ester 3 adds to aldehydes
producing 1,5-ene-diols with complete Z-selectivity.5e Further-
more, both diastereomers 3a and 3b are readily available, which
give us access to both enantiomers of rugulactone (1).
Allylboronic esters 3a and 3b were synthesized starting from
methylsulfonate 4 and isolated in 85% yield as a 50:50 mixture of
diastereomers, which were completely separated by means of
MPLC. The subsequent addition of reagent 3a to aldehyde 5 via
transition state A (see Scheme 2) gave 1,5-ene-diol 16 in 93%
yield, with almost complete Z-selectivity (dr >20:1) and in
excellent enantioselectivity (98.4% ee; determined by means of
HPLC of the corresponding lactone 15) (Scheme 5). The
regioselective oxidation of diol 16 with PhI(OAc)2 (BAIB) and
TEMPO in CH2Cl2 produced lactone 15 (92%); the TBS-group
[phosphomolybdic acid (25 g), Ce(SO4)2 H2O (10 g), concd H2SO4
3
(60 mL), H2O (940 mL)]. Preparative medium pressure liquid chro-
matography (MPLC) was performed with a packed column (25 ꢁ 300
mm or 40 ꢁ 475 mm; Si 60, 15ꢀ25 μm) and a UV detector (254 nm).
HPLC was performed on standard devices equipped with a Chiralcel OB
1
or Chiralcel IA column. H and 13C spectra were recorded at room
temperature in CDCl3 on a spectrometer at 600 and 151 MHz,
respectively. The chemical shifts are given in ppm relative to internal
standard TMS (1H: δ [Si(CH3)4] 0.00 ppm) or relative to the resonance
of the solvent (13C: δ (CDCl3) 77.0 ppm). Coupling constants J are
given in Hz. Higher order δ and J values are not corrected. 13C signals
were assigned by means of C, H, COSY, and HSQC or HMBC
spectroscopy. Optical rotations were measured at 20 °C, using a quartz
cell with 1 mL capacity and a 10 cm path length. Melting points are
uncorrected. Synthesis of allyl boronic esters 2a, 3a, and 3b5f as well as of
aldehyde 58 and dimethyl-(2-oxo-4-phenylbutyl)phosphonate9 was
accomplished according to literature procedures.
was deprotected with BF3 OEt2 to obtain lactone 17 in 92%
3
yield. The oxidation of lactone 17 with BAIB led to aldehyde 18,
which was directly subjected to HWE-olefination giving rugu-
lactone (1) in 48% yield after two steps (38% yield after 5 steps
starting from 3a). Likewise, allylboronic ester 3b was used in the
same sequence producing ent-rugulactone (ent-1) in 38% yield
after 5 steps.
(3S,4R,40R,50R)-Triethylsilyl-4-[40,50-bis(methoxydiphen-
ylmethyl)-10,30,20-dioxaborolan-20-yl)]-1-phenylhex-5-en-3-
ol (2b). Allylboronic ester (3S,4R,40R,50R)-4-[40,50-bis(methoxydiph-
enylmethyl)-10,30,20-dioxaborolan-20-yl]-1-phenylhex-5-en-3-ol (2a)
(200 mg, 0.31 mmol) was dissolved in dry CH2Cl2 (10 mL) and cooled
to 0 °C. To this solution were added 2,6-lutidine (92 mg, 0.62 mmol,
3.00 equiv) and TESOTf (159 mg, 0.62 mmol, 2.00 equiv) under a
atmosphere of dry nitrogen. The reaction mixture was warmed to room
temperature and stirred for 12 h. After full conversion (as judged by
TLC) 10 mL of sat. aq NaHCO3 was added. The layers were separated
and the aqueous layer was washed with CH2Cl2. The combined organic
The enantiomeric purity of the final rugulactones (1 and
ent-1) was highly dependent on the diastereomeric purity of the
allylboronic esters 3a and 3b that were separated by means of
MPLC (Scheme 6). Thus, when we employed allylboronic ester
3a (99.2% de), lactone 15 was obtained after oxidation with
98.4% ee, while allylboronic ester 3b (98.2% de) led to lactone
ent-15 with 96.0% ee. In the literature several different values for
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layers were dried with MgSO4 and filtered, then the solvent was removed
under reduced pressure. The crude product was purified by column
chromatography (petroleum ether/ethyl acetate, 90:10) yielding allyl-
boronic ester 2b (220 mg, 0.29 mmol, 97%) as a colorless foam. Rf 0.81
(petroleum ether/ethyl acetate, 80:20); [R]20D ꢀ85.0 (c 1.20, CHCl3);
IR (film) νmax (cmꢀ1) 3060, 3026, 2833, 1629, 1603, 1495, 1368, 1341,
1231, 1200, 1076, 698; 1H NMR (600 MHz, CDCl3) δ 0.50 (q, J = 7.8
Hz, 6 H, CH3CH2Si), 0.88 (t, J = 7.8 Hz, 9 H, CH3CH2Si), 1.20 (dddd,
J = 13.7, 12.3, 5.5, 4.4 Hz, 1 H, 2-Ha), 1.41 (dddd, J = 13.7, 12.2, 4.9, 4.6
Hz, 1 H, 2-Hb), 1.75 (dd, J = 10.0, 8.1 Hz, 1 H, 4-H), 2.43 (ddd, J = 13.4,
12.3, 4.6 Hz, 1 H, 1-Ha), 2.48 (ddd, J = 13.4, 12.2, 5.5 Hz, 1 H, 1-Hb),
2.98 (s, 6 H, OCH3), 3.58 (ddd, J = 8.1, 4.9, 4.4 Hz, 1 H, 3-H), 4.69 (dd,
J = 17.0, 2.2 Hz, 1 H, 6-HE), 4.78 (dd, J = 10.1, 2.2 Hz, 1 H, 6-HZ), 5.34
(s, 2 H, 40-H and 50-H), 5.47 (ddd, J = 17.0, 10.1, 10.0 Hz, 1 H, 5-H),
6.95ꢀ7.40 (m, 25 H, ArꢀH); 13C NMR (151 MHz, CDCl3) δ 5.2
(CH3CH2Si), 7.0 (CH3CH2Si), 30.2 (C-1), 37.4 (C-4), 37.9 (C-2), 51.8
(OCH3), 71.5 (C-3), 77.7 (C-40 and C-50), 83.6 (CPh2OMe), 115.1
(C-6), 125.3, 127.3, 127.7, 128.1, 128.3, 129.7 (ArꢀC), 136.9 (C-5),
141.1, 141.4 (ArꢀCipso); MS (ESI, positive ion) m/z (%) 775 (100)
[(M þ Na)þ], 770 (30) [(M þ NH4)þ]. Anal. Calcd (%) for
C48H57BO5Si (752.86): C 76.58, H 7.63. Found: C 76.53; H 7.63.
General Procedure A: Allyl Additions. 3-(tert-Butyldimethyl-
silyloxy)propanal (5) (2.00 equiv) was added to a precooled solution of
the allylboronic esters 2b, 2a, 3a, or 3b (1.00 equiv) in dry CH2Cl2
(0.5 mL/mmol allylboronic ester) at 0 °C and the mixture was first
stirred at 0 °C for 12 h and then at room temperature until full
conversion was determined by TLC (3 d). The solvent was removed
under reduced pressure and the products were purified via column
chromatography, yielding the allylic alcohols as colorless oils. In cases
where E/Z-diastereomers of the 1,5-diols were obtained an additional
MPLC was used to separate them.
J = 13.4 11.1, 5.6, 5.5 Hz, 1 H, 8-Ha), 1.86 (dddd, J = 13.4, 11.0, 7.1, 5.3
Hz, 1 H, 8-Hb), 2.20 (dddd, J = 14.5, 7.7, 6.2, 1.5 Hz, 1 H, 4-Ha), 2.27
(dddd, J = 14.5, 7.0, 7.0, 1.8 Hz, 1 H, 4-Hb), 2.61 (ddd, J = 13.8, 11.0, 5.6
Hz, 1 H, 9-Ha), 2.71 (ddd, J = 13.8, 11.1, 5.3 Hz, 1 H, 9-Hb), 3.50 (d, J =
2.3 Hz, 1 H, 3-OH), 3.81 (ddd, J = 10.4, 7.8, 5.3 Hz, 1 H, 1-Ha),
3.84ꢀ3.89 (m, 1 H, 3-H), 3.91 (ddd, J = 10.4, 4.7, 4.5 Hz, 1 H, 1-Hb),
4.46 (dddd, J = 7.1, 6.5, 5.5, 1.2 Hz, 1 H, 7-H), 5.42 (dddd, J = 11.1, 7.7,
7.1, 1.2 Hz, 1 H, 5-H), 5.55 (dddd, J = 11.1, 8.5, 1.8, 1.5 Hz, 1 H, 6-H),
7.15ꢀ7.28 (m, 5 H, ArꢀH); 13C NMR (151 MHz, CDCl3) δ ꢀ5.3
(CH3Si), 5.2 (CH3CH2Si), 7.1 (CH3CH2Si), 18.3 ((CH3)3CSi), 26.1
((CH3)3CSi), 31.9 (C-9), 36.1 (C-4), 38.0 (C-2), 40.4 (C-8), 63.0
(C-1), 68.5 (C-7), 72.2 (C-3), 125.2 (C-5), 125.9, 128.5, 128.6 (ArꢀC),
136.1 (C-6), 142.2 (ArꢀCipso); MS (EI, positive ion, 70 eV) m/z (%)
355 (48), 289 (10), 223 (14), 189 (52) [(C9H21O2Si)þ], 131 (100)
[(C6H15OSi)þ]; HRMS (ESI, positive ion) m/z calcd for C27H50O3S-
i2Na [M þ Na]þ 501.31907, found 501.31906.
(3R,7S,5E)-1-(tert-Butyldimethylsilyloxy)-9-phenylnon-5-
ene-3,7-diol (7a) and (3S,7S,5Z)-1-(tert-Butyldimethylsilylo-
xy)-9-phenylnon-5-ene-3,7-diol (8a). 7a and 8a were prepared
according to general procedure A with allyloronic ester 2a (1.09 g, 1.70
mmol), yielding a mixture of diastereomers 7a and 8a (dr 7a:8a = 60:40;
separated by MPLC, petroleum ether/ethyl acetate, 70:30) (469 mg,
1.29 mmol, 76%) as a colorless oil.
7a: Rf 0.22 (petroleum ether/ethyl acetate, 80:20); [R]20 þ5.5
D
(c 0.52, CHCl3); IR (film) νmax (cmꢀ1) 3352, 2928, 2857, 1496, 1471,
1
1253, 1082, 970; H NMR (600 MHz, CDCl3) δ 0.07, 0.08 (s, 3 H,
CH3Si), 0.09 (s, 9 H, t-BuSi), 1.64ꢀ1.68 (m, 2 H, 2-Ha and 2-Hb), 1.73
(dddd, J = 13.6, 9.8, 6.4, 5.7 Hz, 1 H, 8-Ha), 1.80 (dddd, J = 13.6, 9.6, 7.3,
6.1 Hz, 1 H, 8-Hb), 2.14 (dddd, J = 14.1, 7.0, 5.6, 1.3 Hz, 1 H, 4-Ha), 2.18
(dddd, J = 14.1, 7.1, 6.8, 1.2 Hz, 1 H, 4-Hb), 2.58 (ddd, J = 13.8, 9.6, 6.4
Hz, 1 H, 9-Ha), 2.65 (ddd, J = 13.8, 9.8, 6.1 Hz, 1 H, 9-Hb), 3.70ꢀ3.75
(m, 1 H, 1-Ha), 3.42 (s, 1 H, 7-OH), 3.78ꢀ3.83 (m, 2 H, 1-Hb and 3-H),
4.02 (dddd, J = 7.3, 6.7, 5.7, 1.0 Hz, 1 H, 7-H), 5.52 (dddd, J = 15.4, 6.7,
1.3, 1.2 Hz, 1 H, 6-H), 5.63 (dddd, J = 15.4, 7.1, 7.0, 1.0 Hz, 1 H, 5-H),
7.08ꢀ7.21 (m, 5 H, ArꢀH); 13C NMR (151 MHz, CDCl3) δ ꢀ5.5,
ꢀ5.6 (2 ꢁ CH3Si), 18.1 ((CH3)3CSi), 25.8 ((CH3)3CSi), 31.7 (C-9),
37.7 (C-2), 38.7 (C-8), 40.2 (C-4), 62.6 (C-1), 71.5 (C-7), 72.0 (C-3),
125.7, 128.3, 128.4 (ArꢀC), 127.9 (C-6), 135.6 (C-5), 142.0
(ArꢀCipso); MS (EI, positive ion, 70 eV) m/z (%) 281 (31), 207
(33), 189 (17) [(C9H21O2Si)þ], 131 (100) [C6H15OSiþ)]; HRMS
(ESI, positive ion) m/z calcd for C21H36O3SiNa [M þ Na]þ 387.23259,
found 387.23226.
(3R,7S,5E)-1-(tert-Butyldimethylsiloxy)-9-phenyl-7-(trie-
thylsiloxy)non-5-en-3-ol (7b) and (3S,7S,5Z)-1-(tert-Butyl-
dimethylsiloxy)-9-phenyl-7-(triethylsiloxy)non-5-en-3-ol
(8b). 7b and 8b were synthesized according to general procedure A with
allylboronic ester 2b (1.36 g, 1.80 mmol), yielding a mixture of
diastereomers 7b and 8b (dr 7b:8b = 40:60; separated by MPLC,
petroleum ether/ethyl acetate, 77:23) (347 mg, 0.96 mmol, 53%) as a
colorless oil.
7b: Rf 0.71 (petroleum ether/ethyl acetate, 80:20); [R]20 þ2.1
D
(c 0.49, CHCl3); IR (film) νmax (cmꢀ1) 3461, 2952, 2876, 1462, 1253,
1082, 1004; 1H NMR (600 MHz, CDCl3) δ 0.08 (s, 6 H, CH3Si), 0.59
(q, J = 7.9 Hz, 6 H, CH3CH2Si), 0.91 (s, 9 H, t-BuSi), 0.95 (t, J = 7.9 Hz,
9 H, CH3CH2Si), 1.62ꢀ1.71 (m, 2 H, 2-Ha and 2-Hb), 1.78 (dddd, J =
13.6, 10.4, 5.8, 5.8 Hz, 1 H, 8-Ha), 1.85 (dddd, J = 13.6, 10.3, 6.2, 6.2 Hz,
1 H, 8-Hb), 2.19ꢀ2.28 (m, 2 H, 4-Ha and 4-Hb), 2.62 (ddd, J = 13.7,
10.3, 5.8 Hz, 1 H, 9-Ha), 2.67 (ddd, J = 13.7, 10.4, 6.2 Hz, 1 H, 9-Hb),
3.29 (d, J = 2.3 Hz, 3-OH), 3.80 (ddd, J = 10.3, 8.3, 4.4 Hz, 1 H, 1-Ha),
3.84ꢀ3.89 (m, 1 H, 3-H), 3.90 (ddd, J = 10.3, 4.7, 4.7 Hz, 1 H, 1-Hb),
4.12 (dddd, J = 6.7, 6.2, 5.8, 1.0 Hz, 1 H, 7-H), 5.55 (dddd, J = 15.4, 6.7,
1.1, 1.1 Hz, 1 H, 6-H), 5.62 (dddd, J = 15.4, 6.9, 6.8, 1.0 Hz, 1 H, 5-H),
7.15ꢀ7.29 (m, 5 H, ArꢀH); 13C NMR (151 MHz, CDCl3) δ ꢀ5.3
(CH3Si), 5.3 (CH3CH2Si), 7.1 (CH3CH2Si), 18.3 ((CH3)3CSi), 26.1
((CH3)3CSi), 31.9 (C-9), 38.0 (C-2), 40.3 (C-8), 40.5 (C-4), 62.8
(C-1), 71.7 (C-3), 73.2 (C-7), 126.9 (C-5), 125.8, 128.5, 128.6 (ArꢀC),
136.4 (C-6), 142.2 (ArꢀCipso); MS (EI, positive ion, 70 eV) m/z (%)
355 (48), 289 (10), 223 (14), 189 (52) [(C9H21O2Si)þ], 131 (100)
[(C6H15OSi)þ]. Anal. Calcd (%) for C27H50O3Si2 (478.86): C 67.72, H
10.52. Found: C 67.53, H 10.44.
20
8a: Rf 0.31 (petroleum ether/ethyl acetate, 80:20); [R]D ꢀ48.0 (c
0.66, CHCl3); IR (film) νmax (cmꢀ1) 3370, 2928, 2857, 1496, 1471,
1
1253, 1082, 970; H NMR (600 MHz, CDCl3) δ 0.07, 0.08 (s, 3 H,
CH3Si), 0.89 (s, 9 H, t-BuSi), 1.60 (dddd, J = 14.3, 4.3, 3.3, 2.2 Hz, 1 H,
2-Ha), 1.73 (dddd, J = 14.3, 9.9, 9.7, 4.3 Hz, 1 H, 2-Hb), 1.80 (dddd, J =
13.2, 10.2, 6.0, 5.8 Hz, 1 H, 8-Ha), 1.93 (dddd, J = 13.2, 10.0, 7.1, 5.9 Hz,
1 H, 8-Hb), 2.21 (dddd, J = 14.0, 6.8, 5.6, 1.2 Hz, 1 H, 4-Hb), 2.43 (dddd,
J = 14.0, 8.8, 5.1, 1.2 Hz, 1 H, 4-Ha), 2.67 (ddd, J = 13.9, 10.2, 5.9 Hz, 1 H,
9-Ha), 2.74 (ddd, J = 13.9, 10.0, 6.0 Hz, 1 H, 9-Hb), 3.81 (ddd, J = 10.1,
9.9, 3.3 Hz, 1 H, 1-Hb), 3.87 (ddd, J = 10.1, 4.3, 4.3 Hz, 1 H, 1-Ha), 3.97
(dddd, J = 9.7, 5.6, 5.1, 2.2 Hz, 1 H, 3-H), 4.40 (dddd, J = 8.2, 7.1, 5.8, 1.1
Hz, 1 H, 7-H), 5.60 (dddd, J = 11.0, 8.8, 6.8, 1.0 Hz, 1 H, 5-H), 5.67
(dddd, J = 11.0, 8.2, 1.2, 1.2 Hz, 1 H, 6-H), 7.15ꢀ7.29 (m, 5 H, ArꢀH);
13C NMR (151 MHz, CDCl3) δ ꢀ5.4, ꢀ5.3 (2 ꢁ CH3Si), 18.2
((CH3)3CSi), 25.9 ((CH3)3CSi), 32.0 (C-9), 35.1 (C-4), 37.4 (C-2),
38.8 (C-8), 63.4 (C-1), 66.6 (C-7), 71.7 (C-3), 127.7 (C-5), 125.9,
128.5, 128.6 (ArꢀC), 136.1 (C-5), 142.3 (ArꢀCipso); MS (EI, positive
ion, 70 eV) m/z (%) 281 (76), 189 (10) [(C9H21O2Si)þ], 131 (100)
[C6H15OSi)þ]; HRMS (ESI, positive ion) m/z calcd for C21H36O3SiNa
[M þ Na]þ 387.23259, found 387.23221.
8b: Rf 0.71 (petroleum ether/ethyl acetate, 80:20); [R]20D ꢀ43.0 (c
0.51, CHCl3); IR (film) νmax (cmꢀ1) 3480, 2952, 2876, 1462, 1253,
1082, 1004; 1H NMR (600 MHz, CDCl3) δ 0.09 (s, 6 H, CH3Si), 0.59
(q, J = 7.9 Hz, 6 H, CH3CH2Si), 0.91 (s, 9 H, t-BuSi), 0.95 (t, J = 7.9 Hz,
9 H, CH3CH2Si), 1.61ꢀ1.68 (m, 2 H, 2-Ha and 2-Hb), 1.74 (dddd,
(5S,2Z)-7-(tert-Butyldimethylsilyloxy)hept-2-ene-1,5-diol
(16). The title compound was synthesized according to general
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The Journal of Organic Chemistry
ARTICLE
procedure A with allyloronic ester 3a (513 mg, 0.96 mmol) yielding diol
16 (226 mg, 0.87 mmol, 93%) as a colorless oil. Rf 0.26 (petroleum
was monitored by TLC and quenched immediately after full conversion
was detected (2 h) by addition of 10 mL of Et2O and 10 mL of saturated
NH4Cl solution. The layers were separated and the organic layer was
washed with 10 mL of a saturated NaHCO3 solution, dried with MgSO4,
filtered, and concentrated in vacuo, then purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate, 95:5) to afford
acrylate 10 as a colorless oil (142 mg, 0.27 mmol, 96%). Rf 0.39
(petroleum ether/ethyl acetate, 95:5); [R]20D ꢀ24.0 (c 0.51, CHCl3);
IR (film) νmax (cmꢀ1) 2954, 2929, 2857, 1725, 1472, 1405, 1253, 1085;
1H NMR (600 MHz, CDCl3) δ 0.01, 0.02, 0.04, 0.05 (s, 3 H, 4 ꢁ
CH3Si), 0.88, 0.89 (s, 9 H, 2 ꢁ t-BuSi), 1.73 (dddd, J = 13.4, 10.6, 5.8, 5.6
Hz, 1 H, 8-Ha), 1.78 (dddd, J = 13.4, 10.6, 6.4, 6.0 Hz, 1 H, 8-Hb), 1.84
(ddd, J = 6.7, 6.3, 6.0 Hz, 2 H, 2-H), 2.31 (dddd, J = 14.0, 6.5, 6.3, 1.1 Hz,
1 H, 4-Ha), 2.42 (dddd, J = 14.0, 6.0, 5.5, 1.1 Hz, 1 H, 4-Hb), 2.57 (ddd,
J = 13.9, 10.6, 5.8 Hz, 1 H, 9-Ha), 2.63 (ddd, J = 13.9, 10.6, 6.0 Hz, 1 H,
9-Hb), 3.64 (dt, J = 10.3, 6.7 Hz, 1 H, 1-Ha), 3.66 (dt, J = 10.3, 6.3 Hz,
1 H, 1-Hb), 4.10 (dddd, J = 6.4, 5.6, 5.5, 1.1 Hz, 1 H, 7-H), 5.11 (ddt, J =
6.3, 6.0, 6.0 Hz, 1 H, 3-H), 5.50ꢀ5.55 (m, 2 H, 5-H and 6-H), 5.76 (dd,
J = 10.4, 1.5 Hz, 1 H, 12-HZ), 6.08 (dd, J = 17.3, 10.4 Hz, 1 H, 11-H),
ether/ethyl acetate, 75:25); [R]20 (16) ꢀ4.6 (c 1.00, CHCl3); IR
D
(film) νmax (cmꢀ1) 3339, 2929, 2857, 1471, 1253, 1086, 1005, 832, 774;
1H NMR (600 MHz, CDCl3) δ 0.08 (s, 6 H, CH3Si), 0.89 (s, 9 H,
t-BuSi), 1.64 (dddd, J = 14.4, 4.5, 3.5, 2.3 Hz, 1 H, 6-Ha), 1.73 (dddd, J =
14.4, 9.7, 9.4, 4.4 Hz, 1 H, 6-Hb), 2.23 (dddd, J = 14.1, 7.4, 4.2, 1.4 Hz,
1 H, 4-Ha), 2.37 (dddd, J = 14.1, 8.5, 7.4, 1.2 Hz, 1 H, 4-Hb), 2.58 (s, 1 H,
5-OH), 3.83 (ddd, J = 10.2, 4.5, 4.4 Hz, 1 H, 7-Ha), 3.88 (dddd, J = 9.4,
7.8, 3.2, 2.3 Hz, 1 H, 5-H), 3.91 (ddd, J = 10.2, 4.5, 4.4 Hz, 1 H, 7-Hb),
4.06 (ddd, J = 12.5, 7.0, 1.4 Hz, 1 H, 1-Ha), 4.18 (ddd, J = 12.5, 8.0, 1.4
Hz, 1-Hb), 5.66 (ddddd, J = 10.9, 8.0, 7.0, 1.4, 1.2 Hz, 1 H, 2-H), 5.90
(ddddd, J = 10.9, 7.4, 7.4, 1.4, 1.4 Hz, 1 H, 3-H); 13C NMR (151 MHz,
CDCl3) δ ꢀ5.4, ꢀ5.5 (2 ꢁ CH3Si), 18.3 ((CH3)3CSi), 26.0
((CH3)3CSi), 35.4 (C-4), 38.0 (C-6), 57.7 (C-1), 63.1 (C-7), 71.3
(C-5), 129.5 (C-3), 131.5 (C-2); MS (EI, positive ion, 70 eV) m/z (%)
189 (40), 131 (100), 105 (50), 75 (70). Anal. Calcd (%) for C13H28O3Si
(260.45): C 59.95, H 10.84. Found: C 59.65, H 10.68.
(5R,2Z)-7-(tert-Butyldimethylsilyloxy)hept-2-ene-1,5-diol
(ent-16) (151 mg, 0.57 mmol, 93%): [R]20D (ent-16) þ3.1 (c 0.81,
CHCl3); the spectroscopic data are identical with those of compound
16.
6.38 (dd, J = 17.3, 1.5 Hz, 1 H, 12-HE), 7.15ꢀ7.28 (m, 5 H, ArꢀH); 13
C
NMR (151 MHz, CDCl3) δ ꢀ5.3, ꢀ4.6, ꢀ4.3, ꢀ4.0 (4 ꢁ CH3Si), 18.4,
18.5 (2 ꢁ (CH3)3CSi), 26.1, 26.2 (2 ꢁ (CH3)3CSi), 31.8 (C-9), 36.8
(C-2), 37.4 (C-4), 40.3 (C-8), 59.6 (C-1), 71.3 (C-3), 73.2 (C-7),125.2
(C-5), 125.8, 128.5, 128.6 (ArꢀC), 129.0 (OCOCHCH2), 130.6
(OCOCHCH2), 137.0 (C-6), 142.7 (ArꢀCipso.), 165.9 (OCOCH-
CH2); (EI, positive ion, 70 eV) m/z (%) 355 (10), 289 (32), 197
(37), 171 (15), 129 (100). Anal. Calcd (%) for C30H52O4Si2 (532.90):
C, 67.61; H, 9.84. Found: C, 67.65; H. 10.00.
(3R,7S,5E)-1,7-di(tert-Butyldimethylsiloxy)-9-phenylnon-
5-en-3-ol (9). 3,7-Diol 7a (100 mg, 0.27 mmol) was dissolved in 2 mL
of a mixture of dry CH2Cl2 and dry DMF (1:1). To this solution were
added imidazole (30 mg, 0.43 mmol, 1.59 equiv) and DMAP (4 mg, 0.03
mmol, 0.11 equiv) under an atmosphere of dry nitrogen before the
mixture was cooled to 0 °C. At this temperature a solution of TBSCl (64
mg, 0.42 mmol, 1.56 equiv) in 1 mL of dry CH2Cl2 and dry DMF (1:1)
was added dropwise over a period of 20 min. The reaction mixture was
slowly warmed to room temperature and was stirred for an additional 12
h. After dilution with 10 mL of Et2O the reaction was quenched by
addition of 5 mL of saturated NH4Cl solution. The organic layer was
dried with MgSO4, filtered, and concentrated under reduced pressure to
afford a mixture of the desired alcohol 9 and the starting material 7a. The
mixture was separated by chromatography on silica gel (petroleum
ether/ethyl acetate, 97:3 to 60:40) to afford alcohol 9 (56 mg 0.12
mmol, 43%) and the starting material 7a (31 mg 0.09 mmol, 31%) as
colorless oils. Rf 0.61 (petroleum ether/ethyl acetate, 90:10);
(3R,7S,5E)-1,7-Dihydroxy-9-phenylnon-5-en-3-yl acrylate
(11). Silyl protected diol 10 (17 mg, 0.03 mmol) was dissolved in 0.5 mL
of dry THF and charged with HF pyridine (20 μL, 0.16 mmol, 5.33
3
equiv, 70% HF in pyridine) under an atmosphere of dry nitrogen. After
full conversion (judged by TLC, 5 h) the reaction mixture was diluted
with ethyl acetate and washed with saturated NaHCO3 solution (2 ꢁ
10 mL). The organic layer was dried with MgSO4, filtered, and
concentrated in vacuo then purified by column chromatography on
silica gel (petroleum ether/ethyl acetate, 50:50) to afford alcohol 11 as a
colorless oil (8 mg, 0.03 mmol, 88%). Rf 0.25 (petroleum ether/ethyl
acetate, 60:40), [R]20D ꢀ35.7 (c 0.49, CHCl3); IR (film) νmax (cmꢀ1
)
3371, 2924, 1718, 1405, 1295, 1193, 1047; 1H NMR (600 MHz, CDCl3)
δ 1.60 (d, J = 3.7 Hz, 1 H, 7-OH), 1.74 (dddd, J = 14.1, 9.6, 4.4, 4.2 Hz,
1 H, 2-Ha), 1.78 (dddd, J = 13.9, 9.7, 6.5, 5.5 Hz, 1 H, 8-Ha), 1.85 (dddd,
J = 13.9, 9.5, 7.3, 6.2 Hz, 1 H, 8-Hb), 1.89 (dddd, J = 14.1, 9.2, 5.7, 3.3 Hz,
1 H, 2-Hb), 2.28 (dd, J = 7.6, 4.9 Hz, 1 H, 1-OH), 2.39 (ddd, J = 6.3, 4.1,
1.5 Hz, 2 H, 4-H), 2.64 (ddd, J = 14.0, 9.5, 6.5 Hz, 1 H, 9-Ha), 2.69 (ddd,
J = 14.0, 9.7, 6.2 Hz, 1 H, 9-Hb), 3.56 (dddd, J = 11.5, 9.2, 4.9, 4.4 Hz, 1 H,
1-Ha), 3.66 (dddd, J = 11.5, 7.6, 5.7, 4.2 Hz, 1 H, 1-Hb), 4.08 (dddd, J =
7.3, 5.5, 5.4, 3.6 Hz, 1 H, 7-H), 5.17 (dtd, J = 9.6, 6.3, 3.3 Hz, 1 H, 3-H),
5.57ꢀ5.65 (m, 2 H, 5-H and 6-H), 5.84 (dd, J = 10.4, 1.3 Hz, 1 H, 12-
HZ), 6.04 (dd, J = 17.3, 10.4 Hz, 1 H, 11-H), 6.35 (dd, J = 17.3, 10.4 Hz,
1 H, 12-HE), 7.16ꢀ7.29 (m, 5 H, ArꢀH); 13C NMR (151 MHz, CDCl3)
δ 31.9 (C-9), 37.2 (C-2), 37.7 (C-4), 38.8 (C-8), 58.7 (C-1), 71.1 (C-3),
72.2 (C-7), 126.6 (C-5), 126.0, 128.6, 128.6 (ArꢀC), 128.5 (C-11),
131.7 (C-12), 142.0 (ArꢀCipso), 166.9 (C-10); (EI, positive ion, 70 eV)
m/z (%) 405 (11), 355 (12), 281 (92), 253 (20), 207 (100), 133 (27).
Anal. Calcd (%) for C18H24O4 (304.38): C 71.03, H 7.95. Found:
C 71.32, H 7.95.
[R]20 þ4.3 (c 0.48, CHCl3); IR (film) νmax (cmꢀ1) 3459, 2952,
D
2929, 2857, 1472, 1252, 1081, 970; 1H NMR (600 MHz, CDCl3) δ 0.02,
0.05, 0.07, 0.08 (s, 3 H, 4 ꢁ CH3Si), 0.89, 0.90 (s, 9 H, 2 ꢁ t-BuSi), 1.64
(dddd, J = 14.4, 8.5, 8.4, 4.6 Hz, 1 H, 2-Ha), 1.68 (dddd, J = 14.4, 5.1, 4.3,
3.0 Hz, 1 H, 2-Hb), 1.77 (dddd, J = 13.5, 10.6, 5.7, 5.6 Hz, 1 H, 8-Ha),
1.82 (dddd, J = 13.5, 10.6, 6.6, 5.9 Hz, 1 H, 8-Hb), 2.21 (dddd, J = 13.8,
9.6, 6.7, 1.1 Hz, 1 H, 4-Ha), 2.25 (dddd, J = 13.8, 9.8, 6.5, 1.1 Hz, 1 H,
4-Hb), 2.60 (ddd, J = 13.8, 10.6, 5.7 Hz, 1 H, 9-Ha), 2.67 (ddd, J = 13.8,
10.6, 5.9 Hz, 1 H, 9-Hb), 3.28 (d, J = 2.5 Hz, 1 H, 3-OH), 3.80 (ddd, J =
10.2, 8.4, 4.3 Hz, 1 H, 1-Ha), 3.83ꢀ3.87 (m, 1 H, 3-H), 3.89 (ddd, J =
10.2, 5.1, 4.6 Hz, 1 H, 1-Hb), 4.12 (dddd, J = 6.6, 6.5, 5.6, 1.0 Hz, 1 H,
7-H), 5.53 (dddd, J = 15.4, 6.5, 1.1, 1.1 Hz, 1 H, 6-H), 5.60 (dddd, J =
15.4, 6.7, 6.5, 1.0Hz, 1H, 5-H), 7.15ꢀ7.28 (m, 5 H, ArꢀH); 13CNMR(151
MHz, CDCl3) δ ꢀ5.1, ꢀ5.0, ꢀ4.5, ꢀ4.1 (4 ꢁ CH3Si), 18.3, 18.5 (2 ꢁ
(CH3)3CSi), 26.1, 26.2 (2 ꢁ (CH3)3CSi)), 32.0 (C-9), 39.0 (C-8), 40.0
(C-2), 40.6 (C-4), 60.0 (C-1), 69.1 (C-3), 72.6 (C-7), 126.0, 128.6, 128.7
(ArꢀC), 128.6 (C-5), 135.4 (C-6), 142.2 (ArꢀCipso); MS (EI, positive ion,
70 eV) m/z (%) (22), 281 (25), 263 (27), 197 (81), 131 (100). Anal. Calcd
(%) for C27H50O3Si2 (478.86): C 67.72, H 10.52. Found: C 67.74, H 10.53.
(3R,7S,5E)-1,7-di(tert-Butyldimethylsiloxy)-9-phenylnon-
5-en-3-yl acrylate (10). A solution of alcohol 9 (134 mg, 0.28 mmol)
and DMAP (4.2 mg, 0.03 mmol, 0.09 equiv) in 3 mL of dry CH2Cl2 was
cooled to ꢀ78 °C before freshly distilled N,N-diisopropylethylamine
(120 μL, 0.71 mmol, 2.54 equiv) and freshly distilled acryloyl chloride
(50 μL, 0.59 mmol, 2.11 equiv) were added successively. The reaction
(6S)-6-(20-(tert-Butyldimethylsilyloxy)ethyl)-5,6-dihydro-
2H-pyran-2-one (15). To a solution of alcohol 11 (75 mg, 0.29
mmol) in 4 mL of CH2Cl2 were added [bis(acetoxy)iodo]benzene
(BAIB) (388 mg, 1.20 mmol, 4 equiv) and TEMPO (9 mg, 0.06 mmol,
0.05 equiv). The solution was stirred for 4 h at room temperature and
quenched with a mixture of saturated aqueous NaHCO3 (5 mL) and
aqueous Na2S2O3 (5 mL, 10%). The layers were separated and the
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ARTICLE
aqueous layer was extracted with Et2O (3 ꢁ 5 mL). The combined
organic layers were dried with MgSO4, filtered, and concentrated in
vacuo then purified by column chromatography on silica gel (petroleum
ether/ethyl acetate, 90:10) to afford lactone 15 as a colorless oil (68 mg,
0.27 mmol, 92%). Rf 0.54 (petroleum ether/ethyl acetate, 90:10);
added via canula to the cooled mixture of phosphonate. After 1 h at this
temperature the resulting mixture was warmed to room temperature and
quenched by addition of brine (5 mL). The aqueous layer was extracted
with ethyl acetate (3 ꢁ 10 mL) and the combined extracts were washed
with brine (10 mL), dried with MgSO4, filtered, and concentrated in
vacuo. The crude product was purified twice by column chromatography
(first column CH2Cl2, second column petroleum ether/ethyl acetate,
60:40) to afford rugulactone 1 as a colorless oil (22 mg, 0.08 mmol, 48%
[R]20 (15) ꢀ47.3 (c 1.24, CHCl3), ee 98%; HPLC (Chiralcel IA,
D
heptane/iPrOH 97:3, flow = 0.5 mL/min, λ = 205 nm) tR (15) = 12.9
min, tR (ent-15) = 13.7 min; IR (film) νmax (cmꢀ1) 2954, 2929, 1723,
1388, 1251, 1088, 836, 777, 662; 1H NMR (600 MHz, CDCl3) δ 0.05
(s, 6 H, CH3Si), 0.88 (s, 9 H, t-BuSi), 1.84 (dddd, J = 10.1, 8.2, 5.5, 4.7
Hz, 1 H, 10-Ha), 1.99 (dddd, J = 10.1, 7.8, 5.4, 4.6 Hz, 1 H, 10-Hb),
2.33ꢀ2.43 (m, 2 H, 5-Ha and 5-Hb), 3.76 (ddd, J = 10.5, = 5.5, 5.4 Hz,
1 H, 20-Ha), 3.82 (ddd, J = 10.5, 8.2, 4.6 Hz, 1 H, 20-Hb), 4.59ꢀ4.61 (m,
1 H, 6-H), 6.02 (ddd, J = 9.8, 2.3, 1.5 Hz, 1 H, 3-H), 6.87ꢀ6.89 (m, 1 H,
4-H); 13C NMR (151 MHz, CDCl3) δ ꢀ5.3, ꢀ5.2 (2 ꢁ CH3Si), 18.4
((CH3)3CSi), 26.0 ((CH3)3CSi), 29.8 (C-5), 38.0 (C-10), 58.6 (C-20),
76.3 (C-6), 121.6 (C-3), 145.6 (C-4), 164.7 (C-2); MS (EI, positive ion,
70 eV) m/z (%) 204 (100), 127 (10), 77 (50), 51 (20). Anal. Calcd (%)
for C13H24O3Si (256.41): C 60.89, H 11.1. Found: C 60.56, H 9.56.
(6R)-6-(20-(tert-Butyldimethylsilyloxy)ethyl)-5,6-dihydro-
over two steps). Rf 0.21 (petroleum ether/ethyl acetate, 50:50); [R]20
D
(1) ꢀ82.5 (c 1.03, CHCl3); IR (film) νmax (cmꢀ1) 2924, 1722, 1674,
1387, 1246, 1043, 816; 1H NMR (600 MHz, CDCl3) δ 2.32ꢀ2.34 (m,
2 H, 5-Ha, 5-Hb), 2.61 (dddd, J = 14.9, 7.3, 5.5, 1.4 Hz, 1 H, 10-Ha), 2.67
(dddd, J = 14.9, 7.0, 6.8, 1.5 Hz, 1 H and 10-Hb), 2.88ꢀ2.94 (m, 2 H, 60-
H), 2.93ꢀ2.96 (m, 2 H, 50-H), 4.55 (dddd, J = 8.2, 7.6, 6.8, 5.5 Hz, 1 H,
6-H), 6.05 (ddd, J = 9.8, 1.9, 1.9 Hz, 1 H, 3-H), 6.20 (ddd, J = 15.9, 1.5,
1.5 Hz, 1 H, 9-H), 6.80 (ddd, J = 15.9, 7.3, 7.0 Hz, 1 H, 20-H), 6.88 (ddd,
J = 9.8, 4.8, 3.6 Hz, 1 H, 4-H), 7.17ꢀ7.29 (m, 5 H, ArꢀH); 13C NMR
(151 MHz, CDCl3) δ 29.1 (C-5), 30.1 (C-60), 37.7 (C-10), 41.9 (C-50),
76.2 (C-6), 121.7 (C-3), 126.3, 128.5, 128.7 (ArꢀC), 133.7 (C-20),
140.1 (C-4), 141.2 (ArꢀCipso), 144.7 (C-30), 163.8 (C-2), 199.1 (C-40);
HRMS (ESI, positive ion) m/z calcd for C17H18O3Na [M þ Na]þ
293.11482, found 293.11472. Anal. Calcd (%) for C17H18O3 (270.32):
C 75.53, H 6.71. Found: C 75.50, H 6.69.
2H-pyran-2-one (ent-15) (72 mg, 0.28 mmol, 92%): [R]20
D
(ent-15) þ44.9 (c 0.98, CHCl3), ee 96%; the spectroscopic data are
identical with those of compound 15.
(6S)-6-(20-Hydroxyethyl)-5,6-dihydro-2H-pyran-2-one
(17). A solution of TBS-protected lactone 15 (101 mg, 0.39 mmol) in
(S)-Rugulactone (ent-1) (10 mg, 0.04 mmol, 47% over two
steps): [R]20D (ent-1) þ78.9 (c 0.53, CHCl3); the spectroscopic data
are identical with those of (R)-rugulactone (1).
CH2Cl2 (5 mL) was cooled to 0 °C before BF3 OEt2 (124 μL, 0.98
3
mmol, 2.51 equiv) was added. The reaction mixture was stirred at this
temperature for 30 min, quenched with saturated NaHCO3 solution
(1 mL), and extracted with CH2Cl2 (10 ꢁ 2 mL). The combined organic
layers were dried with MgSO4, filtered, and concentrated in vacuo then
purified by column chromatography on silica gel (CH2Cl2/MeOH;
98:2) to afford alcohol 17 as a colorless oil (52 mg, 0.36 mmol, 92%). Rf
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of all
S
b
new products and HPLC chromatograms for 3a/3b and 15/ent-
15. This material is available free of charge via the Internet at
http://pubs.acs.org.
0.33 (petroleum ether/ethyl acetate, 90:10); [R]20 (17) ꢀ118.0
D
(c 1.29, CHCl3); IR (film) νmax (cmꢀ1) 3425, 2927, 1699, 1393,
1
1255, 1056, 818; H NMR (600 MHz, CDCl3) δ 1.91 (dddd, J =
14.5, 8.2, 5.2, 4.2 Hz, 1 H, 10-Ha), 2.03 (dddd, J = 14.5, 8.5, 5.6, 4.6 Hz,
1 H, 10-Hb), 2.39ꢀ2.42 (m, 2 H, 5-Ha and 5-Hb), 3.83 (ddd, J = 10.9, 5.6,
5.2 Hz, 1 H, 10-Ha), 3.90 (ddd, J = 10.9, 5.2, 4.6 Hz, 1 H, 20-Hb), 4.67
(dddd, J = 8.5, 8.5, 7.5, 4.2 Hz, 1 H, 6-H), 6.03 (ddd, J = 9.8, 1.8, 1.8 Hz,
1 H, 3-H), 6.90 (ddd, J = 9.8, 4.3, 4.3 Hz, 1 H, 4-H); 13C NMR (151
MHz, CDCl3) δ 29.8 (C-5), 37.1 (C-10), 58.7 (C-10), 75.8 (C-6), 121.6
(C-3), 145.7 (C-4), 164.2 (C-2); MS (ESI, positive ion) 159.8 (100)
[(M þ NH4)þ], 142.9 (40), [(M)þ]. Anal. Calcd (%) for C7H10O3
(142.15): C 59.14, H 7.09. Found: C 59.10, H 7.03.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: j.pietruszka@fz-juelich.de.
’ ACKNOWLEDGMENT
We gratefully acknowledge the Fonds der Chemischen In-
dustrie (scholarship to D.B.), the Deutsche Forschungsge-
meinschaft (DFG PI 263/5-1), the Ministry of Innovation,
Science, and Research of the German federal state of North
Rhine-Westphalia, the Heinrich-Heine-Universit€at D€usseldorf,
and the Forschungszentrum J€ulich GmbH for their generous
support of our projects. Furthermore, we thank the analytical
departments of the Forschungszentrum J€ulich as well as Dennis
Weidener, Monika Gehsing, Rainer Goldbaum, Birgit Henssen,
Erik Kranz, Vera Ophoven, Bea Paschold, Truc Pham, and Saskia
Schuback for their ongoing support.
(6R)-6-(20-Hydroxyethyl)-5,6-dihydro-2H-pyran-2-one
(ent-17) (40 mg, 0.28 mmol, 93%): [R]20 (ent-17) þ119.6
D
(c 0.54, CHCl3); the spectroscopic data are identical with those of
compound 17.
(6S)-6-(20-Oxoethyl)-5,6-dihydro-2H-pyran-2-one (18). Al-
cohol 17 (25 mg, 0.18 mmol) was dissolved in 3 mL of CH2Cl2 at room
temperature, before BAIB (210 mg, 0.65 mmol, 3.61 equiv) and
TEMPO (4 mg, 0.03 mmol, 0.09 equiv) were added. The reaction
mixture was stirred for 12 h at this temperature, quenched with a mixture
of saturated aqueous NaHCO3 (0.5 mL) and aqueous Na2S2O3 (0.5 mL,
10%), and extracted with CH2Cl2 (5 ꢁ 5 mL). The combined organic
layers were dried with MgSO4, filtered, and concentrated in vacuo. The
crude product was dissolved in dry THF and was used for HWE
olefination reaction without further purification. Rf 0.31 (CH2Cl2/
MeOH, 94:6).
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