Expedient synthesis of a stereoisomer of acremolide B

Article abstract of DOI:10.1021/jo1017487

A highly straightforward strategy for the synthesis of the acremolide class of lipodepsipeptides has been developed. Synthetic highlights include a cross-metathesis to couple the C1-C7 and the C8-C12 fragments, an esterification to introduce the dipeptide unit, a macrolactamization to build the macrolide core, and two stereoselective allylations/crotylations to control all four stereogenic centers of the C1-C12 polypropionate segment.

Full text of DOI:10.1021/jo1017487

pubs.acs.org/joc
Expedient Synthesis of a Stereoisomer of Acremolide B§
Abdelatif ElMarrouni,†,‡ Aya Fukuda,† Montserrat Heras,‡ Stellios Arseniyadis,*,† and
Janine Cossy*,†
†Laboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084, 10 rue Vauquelin,
75231 Paris Cedex 05, France, and Department of Chemistry, Faculty of Sciences, University of Girona,
Campus de Montilivi, E-17071 Girona, Spain
‡
stellios.arseniyadis@espci.fr; janine.cossy@espci.fr
Received September 10, 2010
A highly straightforward strategy for the synthesis of the acremolide class of lipodepsipeptides has
been developed. Synthetic highlights include a cross-metathesis to couple the C1-C7 and the C8-C12
fragments, an esterification to introduce the dipeptide unit, a macrolactamization to build the macrolide
core, and two stereoselective allylations/crotylations to control all four stereogenic centers of the C1-C12
polypropionate segment.
Introduction
(D-Phe) by applying a new C3 Marfey’s method4 specially
developed for amino acid analysis.
In 2008, Capon et al. reported the isolation of four members
of a new family of lipodepsipeptides from an Australian estuarine
isolate of an Acremonium sp. (MST-MF588a), namely acre-
molides A-D (Figure 1).1 While the Acremonium sp. extract,
which contained several mycotoxins such as 19-O-acetyl-
chaetoglobosin B and D2 as well as a known aromatic metabo-
lite RKB 3564S,3 exhibited significant cytotoxic activity
against NS-1 cells (LD99 16 μg/mL), the biological properties
pertaining to the acremolides still remain unknown.
Due to the lack of both the relative and the absolute
configuration of the acremolides, and to the structural similar-
ities with the known histone deacetylase inhibitors FR235222,5
apicidin A,6 and trapoxin,7 which exhibit promising biological
properties, we became particularly interested in developing a
concise and flexible synthesis that would allow a straightforward
access to these natural products and to various analogues
thereof. We report here the results of our endeavor that
eventually led to the synthesis of an isomer of acremolide B.
On the basis of extensive spectroscopic and degradation
studies, the structures of acremolides A-D were proposed to
display a 12-membered-ring lactam constituted of a C1-C12
polypropionate unit linked to a dipeptide. In addition, while
the three-dimensional structure of the acremolides remains
unknown, Capon et al. were able to identify unambiguously the
amino acid content as L-proline (L-Pro) and D-phenylalanine
Results and Discussion
First Strategy. In order to guarantee a high level of flexi-
bility, our initial strategy relied on four key disconnections: a
(4) Fujii, K.; Ikai, Y.; Oka, H.; Suzuki, M.; Harada, K. A. Anal. Chem.
1997, 69, 5146–5151.
(5) Mori, H.; Urano, Y.; Kinoshita, T.; Yoshimura, S.; Takase, S.; Hino, M.
J. Antibiot. 2003, 56, 181–185.
(6) Singh, S. B.; Zink, D. L.; Liesch, J. M.; Mosley, R. T.; Dombrowski,
A. W.; Bills, G. F.; Darkin-Rattray, S. J.; Schmatz, D. M.; Goetz, M. A.
J. Org. Chem. 2002, 67, 815–825.
§ Dedicated to the memory of Marc Julia.
(1) Ratnayake, R.; Fremlin, L. J.; Lacey, E.; Gill, J. H.; Capon, R. J.
J. Nat. Prod. 2008, 71, 403–408.
(2) Probst, A.; Tamm, C. Helv. Chim. Acta 1981, 64, 2056–2064.
(3) Osada, H.; Kakeya, H.; Konno, H.; Kanazawa, S. Japanese Patent
051804, 2003.
(7) Kijima, M.; Yoshida, M.; Sugita, K.; Horinouchi, S.; Beppu, T.
J. Biol. Chem. 1993, 268, 22429–22435.
8478 J. Org. Chem. 2010, 75, 8478–8486
Published on Web 11/24/2010
DOI: 10.1021/jo1017487
r
2010 American Chemical Society

ElMarrouni et al.
JOCArticle
FIGURE 1. Structures of acremolides A-D.
SCHEME 1. Initial Retrosynthetic Analysis
cross-metathesis (CM) to introduce the fatty-acid side chain, an
esterification to link the dipeptide unit to the C1-C12
polypropionate fragment, a macrolactamization to build
the 12-membered ring, and two stereoselective allylations/
crotylations to control the three stereogenic centers at C3,
C5, and C6 (Scheme 1). Two key compounds, 8 and 9, were
therefore identified.
The synthesis of macrolactam 8 started from the commer-
cially available (S)-Roche ester 1 and proceeded through an
initial protection of the primary alcohol as a tert-butyldi-
methylsilyl (TBS) ether (TBSCl, imid., CH2Cl2, 0 °C to rt,
99%) and the reduction of the ester moiety (DIBAL-H,
toluene, -78 °C, 95%) (Scheme 2). Oxidation of the resulting
alcohol using standard Swern8 conditions [(COCl)2, DMSO,
Et3N, CH2Cl2, -78 °C) followed by a diastereoselective allyla-
tion using the highly face-selective titanium complex (R,R)-[Ti]-
I (THF, -78 °C)9 then afford the corresponding homoallylic
alcohol 3 (71% yield from 2, dr >95/5, er >95/5, [R]20D -5.5
(c 1.08, CDCl3); lit. [R]22D -6.4 (c 0.33, CHCl3)),10,11 which was
later protected as a TBS ether (TBSOTf, 2,6-lutidine, CH2Cl2,
-78 °C, 80%) and engaged in an OsO4-catalyzed oxidative
cleavage12 (OsO4, NaIO4, 2,6-lutidine, dioxane/H2O). The alde-
hyde thus formed was then subjected to the (R,R)-[Ti]-II (Et2O,
-78 °C) complex to provide the corresponding homo-
allylic alcohol 4 as a single stereoisomer in 70% yield (dr >95/
5). The next step concerned the esterification of alcohol 4
with the dipeptide unit 5. The latter was prepared in three
steps and 70% overall yield following a reported procedure13
whichinvolved converting L-Pro to the corresponding methyl
ester (SOCl2, MeOH, reflux), coupling the resulting amino
ester with Fmoc-D-Phe-OH (EDCI, HOBt, DIPEA, CH2Cl2,
rt), and ultimately saponifying the ester moiety (LiOH,
THF/H2O, 0 °C).
With the two coupling partners 4 and 5 in hand, our attention
was then turned to the key esterification step. As various
attempts to link alcohol 4 to the dipeptide unit 5 using either
DCC or EDCI proved low-yielding, we finally opted for a
Yamaguchi esterification.14 To our delight, the Yamaguchi
(8) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
(9) (a) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rothe-Streit, P.;
Schwarzenbach, F J. Am. Chem. Soc. 1992, 114, 2321–2336. (b) Duthaler,
R. O.; Hafner, A. Chem. Rev. 1992, 92, 807–832.
(12) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–
3219.
(10) The diastereomeric ratio was determined by crude 1H NMR analysis,
while the absolute configuration of the C3 stereogenic center was determined
as (3S) by comparing the optical rotation of the synthesized compound with
the one reported in the literature {[R]25D -5.5 (c 1.08, CDCl3); lit. [R]22D -6.4
(c 0.33, CDCl3)}.
€
(13) Stuber, W.; Kosina, H.; Heimburger, N. Int. J. Pept. Protein Res.
1988, 31, 63–70.
(14) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993. (b) Kawanami, Y.; Dainobu, Y.;
Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943–
944.
(11) See: Roush, W. R.; Hoong, L. K.; Palmer, M. A.; Straub, J. A.;
Palkowitz, A. D. J. Org. Chem. 1990, 55, 4117–4126.
J. Org. Chem. Vol. 75, No. 24, 2010 8479

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SCHEME 2. First Attempt To Synthesize Acremolide B
conditions (2,4,6-trichlorobenzoyl chloride, DMAP, toluene, rt)
afforded the corresponding ester 6 in 85% yield. The
primary TBS ether was then selectively cleaved using ZnBr2
(CH2Cl2, rt, 94%),15 and the resulting alcohol was subse-
quently oxidized,16 first to the aldehyde (TEMPO, NaOCl,
KBr, CH2Cl2, rt) and then to the carboxylic acid (2-methyl-
2-butene, NaClO2, NaH2PO4, t-BuOH/H2O), to provide the
lactam precursor 7 in 78% yield over three steps. The Fmoc
protecting group was eventually removed under mild condi-
tions (Et2NH, CH3CN), and the resulting amino acid was
engaged in a macrolactamization (EDCI, HOBt, DIPEA,
CH2Cl2, 0 °C), to afford the desired 12-membered-ring macro-
lactam 8 in 95% yield. Finally, in order to introduce the fatty-
acid side chain and complete the synthesis of acremolide B,
(15) Crouch, R. D.; Polizzi, J. M.; Cleiman, R. A.; Yi, J.; Romany, C. A.
Tetrahedron. Lett. 2002, 43, 7151–7153.
(16) Kurosawa, K.; Matsuura, K.; Nagase, T.; Chida, N. Bull. Chem. Soc.
Jpn. 2006, 6, 921–937.
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SCHEME 3. Second Synthetic Strategy
we envisioned a three-step sequence involving a CM with
5-hexen-2-one (9), a hydrogenation of the newly formed
over two steps. Cleavage of the Fmoc protecting group followed
by macrolactamization eventually afforded the desired
12-membered-ring lactam 17 (60% yield over two steps), which
was ultimately deprotected (TBAF, THF, 0 °C, quant.) in
order to complete the synthesis of what we hoped would be
acremolide B. Unfortunately, analysis of the spectroscopic
and physical data of 18 and comparison with the ones reported
in the literature for the natural product1 showed that we had
synthesized a stereoisomer of acremolide B.20
C7-C8 double bond, and
a final cleavage of the
silyl ether. Unfortunately, after multiple attempts to couple
olefins 8 and 9 using various reaction conditions, we were
unable to isolate any of the desired product 10. This
unfortunate outcome is believed to be due either to coordina-
tion between the ruthenium and the carbonyl of the lactone,
which leads to an inactive catalytic species, or to sequestra-
tion of the ruthenium in the marocycle, which could poison
the catalyst. In order to circumvent this dramatic issue, we
therefore decided to slightly modify the current synthesis.
Second Strategy. Our second strategy relied on the same
four disconnections as before but implied the introduction of
the fatty-acid side chain prior to the dipeptide unit (Scheme 3).
Hence, instead of coupling 4 and 5 using a Yamaguchi
esterification, the former was directly engaged in a CM with
5-hexen-2-one (9) using the Hoveyda-Grubbs catalyst,
[Ru]-I (CH2Cl2, 40 °C) (Scheme 4). Fortunately, we were
able to isolate the desired disubstituted olefin in 71% yield.
The latter was then hydrogenated using AcOEt as the solvent
(H2, 10% Pd/C, rt, 90%) in order to avoid complete silyl
ether deprotection which occurred under standard hydro-
genation conditions.17 Next, introduction of the dipeptide
unit 5 using the Yamaguchi esterification conditions affor-
ded the desired coupled product 14 in 75% yield. The
primary TBS ether was then selectively cleaved using SnCl2
(EtOH/H2O, rt, 79%),18,19 and the resulting alcohol was sub-
sequently oxidized to the carboxylic acid using, once again,
the same two-step sequence as the one used previously. This
allowed us to isolate the lactam precursor 16 in 90% yield
Conclusion
In summary, we have completed the synthesis of a stereo-
isomer of acremolide B in 16 steps and 7.6% overall yield
starting from (S)-Roche ester 1. The strategy is particularly
appealing as all the configurations of the stereogenic centers
can be readily controlled by either starting the synthesis from
the (R)-Roche ester, changing the chiral auxiliaries in the
allylations/crotylations, or switching from a titanium- to a
boron-mediated crotylation. As such, this straightforward
approach should allow an easy access to any of the various
stereoisomers of acremolide B as well as to all the other members
of the acremolides.
Experimental Section
The reactions were run under argon atmosphere in oven-dried
glassware unless otherwise specified. 5-Hexen-2-one (9) and other
reagents were obtained from commercial suppliers and used as
received. Fmoc-D-Phe-L-Pro-OH (5)12 was prepared according
to a reported procedure. Its spectroscopic and physical data
(20) After closely examining the discrepancies in the 1H and 13C NMR
spectra of both the natural and the synthetic acremolide B, it is particularly
difficult to speculate on the relative and absolute configuration of the C2, C3,
C5, and C6 stereogenic centers (see Supporting Information for comparative
Table), not to mention that, due to the cyclic nature of the natural product, a
slight modification of one of the stereogenic centers could have a tremendous
impact on the overall configuration of the molecule and therefore on all the
chemical shifts.
(17) Ikawa, T.; Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2004, 60,
6901–6911.
(18) Deprotection of the primary TBS ether in 14 using ZnBr2 afforded
the desired compound in a slightly lower yield (60%).
(19) Hua, J.; Jiang, Z. Y.; Wang, Y. G. Chin. Chem. Lett. 2004, 15, 1430–
1432.
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SCHEME 4. Synthesis of a Stereoisomer of Acremolide B
were identical with those reported in the literature. Analytical
thin-layer chromatography (TLC) was performed on silica gel
plates visualized either with a UV lamp (254 nm) or by using
solutions of p-anisaldehyde/sulfuric acid/acetic acid in EtOH,
phosphomolybdic acid in EtOH, or KMnO4/K2CO3/AcOH in
water followed by heating. Flash chromatography was performed
on silica gel (60-230 mesh mesh). Organic extracts were dried
over anhydrous MgSO4. Infrared spectra were recorded on a
Bruker instrument, and wavenumbers are indicated in cm-1. 1H
NMR spectra were recorded at 400 MHz in CDCl3, and data are
reported as follows: chemical shift in parts per million from
tetramethylsilane as an internal standard, multiplicity (s=singlet,
d = doublet, t = triplet, q = quartet, m = multiplet or overlap of
non equivalent resonances), integration. 13C NMR spectra were
recorded at 100 MHz in CDCl3 (unless otherwise specified), and
data are reported as follows: chemical shift in parts per million
from tetramethylsilane with the solvent as an internal indicator
(CDCl3 δ 77.0 ppm), multiplicity with respect to proton
(deduced from DEPT experiments). Mass spectra (MS) were
recorded using a tandem gas chromatograph/mass spectrometer
(70 eV). High-resolution mass spectra were performed by
ꢀ
“Groupe de Spectrometrie de masse de l’Universite Pierre et
ꢀ
Marie Curie (Paris)”.
(S)-3-(tert-Butyldimethylsilyloxy)-2-methylpropionic Acid Methyl
Ester.21 To a solution of (S)-3-hydroxy-2-methylpropionic acid
methyl ester (1,5g,42.3mmol) inCH2Cl2 (170mL) at0°Cwasadded
imidazole (3.5 g, 50.8 mmol) followed by tert-butyldimethylsilyl
chloride (7.5 g, 46.6 mmol), and the reaction mixture was then
stirred at room temperature for 22 h until complete conversion
of the starting material (reaction monitored by TLC analysis).
The reaction mixture was then filtered and concentrated under
reduced pressure, and the crude residue was purified by flash
chromatography (petroleum ether/Et2O: 99/1) to afford 3-(tert-
butyldimethylsilyloxy)-2-methylpropionic acid methyl ester (9.8 g,
(21) Marshall, J. A.; Blough, B. E. J. Org. Chem. 1990, 55, 1540–1547.
8482 J. Org. Chem. Vol. 75, No. 24, 2010

ElMarrouni et al.
JOCArticle
99%) as a colorless oil. Its spectroscopic and physical data
matched the ones reported in the literature.19
(petroleum ether/Et2O: 99/1); [R]20 þ7.55 (c 1.1, CHCl3); IR
D
(neat) 2929, 2858, 1472, 1253, 1095, 1039, 916 cm-1; 1H NMR
(400MHz,CDCl3) δ5.72 (m, 1H), 5.08-4.94 (m, 2H), 3.81 (m, 1H),
3.50 (dd, J=9.8, 6.8 Hz, 1H), 3.37 (dd, J=9.8, 6.5 Hz, 1H), 2.29-
2.12 (m, 2H), 1.66 (m, 1H), 0.86 (s, 9H), 0.85 (s, 9H), 0.80 (d, J=
6.8 Hz, 3H), 0.02 (s, 3H), 0.01 (s, 6H), 0.00 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ135.6 (CH), 116.4 (CH2), 71.5 (CH), 65.4 (CH2),
39.8 (CH), 39.7 (CH2), 26.0 (3CH3), 25.9 (3CH3), 18.2 (C), 18.1 (C),
10.2 (CH3), -4.1 (CH3), -4.7 (CH3), -5.3 (CH3), -5.4 (CH3).
(3S,4R,6S,7S)-6,8-Bis-(tert-butyldimethylsilyloxy)-3,7-dimethyloct-
1-en-4-ol (4). To a solution of (4S,5S)-4,6-bis-(tert-butyldi-
methylsilyloxy)-5-methylhex-1-ene (2 g, 5.6 mmol) in a 3:1 dioxane/
water mixture (56 mL) at 0 °C were added 2,6-lutidine (1.6 mL,
13.4 mmol), OsO4 (3.5 mL of a 2.5% solution in water, 0.28
mmol), and NaIO4 (4.75 g, 22.3 mmol). The resulting reaction
mixture was stirred for 3.5 h at room temperature until complete
conversion of the starting material (reaction monitored by TLC
analysis). The reaction mixture was then quenched with a saturated
aqueous Na2S2O3 solution (20 mL) and stirred for 20 min. The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2 ꢀ 30 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The resulting crude residue was finally filtered
over a small plug of silica, eluting with a petroleum ether/Et2O
(99/1) mixture. The solvent was removed under reduced pres-
sure, and the resulting crude aldehyde was used in the next step
without further purification. To a solution of the (R,R)-[Ti]-II
complex (5.5 g, 8.9 mmol) in Et2O (56 mL) at -78 °C was added
2-butenylmagnesium chloride (16.6 mL of a 2 M solution in THF,
8.3 mmol), and the resulting reaction mixture was stirred for 2 h
at 0 °C. The solution was then cooled to -78 °C, and the crude
aldehyde (5.6 mmol) was added dropwise. The resulting reaction
mixture was stirred for 4 h at the same temperature until complete
conversion of the starting material (reaction monitored by TLC
analysis), quenched with water (80 mL), and stirred overnight at
room temperature. The reaction mixture was then filtered over
Celite, and the organic layer was separated. The aqueous layer
was extracted with CH2Cl2 (2 ꢀ 30 mL), and the combined
organic layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The resulting crude resi-
due was purified by flash chromatography (petroleum ether/
Et2O: 95/5) to afford (3S,4R,6S,7S)-6,8-bis-(tert-butyldimethyl-
silyloxy)-3,7-dimethyloct-1-en-4-ol (4, 1.6 g, 70%) as a colorless
oil. Rf=0.45 (petroleum ether/Et2O: 95/5); [R]20D -6.37 (c 0.97,
CHCl3); IR (neat) 2929, 2858, 1472, 1389, 1255, 1096, 1047,
1005, 914, 836, 775 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.73 (m,
1H), 5.09-5.00 (m, 2H), 3.93 (tdapp, J=6.8, 3.0 Hz, 1H), 3.57 (dd,
J=9.5, 5.8 Hz, 1H), 3.48 (m, 1H), 3.41 (dd, J=9.5, 7.0 Hz, 1H),
2.39 (bs, 1H), 2.16 (m, 1H), 1.79 (m, 1H), 1.60 (m, 1H), 1.45 (m,
1H), 0.99 (d, J=6.8 Hz, 3H), 0.85 (s, 9H), 0.84 (s, 9H), 0.80 (d, J=
7.0 Hz, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.00 (s, 3H), -0.01 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 140.4 (CH), 115.6 (CH2), 73.2
(CH), 72.7 (CH), 64.8 (CH2), 44.2 (CH), 40.5 (CH), 37.3 (CH2),
26.0 (3CH3), 25.9 (3CH3), 18.3 (C), 18.0 (C), 15.7 (CH3), 11.6
(CH3), -4.3 (CH3), -4.5 (CH3), -5.3 (CH3), -5.4 (CH3);
HRMS (ESI) m/z calcd for C22H48O3NaSi2 [MþNa]þ 439.3034,
found 439.3031.
(R)-3-(tert-Butyldimethylsilyloxy)-2-methylpropan-1-ol (2).22
To a solution of 3-(tert-butyldimethylsilyloxy)-2-methylpropionic
acid methyl ester (9.5 g, 40.8 mmol) in toluene (150 mL) at -78 °C
was slowly added DIBAL-H (98.5 mL of a 1 M solution in toluene,
98.5 mmol). The resulting reaction mixture was stirred for 20 min,
time after which it was quenched with a 1:1 mixture of AcOEt/
saturated aqueous solution of sodium potassium tartrate (200 mL).
Stirring was continued at room temperature overnight before
the organic layer was separated. The aqueous layer was then
extracted with AcOEt (2ꢀ 100 mL), and the combined organic
layers were dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude residue was finally purified
by flash chromatography (petroleum ether/AcOEt: 99/1) to afford
(R)-3-(tert-butyldimethylsilyloxy)-2-methylpropan-1-ol (2) as a
colorless oil (7.9 g, 95%). The spectroscopic and physical data
of 2 matched the ones reported in the literature.20
(2S,3S)-1-(tert-Butyldimethylsilyloxy)-2-methylhex-5-en-3-ol (3).11
To a solution of oxalyl chloride (2.9 mL, 33.2 mmol) in CH2Cl2
(110 mL) at-78 °C was slowly added DMSO (5.1 mL, 66.4 mmol),
and the reaction mixture was stirred for 30 min. (R)-3-(tert-
Butyldimethylsilyloxy)-2-methylpropan-1-ol (2, 3.36 g, 16.1 mmol)
was then added dropwise, and stirring was continued for an addi-
tional 30 min at the same temperature. Et3N (13.9 mL, 99.6 mmol)
was then added, and the reaction mixture was warmed to room
temperature and quenched with a saturated aqueous NH4Cl
solution (50 mL). The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (2 ꢀ 100 mL). The
combined organic layers were dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. Hexane was then
added, and the precipitate was filtered over Celite. The solvent
was removed under reduced pressure, and the resulting crude
aldehyde was used in the next step without further purification.
To a solution of the (R,R)-[Ti]-I complex (13.2 g, 21.9 mmol) in
Et2O (166 mL) at -78 °C was added allylmagnesium chloride
(9.9 mL of a 2 M solution in THF, 19.9 mmol), and the reaction
mixture was stirred for 2 h at 0 °C. The solution was then cooled to
-78 °C, and the crude aldehyde (16.1 mmol) was added dropwise.
The resulting reaction mixture was stirred for 4 h at the same
temperature until complete conversion of the starting material
(reaction monitored by TLC analysis), quenched with water
(80 mL), and stirred overnight at room temperature. The reaction
mixture was then filtered over Celite, and the organic layer was
separated. The aqueous layer was extracted with CH2Cl2 (2 ꢀ
100 mL), and the combined organic layers were dried over anhy-
drous MgSO4, filtered, and concentrated under vacuum. The result-
ing crude residue was purified by flash chromatography (petroleum
ether/AcOEt: 97/3) to afford (2S,3S)-1-(tert-butyldimethylsilyloxy)-
2-methylhex-5-en-3-ol (3) (3.6 g, 71%) as a single stereoisomer
and as a colorless oil. The spectroscopic and physical data of 3
matched the ones reported in the literature.21
(4S,5S)-4,6-Bis-(tert-butyldimethylsilyloxy)-5-methylhex-1-ene.
To a solution of (2S,3S)-1-(tert-butyldimethylsilyloxy)-2-methylhex-
5-en-3-ol (3, 3.6 g, 14.7 mmol) in CH2Cl2 (75 mL) at -78 °C
were added 2,6-lutidine (3.4 mL, 29.5 mmol) and TBSOTf (5.8 g,
22.1 mmol). The resulting reaction mixture was stirred for 90 min
at the same temperature before a saturated aqueous NaHCO3
solution (40 mL) was added. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2 ꢀ 50 mL).
The combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (petroleum ether/
Et2O: 99/1) to afford (4S,5S)-4,6-bis-(tert-butyldimethylsilyloxy)-
5-methylhex-1-ene (4.2 g, 80%) as a colorless oil: Rf = 0.87
(R)-1-[(R)-2-(9H-Fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic Acid (1R,3S,4S)-3,5-Bis-(tert-
butyldimethylsilyloxy)-4-methyl-1-[(S)-1-methylallyl]-pentyl Ester (6).
To a solution of (3S,4R,6S,7S)-6,8-bis-(tert-butyldimethyl-
silyloxy)-3,7-dimethyloct-1-en-4-ol (4, 68 mg, 0.16 mmol) and
Fmoc-D-Phe-L-Pro-OH (5, 87 mg, 0.18 mmol) in toluene (16 mL)
was added DMAP (39 mg, 0.32 mmol). The reaction mixture was
then cooled to -78 °C before DIPEA (98 μL, 0.60 mmol) was
added, followed by 2,4,6-trichlorobenzoyl chloride (74 μL, 0.48
mmol). The resulting slurry was slowly warmed to room tem-
perature over 2 h, stirred for an additional 6 h at the same
(22) Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. Org. Chem. 1987,
52, 316–318.
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ElMarrouni et al.
JOCArticle
temperature, and quenched with a saturated aqueous NaHCO3
solution (10 mL). The aqueous layer was extracted with CH2Cl2
(2 ꢀ 15 mL), and the combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The crude residue was finally purified by flash chroma-
tography (petroleum ether/EtOH: 97/3) to afford (R)-1-[(R)-
2-(9H-fluoren-9-yloxycarbonylamino)-3-phenylpropionyl]-
pyrrolidine-2-carboxylic acid (1R,3S,4S)-3,5-bis-(tert-butyldi-
methylsilyloxy)-4-methyl-1-[(S)-1-methylallyl]-pentyl ester (6,
120 mg, 85%) as a viscous oil. Mixture of rotamers: Rf = 0.67
(CH2Cl2/CH3OH: 99/1); [R]20D-16.4 (c 0.45, CHCl3); IR (neat)
2954, 2929, 2857, 1727, 1644, 1449, 1251, 1187, 1098, 1042, 836,
775 cm-1. Major rotamer: 1H NMR (400 MHz, CDCl3) δ 7.76
(dapp, J=7.5 Hz, 2H), 7.60 (tapp, J=8.2 Hz, 2H), 7.40 (tapp, J=
7.9 Hz, 2H), 7.36-7.29 (m, 2H), 7.28-7.16 (m, 5H), 5.81-5.64
(m, 2H), 5.12-4.98 (m, 2H), 4.88 (m, 1H), 4.69 (m, 1H), 4.38
(dd, J=10.2, 7.9 Hz, 1H), 4.37-4.24 (m, 2H), 4.21 (tapp, J=7.5
Hz, 1H), 3.78 (m, 1H), 3.54-3.43 (m, 2H), 3.37 (dd, J=9.4, 6.7
Hz, 1H), 3.11 (dd, J=13.0, 5.5 Hz, 1H), 2.98 (dd, J=13.0, 9.4
Hz, 1H), 2.63 (m, 1H), 2.51 (m, 1H), 1.96-1.76 (m, 3H), 1.75-1.59
(m, 3H), 1.50 (m, 1H), 1.08 (d, J=6.7 Hz, 3H), 0.87 (s, 9H), 0.86 (s,
9H), 0.77 (d, J=6.7 Hz, 3H), 0.05 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H),
0.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1 (C), 169.6 (C),
155.5 (C), 144.0 (C), 143.8 (C), 141.3 (2C), 138.8 (CH), 136.3 (C),
129.6 (2CH), 128.5 (2CH), 127.7 (2CH), 127.1 (2CH), 127.0 (CH),
125.3 (2CH), 120.0 (2CH), 116.0 (CH2), 75.0 (CH), 68.5 (CH), 67.0
(CH2), 65.5 (CH2), 58.8 (CH), 54.1 (CH), 47.2 (CH), 46.8 (CH2),
41.1 (CH), 40.4 (CH2), 39.6 (CH), 35.9 (CH2), 31.0 (CH2), 26.0
(3CH3), 25.9 (3CH3), 24.3 (CH2), 18.3 (C), 18.1 (C), 15.4 (CH3), 9.8
(CH3), -4.1 (CH3), -4.7 (CH3), -5.3 (CH3), -5.4 (CH3).
(R)-1-[(R)-2-(9H-Fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic Acid (1R,3S,4S)-3-(tert-Butyl-
dimethylsilyloxy)-5-hydroxy-4-methyl-1-[(S)-1-methylallyl]-pentyl
Ester. To a solution of ZnBr2 (110 mg, 0.73 mmol) in CH2Cl2
(8 mL) at room temperature was added a solution of (R)-1-[(R)-
2-(9H-fluoren-9-yloxycarbonylamino)-3-phenylpropionyl]-pyr-
rolidine-2-carboxylic acid (1R,3S,4S)-3,5-bis-(tert-butyldimethyl-
silyloxy)-4-methyl-1-((S)-1-methylallyl)-pentyl ester (6, 110 mg,
0.13 mmol) in CH2Cl2 (16 mL). The resulting reaction mixture
was stirred for 4 h at the same temperature until complete con-
version of the starting material (reaction monitored by TLC
analysis) and then quenched with a saturated aqueous NaHCO3
solution (15 mL). The aqueous layer was extracted with CH2Cl2
(2ꢀ15 mL), and the combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude residue was finally puri-
fied by flash chromatography, eluting with CHCl3, to afford
(R)-1-[(R)-2-(9H-fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic acid (1R,3S,4S)-3-(tert-butyl-
dimethylsilyloxy)-5-hydroxy-4-methyl-1-[(S)-1-methylallyl]-pentyl
ester (83 mg, 83%) as a viscous oil. Mixture of rotamers: Rf =
0.21 (9.9/0.1: CH2Cl2/CH3OH); [R]20D -12.65 (c 0.63, CHCl3);
IR (neat) 2956, 2928, 2856, 1722, 1639, 1524, 1450, 1251, 1188,
1086, 1041, 837, 775 cm-1. Major rotamer: 1H NMR (400 MHz,
CDCl3) δ 7.75 (dapp, J=7.5 Hz, 2H), 7.59 (dd, J=11.5, 7.5 Hz,
2H), 7.38 (tapp, J = 7.5 Hz, 2H), 7.30 (tapp, J = 7.2 Hz, 2H),
7.27-7.14 (m, 5H), 5.86 (d, J = 8.2 Hz, 1H), 5.72 (m, 1H),
5.10-4.98 (m, 2H), 4.99 (m, 1H), 4.70 (m, 1H), 4.41 (dd, J =
10.4, 7.2 Hz, 1H), 4.35-4.22 (m, 2H), 4.19 (tapp, J=7.2 Hz, 1H),
3.80 (td, J=7.6, 1.6 Hz, 1H), 3.55-3.36 (m, 3H), 3.10 (dd, J=
12.9, 5.4 Hz, 1H), 2.95 (dd, J=12.9, 9.3 Hz, 1H), 2.63 (m, 1H),
2.41 (m, 1H), 1.98-1.74 (m, 4H), 1.72-1.62 (m, 3H), 1.49 (m, 1H),
1.04 (d, J =6.8 Hz, 3H), 0.84 (s, 9H), 0.73 (d, J= 6.8 Hz, 3H),
0.02 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.4 (C), 169.9 (C),
155.6 (C), 144.0 (C), 143.8 (C), 141.3 (2C), 138.9 (CH), 136.2 (C),
129.5 (2CH), 128.5 (2CH), 127.7 (2CH), 127.1 (3CH), 125.3
(2CH), 120.0 (2CH), 116.1 (CH2), 74.8 (CH), 68.6 (CH), 67.0
(CH2), 65.4 (CH2), 59.1 (CH), 54.2 (CH), 47.2 (CH), 46.9 (CH2),
41.9 (CH), 40.4 (CH2), 38.4 (CH), 35.7 (CH2), 29.0 (CH2), 25.8
(3CH3), 24.3 (CH2), 18.0 (C), 15.8 (CH3), 9.8 (CH3), -4.3 (CH3),
-4.8 (CH3); HRMS (ESI) m/z calcd for C45H60O7N2NaSi
[MþNa]þ 791.4062, found 791.4057.
(R)-1-[(R)-2-(9H-Fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic Acid (1R,3S,4R)-3-(tert-Butyl-
dimethylsilyloxy)-4-carboxy-1-[(S)-1-methylallyl]-pentyl Ester (7).
To a solution of (R)-1-[(R)-2-(9H-fluoren-9-yloxycarbonylamino)-
3-phenylpropionyl]-pyrrolidine-2-carboxylic acid (1R,3S,4S)-
3-(tert-butyldimethylsilyloxy)-5-hydroxy-4-methyl-1-[(S)-1-methyl-
allyl]-pentyl ester (77 mg, 0.1 mmol) in CH2Cl2 (1 mL) at 0 °C
were added TEMPO (22 mg, 0.14 mmol), KBr (50 μL of a 0.2 M
solution in water, 0.01 mmol), and NaOCl (52 μL of a 13%
solution in water, 0.1 mmol). After the mixture was stirred for
30 min at the same temperature, the organic layer was dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The resulting crude aldehyde was used in the next step
without further purification. The crude aldehyde (0.1 mmol),
t-BuOH (5 mL), 2-methyl-2-butene (0.74 mL, 7.0 mmol), water
(1 mL), NaClO2 (68 mg, 0.6 mmol), and NaH2PO4 (36 mg, 0.3
mmol) were mixed at 0 °C, and the reaction mixture was stirred
at room temperature for 30 min. t-BuOH was then removed
under reduced pressure, and AcOEt (15 mL) was added. The organic
layer was separated, and the aqueous layer was extracted with
AcOEt (2 ꢀ 15 mL). The combined organic layers were com-
bined and dried over anhydrous MgSO4, filtered, and concen-
trated under reduced pressure. The crude residue was finally
purified by flash chromatography (CH2Cl2/CH3OH: 99/1) to
afford (R)-1-[(R)-2-(9H-fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic acid (1R,3S,4R)-3-(tert-butyl-
dimethylsilyloxy)-4-carboxy-1-[(S)-1-methylallyl]-pentyl ester
(7, 73 mg, 93%) as a viscous oil. Mixture of rotamers: Rf =
0.22 (CH2Cl2/CH3OH: 98/2); [R]20D -24.0 (c 0.87, CHCl3); IR
(neat) 2928, 2856, 1713, 1618, 1451, 1251, 1186, 1095, 1033, 837,
776, 759, 741 cm-1. Major rotamer: 1H NMR (400 MHz, CDCl3)
δ 7.74 (d, J = 7.4 Hz, 2H), 7.58 (dd, J = 9.6, 7.6 Hz, 2H), 7.38
(tapp, J=7.6 Hz, 2H), 7.29 (dd, J=7.6, 0.8 Hz, 2H), 7.26-7.14
(m, 5H), 5.80 (d, J = 8.4 Hz, 1H), 5.72 (m, 1H), 5.11-4.96 (m,
2H), 4.91 (m, 1H), 4.71 (m, 1H), 4.40-4.32 (m, 2H), 4.29 (dd, J=
10.8, 7.2 Hz, 1H), 4.19 (tapp, J=7.3 Hz, 1H), 4.09 (m, 1H), 3.51
(m, 1H), 3.08 (dd, J=12.8, 5.6 Hz, 1H), 2.96 (dd, J=12.8, 9.2
Hz, 1H), 2.68-2.52 (m, 2H), 2.43 (m, 1H), 1.96-1.72 (m, 3H),
1.71-1.62 (m, 2H), 1.49 (m, 1H), 1.10-0.99 (2d, J=7.0 Hz, 6H)
0.83 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 178.8 (C), 171.3 (C), 170.0 (C), 155.6 (C), 144.0 (C),
143.8 (C), 141.3 (2C), 138.6 (CH), 136.2 (C), 129.5 (2CH), 128.5
(2CH), 127.7 (2CH), 127.1 (3CH), 125.3 (2CH), 120.0 (2CH), 116.3
(CH2), 74.1 (CH), 69.8 (CH), 67.1 (CH2), 58.8 (CH), 54.1 (CH),
47.1 (CH), 46.9 (CH2), 43.2 (CH), 41.8 (CH), 40.3 (CH2), 35.9
(CH2), 29.0 (CH2), 25.7 (3CH3), 24.2 (CH2), 17.9 (C), 15.4 (CH3),
9.3 (CH3), -4.3 (CH3), -4.9 (CH3); HRMS (ESI) m/z calcd for
C45H58O8N2NaSi [MþNa]þ 805.3855, found 805.3859.
(5R,8R,9S,11R,13aR)-5-Benzyl-9-(tert-butyldimethylsilyloxy)-
8-methyl-11-[(S)-1-methylallyl]-decahydro-12-oxa-3a,6-diaza-
cyclopentacyclododecene-4,7,13-trione (8). To a solution of
(R)-1-[(R)-2-(9H-fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic acid (1R,3S,4R)-3-(tert-butyl-
dimethylsilyloxy)-4-carboxy-1-[(S)-1-methylallyl]-pentyl ester
(7, 70 mg, 0.09 mmol) in CH3CN (3.2 mL) at room temperature
was added Et2NH (1.6 mL), and the reaction mixture was stirred
at room temperature until complete conversion of the starting
material (reaction monitored by TLC analysis). The solvent was
then removed under reduced pressure, and the resulting crude
amino acid was used in the next step without further purification.
To a solution of the amino acid (0.09 mmol) in CH2Cl2 (13 mL) at
0 °C were added EDCl (33 mg, 0.17 mmol), HOBt (23 mg, 0.17
mmol), and DIPEA (64 μL, 0.39 mmol), and the resulting reaction
mixture was stirred for 3 h at room temperature. The reaction was
8484 J. Org. Chem. Vol. 75, No. 24, 2010

ElMarrouni et al.
JOCArticle
then quenched with a saturated aqueous NH4Cl solution (10 mL),
and the organic phase was separated. The aqueous layer was then
extracted with CH2Cl2 (2ꢀ15 mL), and the combined organic layers
were dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude residue was finally purified by
flash chromatography, eluting with CHCl3, to afford (5R,8R,9S,
11R,13aR)-5-benzyl-9-(tert-butyldimethylsilyloxy)-8-methyl-11-[(S)-
1-methylallyl]-decahydro-12-oxa-3a,6-diaza-cyclopentacyclo-
dodecene-4,7,13-trione (8, 46 mg, 95%) as an amorphous solid.
chloride (0.94 mL, 6.1 mmol). The resulting slurry was slowly
warmed to room temperature over 2 h, stirred for an additional 6 h
at the same temperature, and quenched with a saturated aqueous
NaHCO3 solution (30 mL). The aqueous layer was extracted
with CH2Cl2 (2ꢀ 30 mL), and the combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude residue was finally purified by flash
chromatography (petroleum ether/AcOEt: 80/20) to afford (R)-
1-[(R)-2-(9H-fluoren-9-yloxycarbonylamino)-3-phenylpropionyl]-
pyrrolidine-2-carboxylic acid (1R,2S)-1-[(2S,3S)-2,4-bis-(tert-butyl-
dimethylsilyloxy)-3-methylbutyl]-2-methyl-7-oxooctyl ester
(14, 1.32 g, 75%) as a viscous oil. Mixture of rotamers: Rf = 0.33
(petroleum ether/AcOEt: 80/20); [R]20D -12.9 (c 0.83, CHCl3); IR
(neat) 3294, 2954, 2927, 2856, 1716, 1642, 1449, 1250, 1187, 1099,
Mixture of rotamers: Rf = 0.66 (9.5/0.5: CH2Cl2/CH3OH); [R]20
D
-12.7 (c 0.3, CHCl3); IR (neat) 3675, 2987, 2972, 2901, 1733, 1665,
1621, 1542, 1452, 1406, 1394, 1382, 1252, 1229, 1075, 1066 cm-1
.
Major rotamer: 1H NMR (400 MHz, acetone-d6) δ 7.32-7.12
(m, 6H), 5.67 (ddd, J=17.3, 10.3, 7.3 Hz, 1H), 5.21 (m, 1H), 5.08-
4.96 (m, 2H), 4.72-4.62 (m, 2H), 3.76 (td, J=9.4, 2.9 Hz, 1H), 3.56
(m, 1H), 3.33 (m, 1H), 3.16-2.98 (m, 2H), 2.30 (m, 1H), 2.26-2.02
(m, 3H), 1.85 (m, 1H), 1.69 (m, 1H), 1.57 (dd, J=15.6, 3.3 Hz, 2H),
0.97 (d, J=7.0 Hz, 3H), 0.91 (d, J=7.0 Hz, 3H), 0.85 (s, 9H), 0.03
(s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 179.9 (C),
177.4 (C), 175.6 (C), 144.6 (CH), 143.5 (C), 134.5 (2CH), 133.8
(2CH), 132.1 (CH), 121.0 (CH2), 77.4 (CH), 65.4 (CH), 62.7 (CH),
52.9 (CH2), 49.5 (CH), 48.8 (CH), 41.6 (CH2), 41.0 (CH2), 38.2
(CH2), 35.0 (CH), 30.9 (3CH3), 26.7 (CH2), 23.1 (C), 22.6 (CH3),
20.0 (CH3), 0.9 (CH3), 0.0 (CH3); HRMS (ESI) m/z calcd for
C30H46O5N2NaSi [MþNa]þ 565.3068, found 565.3060.
1
1040, 835, 774, 739 cm-1. Major rotamer: H NMR (400 MHz,
CDCl3) δ 7.81-7.71 (d, J=7.5 Hz, 2H), 7.64-7.56 (tapp, J=8.0
Hz, 2H), 7.44-7.36 (m, 2H), 7.35-7.26 (m, 2H), 7.25-7.14 (m,
5H), 5.77 (m, 1H), 4.78 (m, 1H), 4.70 (m, 1H), 4.39 (m, 1H),
4.35-4.25 (m, 2H), 4.21 (m, 1H), 3.75 (m, 1H), 3.54-3.42 (m, 2H),
3.37 (m, 1H), 3.10 (dd, J=12.5, 5.0 Hz, 1H), 2.96 (m, 1H), 2.54 (m,
1H), 2.46-2.30 (m, 2H), 2.09 (s, 3H), 1.99-1.62 (m, 8H), 1.60-
1.47 (m, 2H), 1.43-1.08 (m, 4H), 0.92 (d, J=7.3 Hz, 3H), 0.86 (s,
9H), 0.85 (s, 9H), 0.76 (d, J=6.5 Hz, 3H), 0.04 (s, 3H), 0.01 (s, 3H),
0.00 (s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 209.2
(C), 171.2 (C), 169.6 (C), 155.5 (C), 144.0 (C), 143.8 (C), 141.3 (2C),
136.3 (C), 129.6 (2CH), 128.4 (2CH), 127.7 (CH), 127.1 (2CH),
127.0 (2CH), 125.2 (2CH), 119.9 (2CH), 75.6 (CH), 68.2 (CH), 67.0
(CH2), 65.8 (CH2), 58.7 (CH), 54.1 (CH), 47.2 (CH), 46.8 (CH2),
43.7 (CH2), 40.4 (CH2), 38.9 (CH), 36.3 (CH), 34.9 (CH2), 31.8
(CH2), 29.9 (CH3), 29.0 (CH2), 26.7 (CH2), 26.0 (3CH3), 25.9
(3CH3), 24.4 (CH2), 24.1 (CH2), 18.4 (C), 18.1 (C), 14.7 (CH3),
9.4 (CH3), -4.0 (CH3), -4.8 (CH3), -5.3 (CH3), -5.4 (CH3);
HRMS (ESI) m/z calcd for C55H82O8N2NaSi2 [MþNa]þ 977.5502,
found 977.5500.
(7S,8R,10S,11S)-10,12-bis-(tert-Butyldimethylsilyloxy)-8-hydroxy-
7,11-dimethyldodecan-2-one (13). To a stirred solution of (3S,4R,
6S,7S)-6,8-bis-(tert-butyldimethylsilyloxy)-3,7-dimethyloct-
1-en-4-ol (4, 1.6 g, 3.84 mmol) and 5-hexen-2-one (9, 753 mg, 7.68
mmol) in CH2Cl2 (40 mL) was added the Hoveyda-Grubbs
catalyst (480 mg, 0.77 mmol), and the resulting reaction mixture
was refluxed for 24 h until complete conversion of the starting
material (reaction monitored by TLC analysis). The solvent was
then removed under reduced pressure, and the crude residue was
filtered over a short plug of silica eluting with petroleum ether/Et2O
(90/10) and concentrated under reduced pressure. To a stirred
solution of the resulting disubstituted olefin (3.84 mmol) in AcOEt
(10 mL) at room temperature was added 10% Pd/C (120 mg).
The resulting reaction mixture was stirred under a hydrogen atmo-
sphere (1 atm) at room temperature until complete conversion of
the starting material (reaction monitored by TLC analysis). The
crude reaction mixture was then filtered over Celite, the solvent was
removed under reduced pressure, and the residue was finally
purified by column chromatography (petroleum ether/Et2O:
80/20) to afford (7S,8R,10S,11S)-10,12-bis-(tert-butyldimethyl-
silyloxy)-8-hydroxy-7,11-dimethyldodecan-2-one (13, 1.08 g,
64% over two steps) as a colorless oil. Rf = 0.28 (petro-
(R)-1-[(R)-2-(9H-Fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic Acid (1R,2S)-1-[(2S,3S)-2-(tert-
Butyldimethylsilyloxy)-4-hydroxy-3-methylbutyl]-2-methyl-7-oxooctyl
Ester (15). SnCl2 (60 mg, 0.3 mmol) was added to a 6:1 EtOH/water
(7 mL) mixture at room temperature. Once the reaction mixture
became homogeneous, (R)-1-[(R)-2-(9H-fluoren-9-yloxycarbonyl-
amino)-3-phenylpropionyl]-pyrrolidine-2-carboxylic acid (1R,2S)-
1-[(2S,3S)-2,4-bis-(tert-butyldimethylsilyloxy)-3-methylbutyl]-
2-methyl-7-oxooctyl ester (14, 600 mg, 0.6 mmol) was added, and
the resulting reaction mixture was stirred for 2 h at room temperature.
CH2Cl2 (10 mL) and water (4 mL) were then added, and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2
(2 ꢀ 10 mL), and the combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure.
The crude residue was finally purified by flash chromatography
(petroleum ether/AcOEt: 80/20) to afford (R)-1-[(R)-2-(9H-fluoren-
9-yloxycarbonylamino)-3-phenylpropionyl]-pyrrolidine-2-carboxylic
acid (1R,2S)-1-[(2S,3S)-2-(tert-butyldimethylsilyloxy)-4-hydroxy-
3-methylbutyl]-2-methyl-7-oxooctyl ester (15,418mg,79%).Mixture
of rotamers: Rf=0.27 (petroleum ether/AcOEt: 70/30); [R]20D -14.91
(c 1.63, CHCl3); IR (neat) 3430, 2955, 2926, 2855, 1716, 1643, 1450,
leum ether/Et2O: 80/20); [R]20 -4.73 (c 1.1, CHCl3); IR (neat)
D
3481, 2955, 2928, 2857, 1716, 1463, 1361, 1253, 1094, 1045, 835, 775
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.89 (m, 1H), 3.60 (dd, J=
9.5, 5.5 Hz, 1H), 3.52-3.38 (m, 2H), 2.38 (t, J=7.3 Hz, 2H), 2.09 (s,
3H), 1.81 (m, 1H), 1.64-1.32 (m, 8H), 1.14-0.98 (m, 2H), 0.86 (s,
9H), 0.85-0.79 (m, 15H), 0.06 (s, 3H), 0.04 (s, 3H), 0.00 (s, 3H),
-0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ209.3 (C), 74.6 (CH),
74.1 (CH), 64.4 (CH2), 43.7 (CH2), 40.9 (CH), 38.9 (CH), 35.9
(CH2), 31.8 (CH2), 29.9 (CH3), 26.9 (CH2), 26.0 (3CH3), 25.9
(3CH3), 24.1 (CH2), 18.3 (C), 18.0 (C), 15.0 (CH3), 12.2 (CH3),
-4.3 (CH3), -4.4 (CH3), -5.3 (CH3), -5.4 (CH3); HRMS (ESI)
m/z calcd for C26H56O4NaSi2 [MþNa]þ 511.3609, found 511.3599.
(R)-1-[(R)-2-(9H-Fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic Acid (1R,2S)-1-[(2S,3S)-2,4-Bis-
(tert-butyldimethylsilyloxy)-3-methylbutyl]-2-methyl-7-oxooctyl Ester
(14). To a solution of (7S,8R,10S,11S)-10,12-bis-(tert-butyldi-
methylsilyloxy)-8-hydroxy-7,11-dimethyldodecan-2-one (13, 1.0 g,
2.0 mmol) and L-Pro-D-Phe (5, 1.09 g, 2.2 mmol) in toluene (40 mL)
at room temperature was added DMAP (498 mg, 4.1 mmol).
The reaction mixture was then cooled to -78 °C before DIPEA
(1.2 mL, 7.4mmol) was added, followed by 2,4,6-trichlorobenzoyl
1
1250, 1189, 1094, 1042, 837 cm-1. Major rotamer: H NMR (400
MHz, CDCl3) δ 7.79-7.68 (d, J=7.6 Hz, 2H), 7.61-7.52 (dd, J=
7.6 Hz, 2H), 7.39-7.31 (tapp, J=7.6 Hz, 2H), 7.30-7.24 (tapp, J=
7.3 Hz, 2H), 7.23-7.10 (m, 5H), 5.87 (m, 1H), 4.79 (m, 1H), 4.68 (m,
1H), 4.39 (m, 1H), 4.30-4.20 (m, 2H), 4.15 (m, 1H), 3.80 (tapp, J=
8.0 Hz, 2H), 3.52-3.44(m, 2H), 3.41(dapp, J=6.8 Hz, 1H), 3.07 (dd,
J=12.7, 5.1 Hz, 1H), 2.93 (dd, J=12.7, 9.6 Hz, 1H), 2.65 (m, 1H),
2.41-2.32 (m, 2H), 2.08 (s, 3H), 1.93-1.62 (m, 8H), 1.61-1.43 (m,
2H), 1.39-1.08 (m, 4H), 0.92-0.73 (m, 12H), 0.72 (d, J=7.1Hz,3H),
0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 209.0 (C),
171.6 (C), 169.8 (C), 155.6 (C), 144.0 (C), 143.8 (C), 141.3 (2C), 136.3
(C), 129.5 (2CH), 128.4 (2CH), 127.7 (CH), 127.1 (2CH), 127.0
(2CH), 125.2(2CH),119.9(2CH),75.5(CH),68.1(CH), 67.0(CH2),
J. Org. Chem. Vol. 75, No. 24, 2010 8485

ElMarrouni et al.
JOCArticle
65.4 (CH2),59.1(CH),54.2(CH),47.2(CH),46.9(CH2),43.6(CH2),
40.3 (CH2), 38.2 (CH), 36.6 (CH), 34.7 (CH2), 31.9 (CH2), 29.6
(CH3), 29.0 (CH2), 26.6 (CH2), 25.8 (3CH3), 24.3 (CH2), 23.9 (CH2),
18.0 (C), 14.7 (CH3), 9.2 (CH3), -4.2 (CH3), -4.9 (CH3); HRMS
(ESI) m/z calcd for C49H68O8N2NaSi1 [MþNa]þ 863.4637, found
863.4623.
purification. To a solution of amino acid (0.4 mmol) in CH2Cl2
(50 mL) at 0 °C were added EDCl (153 mg, 0.8 mmol), HOBt
(108 mg, 0.8 mmol), and DIPEA (0.3 mL, 1.8 mmol), and the
resulting reaction mixture was stirred for 3 h at room tempera-
ture. The reaction was then quenched with a saturated aqueous
NH4Cl solution (30 mL), and the organic phase was separated.
The aqueous layer was then extracted with CH2Cl2 (2ꢀ30 mL),
and the combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
The crude residue was finally purified by flash chromatography
(petroleum ether/acetone: 90/10) to afford (5R,8R,9S,11R,
13aR)-5-benzyl-9-(tert-butyldimethylsilyloxy)-8-methyl-11-[(S)-
1-methyl-6-oxoheptyl]-decahydro-12-oxa-3a,6-diazacyclopenta-
cyclododecene-4,7,13-trione (17, 150 mg, 60%). Mixture of rotamers:
(R)-1-[(R)-2-(9H-Fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic acid (1R,2S)-1-[(2S,3R)-
2-(tert-Butyldimethylsilyloxy)-3-carboxybutyl]-2-methyl-7-oxooctyl
Ester (16). To a solution of (R)-1-[(R)-2-(9H-fluoren-9-yloxy-
carbonylamino)-3-phenylpropionyl]-pyrrolidine-2-carboxylic acid
(1R,2S)-1-[(2S,3S)-2-(tert-butyldimethylsilyloxy)-4-hydroxy-3-
methylbutyl]-2-methyl-7-oxooctyl ester (15, 420 mg, 0.5 mmol)
in CH2Cl2 (5 mL) at 0 °C were added TEMPO (117 mg, 0.7
mmol), KBr (0.25 mL of a 0.2 M solution in water, 0.05 mmol),
and NaOCl (0.26 mL of a 13% solution in water, 0.5 mmol).
After the mixture was stirred for 30 min at the same temperature,
the organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The resulting crude alde-
hyde was used in the next step without further purification. The
crude aldehyde (0.5 mmol), t-BuOH (25 mL), 2-methyl-2-butene
(3.7 mL, 35 mmol), water (5 mL), NaClO2 (337 mg, 3 mmol),
and NaH2PO4 (180 mg, 1.5 mmol) were combined at 0 °C, and
the reaction mixture was stirred at room temperature for 30 min.
t-BuOH was then removed under reduced pressure, and AcOEt
(35 mL) was added. The organic layer was separated, and the
aqueous layer was extracted with AcOEt (2 ꢀ 15 mL). The
combined organic layers were combined and dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pressure.
The crude residue was finally purified by flash chromatography
(petroleum ether/acetone: 90/10) to afford (R)-1-[(R)-2-(9H-
fluoren-9-yloxycarbonylamino)-3-phenylpropionyl]-pyrrolidine-
2-carboxylic acid (1R,2S)-1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-
3-carboxybutyl]-2-methyl-7-oxooctyl ester (16, 375 mg, 90%) as
a viscous oil. Mixture of rotamers: Rf = 0.5 (petroleum ether/
Rf = 0.7 (petroleum ether/acetone: 70/30); [R]20 -28.9 (c 1.25,
D
CHCl3); IR (neat) 3263, 2931, 1721, 1661, 1622, 1541, 1439, 1256,
1080, 1052, 835 cm-1. Major rotamer: 1H NMR (400 MHz, CDCl3)
δ 7.34-7.14 (m, 5H), 5.36 (m, 1H), 5.23 (dd, J= 8.5, 3.5 Hz, 1H),
4.89 (m, 1H), 4.04 (dapp, J=8.0Hz, 1H), 3.86 (m, 1H), 3.65 (m, 1H),
3.54 (m, 1H), 3.21 (dd, J=14.5, 4.8 Hz, 1H), 2.95 (dd, J=14.5, 10.5
Hz, 1H), 2.43-2.34 (m, 2H), 2.21 (m, 1H), 2.14-2.02 (m, 6H), 1.91
(m, 1H), 1.70 (m, 1H), 1.59-1.42 (m, 4H), 1.39-1.12 (m, 4H), 0.96
(d, J=7.0 Hz, 3H), 0.85 (s, 9H), 0.79 (d, J=6.8 Hz, 3H), 0.00 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 208.7 (C), 174.8 (C), 172.3 (C),
170.5 (C), 135.9 (C), 129.0 (2CH), 128.7 (2CH), 127.4 (CH), 74.6
(CH), 71.3 (CH), 60.3 (CH), 55.9 (CH), 48.0 (CH2), 43.9 (CH), 43.5
(CH2), 38.7 (CH), 36.2 (CH2), 35.3 (CH2), 33.1 (CH2), 31.8 (CH2),
29.8 (CH3), 26.8 (CH2), 25.8 (3CH3), 23.8 (CH2), 21.5 (CH2), 17.9
(C), 17.4 (CH3), 14.4 (CH3), -3.8 (CH3), -4.8 (CH3); HRMS (ESI)
m/z calcd for C34H54O6N2SiNa [MþNa]þ 637.3643, found 637.3627.
(5R,8R,9S,11R,13aR)-5-Benzyl-9-hydroxy-8-methyl-11-((S)-
1-methyl-6-oxo-heptyl)-decahydro-12-oxa-3a,6-diazacyclopentacyclo-
dodecene-4,7,13-trione (epi-Acremolide B, 18). To a solution of (5R,
8R,9S,11R,13aR)-5-benzyl-9-(tert-butyldimethylsilyloxy)-8-methyl-
11-((S)-1-methyl-6-oxoheptyl)-decahydro-12-oxa-3a,6-diazacyclo-
pentacyclododecene-4,7,13-trione (17, 75 mg, 0.12 mmol) in THF
(4.7 mL) at 0 °C was added TBAF (0.1 mL, 0.4 mmol), and the
resulting reaction mixture was stirred at the same temperature until
complete conversion of the starting material (reaction monitored by
TLC analysis). The solvent was then removed under reduced pres-
sure, and the resulting crude residue was purified by flash chroma-
tography (petroleum ether/acetone: 70/30) to afford epi-acremolide
B (18) as a colorless solid (46 mg, 75%). Mixture of rotamers: Rf=
0.4 (petroleum ether/acetone: 70/30); [R]20D -65.2 (c 0.02, MeOH);
IR (neat) 3307, 2933, 1714, 1659, 1622, 1524, 1454, 1426, 1272, 733,
700 cm-1. Major isomer: 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d,
J=7.0 Hz, 1H), 7.35-7.15(m, 5H), 5.11(m, 1H), 4.81(m, 1H), 4.72
(m, 1H), 4.35 (m, 1H), 3.58-3.41 (m, 2H), 3.23 (m, 1H), 2.97 (dd,
J=14.0, 10.3 Hz, 1H), 2.85 (dd, J=14.0, 5.3 Hz, 1H), 2.41 (tapp, J=
7.3 Hz, 2H), 2.21-2.12 (m, 2H), 2.07 (s, 3H), 2.03-1.94 (m, 2H),
1.89(m, 1H),1.58-1.38 (m, 5H), 1.32-1.14 (m, 4H), 1.00 (d, J=7.0
Hz, 3H), 0.73 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
δ 208.4 (C), 174.6 (C), 171.3 (C), 169.9 (C), 138.0 (C), 128.9 (2CH),
128.0 (2CH), 126.3 (CH), 73.3 (CH), 69.1 (CH), 59.4 (CH), 57.3
(CH), 46.9 (CH2), 42.7 (CH), 42.6 (CH2), 37.2 (CH), 35.2 (CH2),
33.5 (CH2), 32.4 (CH2), 31.6 (CH2), 29.6 (CH3), 26.0 (CH2), 23.3
(CH2), 20.9 (CH2), 17.1 (CH3), 14.0 (CH3); HRMS (ESI) m/z calcd
for C28H40O6N2Na [MþNa]þ 523.2779, found 523.2758.
acetone: 7/3); [R]20 -25.2 (c 1.2, CHCl3); IR (neat) 3292,
D
2930, 1712, 1650, 1616, 1450, 1250, 1186, 1094, 837 cm-1. Major
rotamer: 1H NMR (400 MHz, CDCl3) δ 7.79-7.73 (d, J =
7.5 Hz, 2H), 7.64-7.56 (tapp, J= 7.5 Hz, 2H), 7.44-7.35 (m, 2H),
7.34-7.28 (m, 2H), 7.27-7.16 (m, 5H), 5.84 (m, 1H), 4.81 (m,
1H), 4.73 (m, 1H), 4.46-4.27 (m, 3H), 4.26-4.05 (m, 2H), 3.55
(m, 1H), 3.10 (dd, J=12.7, 5.3 Hz, 1H), 2.99 (m, 1H), 2.75-2.59
(m, 2H), 2.46-2.37 (m, 2H), 2.10 (s, 3H), 2.01-1.65 (m, 6H),
1.63-1.49 (m, 3H), 1.45-1.23 (m, 4H), 1.09 (d, J=7.0 Hz, 3H),
1.00-0.88 (m, 3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.00 (s, 3H); 13C
NMR (400 MHz, CDCl3) δ 209.2 (C), 179.2 (C), 171.4 (C), 169.8
(C), 155.6 (C), 144.0 (C), 143.8 (C), 141.3 (2C), 136.3 (C), 129.5
(2CH), 128.4 (3CH), 127.7 (2CH), 127.1 (2CH), 125.2 (2CH),
119.9 (2CH), 74.9 (CH), 69.7 (CH), 67.0 (CH2), 58.9 (CH), 54.1
(CH), 47.2 (CH), 46.8 (CH2), 43.6 (CH2), 42.8 (CH2), 40.2 (CH),
36.7 (CH), 35.1 (CH2), 31.8 (CH2), 29.8 (CH3), 28.9 (CH2), 26.6
(CH2), 25.7 (3CH3), 24.2 (CH2), 23.9 (CH2), 17.9 (C), 14.7 (CH3),
8.8 (CH3), -4.2 (CH3), -5.0 (CH3); HRMS (ESI) m/z calcd for
C49H66O9N2NaSi [MþNa]þ 877.4430, found 877.4418.
(5R,8R,9S,11R,13aR)-5-Benzyl-9-(tert-butyldimethylsilyloxy)-
8-methyl-11-((S)-1-methyl-6-oxoheptyl)-decahydro-12-oxa-3a,6-
diazacyclopentacyclododecene-4,7,13-trione (17). To a solution
of (R)-1-[(R)-2-(9H-fluoren-9-yloxycarbonylamino)-3-phenyl-
propionyl]-pyrrolidine-2-carboxylic acid (1R,2S)-1-[(2S,3R)-
2-(tert-butyldimethylsilyloxy)-3-carboxybutyl]-2-methyl-7-oxooctyl
ester (16, 360 mg, 0.4 mmol) in CH3CN (15 mL) at room tem-
perature was added Et2NH (7.6 mL), and the reaction mixture
was stirred at room temperature until complete conversion
of the starting material (reaction monitored by TLC analysis).
The solvent was then removed under reduced pressure, and the
resulting crude amino acid was used in the next step without further
Acknowledgment. We thank Generalitat de Catalunya (A.E.)
and the Renault Fondation (A.F.) for financial support.
Supporting Information Available: Experimental procedures,
spectroscopic data, and 1H and 13C NMR spectra for all new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
8486 J. Org. Chem. Vol. 75, No. 24, 2010