Parallel, stereoselective syntheses of both enantiomers of muricatacin and their sulfur and nitrogen relatives using the silyloxy diene-based methodology

Full text of DOI:10.1021/jo970205z

J . Org. Chem. 1997, 62, 4513-4517
4513
for this chemistry to further enlarge the synthetic
horizons, we envisaged preparing both enantiomers of
muricatacin, (R,R)- and (S,S)-1a ,5,6 and their sulfur and
nitrogen relatives, (R,R)- and (S,S)-1b and (R,R)- and
(S,S)-1c, moving from the above-mentioned silyloxy
dienes according to a chemically uniformed reaction pro-
tocol, using both enantiomers of glyceraldehyde acetonide
[(R)- and (S)-2] as the chiral sources.
Muricatacin, an acetogenin derivative that shows
cytotoxic activity against certain human tumor cell lines,7
has been isolated from the seeds of Annona muricata,5
and remarkably, the natural compound comprises both
(-)-muricatacin [(R,R)-1a ] and its enantiomer (+)-mu-
ricatacin [(S,S)-1a ].8
P a r a llel, Ster eoselective Syn th eses of both
En a n tiom er s of Mu r ica ta cin a n d Th eir
Su lfu r a n d Nitr ogen Rela tives Usin g th e
Silyloxy Dien e-Ba sed Meth od ology
Gloria Rassu*,† Luigi Pinna,‡ Pietro Spanu,†
Franca Zanardi,§ Lucia Battistini,§ and
Giovanni Casiraghi*,§
Istituto per l’Applicazione delle Tecniche Chimiche
Avanzate del CNR, Via Vienna 2, I-07100 Sassari, Italy,
Dipartimento di Chimica dell’Universita`, Via Vienna 2,
I-07100 Sassari, Italy, and Dipartimento Farmaceutico
dell’Universita`, Viale delle Scienze, I-43100 Parma, Italy
Received February 5, 1997
Resu lts a n d Discu ssion
In tr od u ction
The retrosynthetic analysis of the muricatacin targets,
outlined in Scheme 1, simply entailed diastereoselective
coupling of TBSOF, TBSOT, and TBSOP to suitably
protected glyceraldehyde derivative A to form unsatur-
ated adducts B, and subsequent saturation of the double
bond within B and oxidative sacrifice of the C-7 carbon
atom to aldehydes C, followed by final Wittig elongation/
hydrogenation maneuver. The Lewis acid-promoted
conjugate Mukaiyama-aldol addition of the silyloxy diene
reagents to chiral R-alkoxy aldehydes proved to be highly
4,5-syn selective, with R-R-configured aldehydes forming
4R adducts and vice versa.2-4 It was thus expected that
D-glyceraldehyde (R)-2 would produce (4R,5R)-configured
muricatacin derivatives, while L-glyceraldehyde (S)-2
would furnish (4S,5S) congeners.
A prominent objective of our laboratory is to develop
flexible, chemically uniformed methodology to assemble
diverse collections of chiral nonracemic bioactive mol-
ecules and variants thereof to be used to discover
potential therapeutic candidates of novel or improved
functional profiles.1 To this end, we recently introduced
a homogeneous triad of nucleophilic reactants, namely,
2-[(tert-butyldimethylsilyl)oxy]furan (hereafter TBSOF),
2-[(tert-butyldimethylsilyl)oxy]thiophene (TBSOT), and
N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl)oxy-
]pyrrole (TBSOP), whose application in synthesis has
been thoroughly pursued and demonstrated.2-4 In order
† CNR, Sassari. E-mail: rassu@hpj.area.ss.cnr.it.
‡ Universita` di Sassari.
For the (R,R)-muricatacin series, the three parallel
syntheses commenced with (+)-(R)-glyceraldehyde aceto-
nide (R-2), which was coupled to TBSOF, TBSOT, and
TBSOP under BF3 etherate (TBSOF and TBSOT) or
SnCl4 assistance (TBSOP).9 Under optimal conditions
(Scheme 2), 4,5-syn-configured adducts 3a -c preferen-
tially formed, contaminated by only marginal amounts
of the corresponding 4,5-anti diastereoisomers that were
easily separated by flash chromatography on silica gel.
The de values ranged from 88% for 3a to 82% for 3b to
89% for 3c.10 At this point of the synthesis, it was
necessary to saturate the double bond within 3 and
protect the free hydroxyl at C-5 before fission of the C-6-
C-7 carbon-carbon bond. Thus, compounds 3a -c were
subjected to sequential catalytic hydrogenation (H2, Pd
§Universita` di Parma. E-mail: casirag@ipruniv.cce.unipr.it.
(1) For recent reviews on the synthesis and applications of small
molecule libraries, see, for example: Thompson, L. A.; Ellman, J . A.
Chem. Rev. 1996, 96, 555-600. Balkenhohl, F.; von dem Bussche-
Hu¨nnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl.
1996, 35, 2288-2337.
(2) Works from our laboratory: (a) Casiraghi, G.; Rassu, G. Synthesis
1995, 607-629. (b) Casiraghi, G.; Colombo, L.; Rassu, G.; Spanu, P.
J . Org. Chem. 1991, 56, 6523-6527. (c) Casiraghi, G.; Rassu, G.;
Spanu, P.; Pinna, L. J . Org. Chem. 1992, 57, 3760-3763. (d) Casiraghi,
G.; Rassu, G.; Spanu, P.; Pinna, L.; Ulgheri, F. J . Org. Chem. 1993,
58, 3397-3400. (e) Casiraghi, G.; Ulgheri F.; Spanu, P.; Rassu, G.;
Pinna, L.; Gasparri Fava, G.; Belicchi Ferrari, M.; Pelosi, G. J . Chem.
Soc., Perkin Trans. 1 1993, 2991-2997. (f) Casiraghi, G.; Spanu, P.;
Rassu, G.; Pinna, L.; Ulgheri, F. J . Org. Chem. 1994, 59, 2906-2909.
(g) Rassu, G.; Zanardi, F.; Cornia, M.; Casiraghi, G. J . Chem. Soc.,
Perkin Trans. 1 1994, 2431-2437. (h) Rassu, G.; Spanu, P.; Pinna,
L.; Zanardi, F.; Casiraghi, G. Tetrahedron Lett. 1995, 36, 1941-1944.
(i) Zanardi, F.; Battistini, L.; Rassu, G.; Cornia, M.; Casiraghi, G. J .
Chem. Soc., Perkin Trans. 1 1995, 2471-2475. (j) Spanu, P.; Rassu,
G.; Ulgheri, F.; Zanardi, F.; Battistini, L.; Casiraghi, G. Tetrahedron
1996, 52, 4829-4838. (k) Zanardi, F.; Battistini, L.; Nespi, M.; Rassu,
G.; Spanu, P.; Casiraghi, G. Tetrahedron: Asymmetry 1996, 7, 1167-
1180. (l) Soro, P.; Rassu, G.; Pinna, L.; Zanardi, F.; Casiraghi, G. J .
Org. Chem. 1996, 61, 5172-5174. (m) Rassu, G.; Zanardi, F.; Battis-
tini, L.; Gaetani, E.; Casiraghi, G. J . Med. Chem. 1997, 40, 168-180.
(3) Related works: J efford, C. W.; J aggi, D.; Sledeski, A. W.;
Boukouvalas, J . In Studies of Natural Products Chemistry, Stereose-
lective Synthesis (Part B); Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1989; Vol. 3, pp 157-171. Pelter, A.; Ward, R. S.; Sirit, A. Tetrahe-
dron: Asymmetry 1994, 5, 1745-1762. Xu, D.; Sharpless, K. B.
Tetrahedron Lett. 1994, 35, 4685-4688. Camiletti, C.; Poletti, L.;
Trombini, C. J . Org. Chem. 1994, 59, 6843-6846. Ko, S. Y.; Lerpiniere,
J . Tetrahedron Lett. 1995, 36, 2101-2104. Poli, G.; Ciofi, S.; Maccagni,
E.; Sardone, N. Tetrahedron Lett. 1995, 36, 8669-8672. Baussanne,
I.; Royer, J . Tetrahedron Lett. 1996, 37, 1213-1216. Hanessian, S.;
McNaughton-Smith, G. Bioorg. Med. Chem. Lett. 1996, 6, 1567-1572.
Pichon, M.; Figade`re, B.; Cave´, A. Tetrahedron Lett. 1996, 37, 7963-
7966.
(5) Isolation: Rieser, M. J .; Kozlowski, J . F.; Wood, K. V.; McLaugh-
lin, J . L. Tetrahedron Lett. 1991, 32, 1137-1140.
(6) Previous syntheses: (a) Scholz, G.; Tochtermann, W. Tetrahedron
Lett. 1991, 32, 5535-5538. (b) Figade`re, B.; Harmange, J .-C.; Laurens,
A.; Cave´, A. Tetrahedron Lett. 1991, 32, 7539-7542. (c) Wang, Z.-M.;
Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.; Sinha-Bagchi, A.; Keinan,
E. Tetrahedron Lett. 1992, 33, 6407-6410. (d) Marshall, J . A.;
Welmaker, G. S. J . Org. Chem. 1994, 59, 4122-4125. (e) Somfai, P.
J . Chem. Soc., Perkin Trans. 1 1995, 817-819. (f) Quayle, P.; Rahman,
S.; Herbert, J . Tetrahedron Lett. 1995, 36, 8087-8088.
(7) For recent reviews on the occurrence, synthesis, and activity of
Annonaceous acetogenins, see: Hoppe, R.; Scharf, H.-D. Synthesis
1995, 1447-1464. Koert, U. Synthesis 1995, 115-132. Zeng, L.; Ye,
Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J . L. Nat.
Prod. Rep. 1996, 13, 275-306. Gu, Z.-M.; Zhao, G.-X.; Oberlies, N.
H.; Zeng, L.; McLaughlin, J . L. In Recent Advances in Phytochemistry;
Arnason J . T., Mata, R., Romeo, J . T., Eds.; Plenum Press: New York,
1995; Vol. 29, pp 249-310. Figade`re, B. Acc. Chem. Res. 1995, 28,
359-365.
(8) Muricatacin is probably a product of oxidative fission of the
various monotetrahydrofuranic acetogenins in the plant (ref 6b).
(9) For each coupling reaction, the choice of the optimum protocol
(Lewis acid activator, solvent, temperature) resulted from previous
extensive work in our laboratory (see ref 2).
(4) For pioneering work in this area, see: Asaoka, M.; Sugimura,
N.; Takei, H. Bull. Chem. Soc. J pn. 1979, 52, 1953-1956. Fiorenza,
M.; Reginato, G.; Ricci, A.; Taddei, M.; Dembech, P. J . Org. Chem. 1984,
49, 551-553. Brown, D. W.; Campbell, M. M.; Taylor, A. P.; Zhang,
X.-A. Tetrahedron Lett. 1987, 28, 985-988. J efford, C. W.; J aggi, D.;
Boukouvalas, J . Tetrahedron Lett. 1987, 28, 4037-4040.
S0022-3263(97)00205-3 CCC: $14.00 © 1997 American Chemical Society

4514 J . Org. Chem., Vol. 62, No. 13, 1997
Notes
Sch em e 1. Retr osyn th etic An a lysis of
(R,R)-Mu r ica ta cin a n d Its Con gen er s Usin g th e
Silyloxy Dien e Meth od ologya
Sch em e 3. Syn th esis of (S,S)-Mu r ica ta cin
Der iva tivesa
a
PG ) protective groups.
Sch em e 2. Syn th esis of (R,R)-Mu r ica ta cin
Der iva tivesa
a
Reaction conditions, see Scheme 2. The yields quoted refer
to oxygen, sulfur, and nitrogen derivatives, respectively.
pounds, which were quickly transformed to muricatacin
derivatives (R,R)-1a -c by catalytic hydrogenation (Pd on
carbon, THF) followed by BF3 etherate-promoted desily-
lation12 (50%, 61%, and 56% yields for the three reac-
tions). The overall yields from (R)-2 were 25%, 24%, and
32%, respectively, over eight steps.
The synthetic paths to (+)-muricatacin enantiomers
from L-glyceraldehyde (S)-2 (Scheme 3) were similar to
those of their (4R,5R)-configured counterparts and pro-
ceeded uneventfully to afford, first, adducts ent-3a -c,
which were then transformed to target compounds (S,S)-
1a -c via the respective intermediates ent-4a -c and ent-
5a -c. Corroborating the reliability of the strategy, (+)-
muricatacin [(S,S)-1a ] and its sulphur and nitrogen
relatives, (S,S)-1b and (S,S)-1c, were thus prepared in
24%, 22%, and 32% overall yields, respectively, from
L-glyceraldehyde (S)-2.
In conclusion, what we have reported is a concise,
diastereoselective synthesis of both enantiomers of mu-
ricatacin and their sulfur and nitrogen relatives that uses
readily available D- and L-glyceraldehyde acetonides as
the sole sources of chirality. In the course of this
investigation, TBSOF, TBSOT, and TBSOP have emerged
as a modular triad of reactants that features uniform
a
The yields quoted refer to oxygen, sulfur, and nitrogen
derivatives, respectively.
on carbon) and protection of the OH function as TBS
ether (TBSCl, imidazole, DMF) to afford seven-carbon
intermediates 4a -c in excellent isolated yields.11
The oxidative removal of the C-7 carbon atom within
4a -c to generate the six-carbon aldehydes 5a -c was
effected by cleaving of the terminal acetonide (70%
aqueous AcOH, 50 °C) followed by fission of the diol so
formed by NaIO4-impregnated wet silica in CH2Cl2. The
sequences afforded configurationally stable compounds
5a -c in high yields, which were used as such in the next
stages of the syntheses. There remained to carry out
suitable elongations on 5a -c in order to complete the
elaboration of the muricatacin side chains. Indeed,
Wittig olefination of aldehydes 5a -c in THF with the
appropriate C11 ylide (undecylphosphonium bromide/
BuLi) gave rise to the corresponding unsaturated com-
(10) The relative (and hence absolute) configuration of the key 4,5-
syn-configured adducts 3a -c was unambiguously determined by
single-crystal X-ray analysis. 3a : Casiraghi, G.; Colombo, L.; Rassu,
G.; Spanu, P.; Gasparri Fava, G.; Ferrari Belicchi, M. Tetrahedron
1990, 46, 5807-5824. 3b: Gasparri Fava, G.; Ferrari Belicchi, M.;
Pelosi, G.; Zanardi, F.; Casiraghi, G.; Rassu, G. J . Chem. Crystallogr.
1996, 26, 509-513. 3c: Rassu, G.; Casiraghi, G.; Spanu, P.; Pinna,
L.; Gasparri Fava, G.; Ferrari Belicchi, M.; Pelosi, G. Tetrahedron:
Asymmetry 1992, 3, 1035-1048. The configuration of the respective
4,5-anti congeners was judged as such on the basis of clean base-
promoted C-4 epimerization experiments.
(11) We were unsuccessful in obtaining the intended derivatives
4a -c by adopting the reverted maneuver (protection, then reduction),
since unwanted epimerization at C-4 occurred under the basic condi-
tions of the TBS-protection protocol.
(12) Kelly, D. R.; Roberts, S. M.; Newton, R. F. Synth. Commun.
1979, 9, 295-298.

Notes
J . Org. Chem., Vol. 62, No. 13, 1997 4515
Compound 4-epi-3b: an oil; [R]20 -58.0 (c 2.7, CHCl3); 1H
reactivity and wide, confident applicability. The trans-
formations disclosed herein promise to elevate the syn-
thetic utility of the title heterocyclic silyloxy dienes for
the preparation of constitutionally and chirally diverse
compounds, both individuals and ensembles, equipped
with a variety of oxygen, sulfur, and nitrogen combina-
tions.
D
NMR (300 MHz, CDCl3) δ 7.68 (dd, J ) 6.0, 2.7 Hz, 1H), 6.37
(dd, J ) 6.0, 2.1 Hz, 1H), 4.76 (ddd, J ) 5.1, 2.7, 2.1 Hz, 1H),
3.9-4.2 (m, 4H), 3.33 (bs, 1H), 1.44 (s, 3H), 1.37 (s, 3H). Anal.
Calcd for C10H14O4S: C, 52.16; H, 6.13. Found: C, 52.21; H,
6.20.
4-[(ter t-Bu t oxyca r b on yl)a m in o]-6,7-O-isop r op ylid en e-
2,3,4-t r id eoxy-D-a r a bin o-h ep t -2-en on ic Acid 1,4-La ct a m
(3c). The above procedure described for 3a was here adopted,
with slight modifications concerning the Lewis acid promoter
(SnCl4 instead of BF3 etherate) and the solvent (Et2O instead of
CH2Cl2). Starting from 2.45 g (8.2 mmol) of TBSOP, 1.39 g (10.7
mmol) of D-glyceraldehyde (R)-2, and 0.97 mL (8.2 mmol) of
SnCl4 in anhydrous Et2O (50 mL) for 5 h at -80 °C, there was
obtained a crude product, which was purified by crystallization
from CH2Cl2/hexane to furnish 2.06 g (80%) of pure 3c, ac-
companied by 0.12 g (4.7% yield) of its diastereoisomer 4-epi-
3c, which was obtained in a pure form by flash chromatography
of the mother liquor residue (1:1 hexanes/EtOAc).
Exp er im en ta l Section 13
Mater ials. 2,3-O-Isopropylidene-D-glyceraldehyde [(R)-2] was
prepared from D-mannitol (Aldrich) according to the literature.14
The preparation of 2,3-O-isopropylidene-L-glyceraldehyde [(S)-
2] was carried out starting with 5,6-O-isopropylidene-L-gulonic
acid 1,4-lactone (Fluka) following a known protocol.15 2-[(tert-
Butyldimethylsilyl)oxy]furan (TBSOF) was obtained from 2-fural-
dehyde (Aldrich) following
a
reported method.2m 2-[(tert-
Butyldimethylsilyl)oxy]thiophene (TBSOT) was prepared from
thiophene (Aldrich) according to the method in a precedent
paper.2h The synthesis of N-(tert-butoxycarbonyl)-2-[(tert-bu-
tyldimethylsilyl)oxy]pyrrole (TBSOP) was carried out starting
with pyrrole (Aldrich) according to a precedent protocol.2c
Undecyltriphenylphosphonium bromide was obtained from 1-bro-
moundecane (Aldrich) and triphenylphosphine according to a
standard protocol. The gummy salt was thoroughly dried under
vacuum (P2O5) prior to use.
6,7-O-Isop r op ylid e n e -2,3-d id e oxy-D -a r a bin o-h e p t -2-
en on ic Acid 1,4-La cton e (3a ). Gen er a l P r oced u r e. To a
solution of TBSOF (3.05 mL, 15.4 mmol) in anhydrous CH2Cl2
(60 mL) under argon atmosphere was added 2,3-O-isopro-
pylidene-D-glyceraldehyde [(R)-2] (2.60 g, 20 mmol), and the
resulting mixture was cooled to -80 °C. BF3 etherate (1.89 mL,
15.4 mmol), cooled to the same temperature, was added dropwise
to the stirring solution, and the reaction was allowed to proceed
for 6 h at -80 °C. The reaction was then quenched at -80 °C
by the addition of saturated aqueous NaHCO3, and after ambient
temperature was reached, the mixture was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with brine, dried (MgSO4), filtered, and concentrated in vacuum
to give a solid crude residue, which was subjected to flash
chromatographic purification (3:2 hexanes/EtOAc). There were
obtained 2.47 g (75%) of pure 3a along with 0.16 g (5%) of the
corresponding epimer 4-epi-3a .
Compound 3c: white solid; mp 138-140 °C; [R]20 +197.6 (c
D
0.83, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.43 (dd, J ) 6.3,
2.1 Hz, 1H), 6.13 (dd, J ) 6.3, 1.5 Hz, 1H), 4.81 (dt, J ) 5.7, 2.4
Hz, 1H), 4.09 (ddd, J ) 6.0, 5.7, 3.9 Hz, 1H), 4.01 (q, J ) 6.0,
1H), 3.94 (dd, J ) 8.1, 6.0 Hz, 1H), 3.86 (dd, J ) 8.1, 6.0 Hz,
1H), 3.63 (d, J ) 3.9 Hz, 1H), 1.57 (s, 9H), 1.37 (s, 3H), 1.32 (s,
3H); 13C NMR (75.4 MHz, CDCl3) δ 168.9, 150.9, 148.2, 126.9,
109.2, 83.8, 75.6, 72.6, 66.4, 65.6, 28.0 (3 C), 26.4, 25.1. Anal.
Calcd for C15H23NO6: C, 57.50; H, 7.40; N, 4.47. Found: C,
57.31; H, 7.35; N, 4.32.
Compound 4-epi-3c: white solid; mp 118-120 °C; [R]20
D
-120.0 (c 0.8, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, J
) 6.3, 2.1 Hz, 1H), 6.16 (dd, J ) 6.3, 2.0 Hz, 1H), 4.97 (q, J )
2.1 Hz, 1H), 4.20 (m, 1H), 4.15 (td, J ) 6.6, 2.2 Hz, 1H), 4.03
(m, 2H), 3.49 (d, J ) 6.6 Hz, 1H), 1.56 (s, 9H), 1.46 (s, 3H), 1.37
(s, 3H). Anal. Calcd for C15H23NO6: C, 57.50; H, 7.40; N, 4.47.
Found: C, 57.30; H, 7.55; N, 4.31.
6,7-O-Isop r op ylid e n e -2,3-d id e oxy-L -a r a bin o-h e p t -2-
en on ic Acid 1,4-La cton e (en t-3a ). The title compound was
prepared according to the synthetic protocol described for its
enantiomer 3a by employing L-glyceraldehyde (S)-2 in place of
(R)-2. Starting with TBSOF (2.85 g, 14.4 mmol), pure ent-3 was
obtained (2.22 g, 72%) as colorless crystals: mp 123 °C; [R]20
D
-68.9 (c 1.0, CHCl3). 1H and 13C NMR spectra fully coincided
with those of its enantiomeric counterpart 3a . Anal. Calcd for
C
10H14O5: C, 56.07; H, 6.59. Found: C, 55.88; H, 6.70.
6,7-O-Isop r op ylid en e-4-t h io-2,3,4-t r id eoxy-L-a r a bin o-
h ep t-2-en on ic Acid 1,4-Th iola cton e (en t-3b). The above
procedure to 3b was adopted, employing L-glyceraldehyde (S)-2
in place of (R)-2. Starting with 2.71 g (12.6 mmol) of TBSOT,
Compound 3a : white crystals; mp 125 °C; [R]20D +69.6 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.59 (dd, J ) 5.8, 1.7 Hz,
1H), 6.17 (dd, J ) 5.8, 1.9 Hz, 1H), 5.27 (m, 1H), 4.18 (m, 2H),
4.05 (m, 1H), 3.67 (m, 1H), 2.94 (d, J ) 6.6 Hz, 1H), 1.42 (s,
3H), 1.37 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 176.4, 154.3,
122.1, 109.8, 84.2, 75.5, 72.9, 67.1, 26.7, 25.1. Anal. Calcd for
thiolactone ent-3b was obtained (2.06 g, 71%) as an oil: [R]20
D
-65.9 (c 2.4, CHCl3). 1H and 13C NMR spectra were in perfect
agreement with those of enantiomeric thiolactone 3b. Anal.
Calcd for C10H14O4S: C, 52.16; H, 6.13. Found: C, 52.34; H,
6.09.
C
10H14O5: C, 56.07; H, 6.59. Found: C, 55.94; H, 6.71.
Compound 4-epi-3a : an oil; [R]20 -79.4 (c 0.6, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 7.61 (dd, J ) 5.6, 1.5 Hz, 1H), 6.22
(dd, J ) 5.6, 2.0 Hz, 1H), 5.20 (ddd, J ) 4.7, 2.0, 1.5 Hz, 1H),
4.0 - 4.2 (m, 3H), 3.97 (dd, J ) 7.1, 4.7 Hz, 1H), 2.60 (bs, 1H),
1.45 (s, 3H), 1.37 (s, 3H). Anal. Calcd for C10H14O5: C, 56.07;
H, 6.59. Found: C, 56.39; H, 6.40.
4-[(ter t-Bu t oxyca r b on yl)a m in o]-6,7-O-isop r op ylid en e-
2,3,4-t r id eoxy-L-a r a bin o-h ep t -2-en on ic Acid 1,4-La ct a m
(en t-3c). The above procedure to 3c was followed by replacing
(R)-2 with (S)-2. Starting with 2.0 g (6.72 mmol) of TBSOP,
there was obtained a crude product that was crystallized from
CH2Cl2/hexane to afford 1.64 g (78%) of lactam ent-3c as a white
6,7-O-Isop r op ylid en e-4-t h io-2,3,4-t r id eoxy-D-a r a bin o-
h ep t-2-en on ic Acid 1,4-Th iola cton e (3b). The title compound
was prepared according to the procedure described for 3a ,
employing 2.71 g (12.6 mmol) of TBSOT, 2.13 g (16.4 mmol) of
D-glyceraldehyde (R)-2, and 1.55 mL (12.6 mmol) of BF3 etherate
in CH2Cl2 (50 mL) at -80 °C for 4 h. After flash chromato-
graphic purification (1:1 hexanes/EtOAc), thiolactone 3b was
recovered in 78% yield (2.26 g), along with the corresponding
epimer 4-epi-3b (0.23 g, 8% yield).
solid: mp 135-136 °C; [R]20 -195.66 (c 0.4, CHCl3). 1H and
D
13C NMR spectra were in perfect agreement with those of
enantiomeric lactam 3c. Anal. Calcd for C15H23NO6: C, 57.50;
H, 7.40; N, 4.47. Found: C, 57.39; H, 7.63; N, 4.28.
5-O-(ter t-Bu t yld im et h ylsilyl)-6,7-O-isop r op ylid en e-2,3-
d id eoxy-D-a r a bin o-h ep ton ic Acid 1,4-La cton e (4a ). Gen -
er a l P r oced u r e. Palladium on carbon (10%, 0.3 g) was added
to a solution of R,â-unsaturated lactone 3a (2.4 g, 11.2 mmol) in
anhydrous THF (60 mL) in the presence of a small amount of
NaOAc (0.09 g) at room temperature. The reaction vessel was
evacuated by aspirator and thoroughly purged with hydrogen
(three times), and the resulting heterogeneous mixture was
stirred under a balloon of hydrogen. After 24 h, the hydrogen
was evacuated, the catalyst filtered off, and the filtrate concen-
trated under vacuum to give a crude residue that was subjected
to flash chromatographic purification (3:2 EtOAc/hexanes).
There was obtained 2.2 g (90%) of saturated lactone as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 4.77 (td, J ) 7.5, 2.1 Hz, 1H),
Compound 3b: an oil; [R]20 +67.0 (c 2.5, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 7.54 (dd, J ) 6.1, 2.9 Hz, 1H), 6.31 (dd, J )
6.1, 1.9 Hz, 1H), 4.91 (m, 1H), 3.8-4.2 (m, 4H), 2.74 (bs, 1H),
1.41 (s, 3H), 1.32 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 199.6,
156.7, 133.4, 110.0, 78.1, 72.9, 67.1, 58.4, 26.7, 24.9. Anal. Calcd
for C10H14O4S: C, 52.16; H, 6.13. Found: C, 52.24; H, 6.01.
(13) For general experimental procedures, see ref 2m.
(14) Schmid, C. R.; Bryant, J . D. Org. Synth. 1995, 72, 6-13.
(15) Hubschwerlen, C.; Specklin, J .-L.; Higelin, J . Org. Synth. 1995,
72, 1-5.

4516 J . Org. Chem., Vol. 62, No. 13, 1997
Notes
4.14 (m, 2H), 4.01 (m, 1H), 3.53 (bs, 1H), 3.35 (bs, 1H), 2.5-2.7
(m, 2H), 2.31 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H). The saturated
lactone was subjected to 5-O-TBS protection. Thus, TBSCl (4.4
g, 29.1 mmol) and imidazole (2.0 g, 29.1 mmol) were sequentially
added to a solution of the saturated lactone (2.1 g, 9.7 mmol) in
anhydrous DMF (15 mL) under stirring at room temperature.
After 24 h, further portions of TBSCl (1.4 g, 9.28 mmol) and
imidazole (0.63 g, 9.3 mmol) were added, and the resulting
solution was allowed to stir for an additional 12 h. The reaction
was then quenched with 5% aqueous citric acid and the resulting
mixture extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were dried (MgSO4) and concentrated under
vacuum to afford a crude residue that was purified by flash
chromatography (1:1 hexanes/EtOAc). Protected lactone 4a (2.9
protected lactone ent-4a (2.6 g, 78%) as an oil: [R]20 +11.3 (c
D
1.2, CHCl3); 1H and 13C NMR spectra fully coincided with those
of its enantiomer 4a . Anal. Calcd for C16H30O5Si: C, 58.15; H,
9.15. Found: C, 58.22; H, 9.20.
5-O-(ter t-Bu tyldim eth ylsilyl)-6,7-O-isopr opyliden e-4-th io-
2,3,4-tr ideoxy-L-a r a bin o-h epton ic Acid 1,4-Th iolacton e (en t-
4b). The above hydrogenation-protection procedure to 4b was
adopted with 2.0 g (8.69 mmol) of unsaturated thiolactone ent-
3b to afford protected thiolactone ent-4b (1.8 g, 60%) as an oil:
[R]20 +61.2 (c 2.5, CHCl3); 1H and 13C NMR spectra fully
D
coincided with those of its enantiomer 4b . Anal. Calcd for
C
16H30O4SSi: C, 55.45; H, 8.73. Found: C, 55.30; H, 8.90.
4-(ter t-Bu toxyca r bon yl)a m in o]-5-O-(ter t-bu tyld im eth yl-
silyl)-6,7-O-isop r op ylid en e-2,3,4-t r id eoxy-L-a r a bin o-h ep -
ton ic Acid 1,4-La cta m (en t-4c). The above hydrogenation-
protection procedure to 4c was adopted, with 2.20 g (7.0 mmol)
of unsaturated lactam ent-3c, to afford saturated and protected
lactam ent-4c (2.6 g, 86%) as an oil: [R]20D -24.4 (c 1.8, CHCl3);
1H and 13C NMR spectra fully coincided with those of its
enantiomer 4c. Anal. Calcd for C21H39NO6Si: C, 58.71; H, 9.15;
N, 3.26. Found: C, 58.60; H, 9.29; N, 3.18.
g, 90%) was obtained as a colorless oil: [R]20 -9.5 (c .0.6,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 4.60 (dt, J ) 6.6, 3.6 Hz,
1H), 4.13 (m, 1H), 4.06 (dd, J ) 8.1, 6.3 Hz, 1H), 3.87 (dd, J )
8.1, 6.9 Hz, 1H), 3.78 (dd, J ) 6.0, 3.6 Hz, 1H), 2.51 (m, 2H),
2.21 (m, 2H), 1.41 (s, 3H), 1.33 (s, 3H), 0.89 (s, 9H), 0.13 (s, 6H);
13C NMR (75.4 MHz, CDCl3) δ 176.5, 109.0, 81.2, 76.3, 74.3, 66.6,
28.4, 26.5, 25.8 (3C), 27.2, 23.6, 18.1, -4.0 (2C). Anal. Calcd
for C16H30O5Si: C, 58.15; H, 9.15. Found: C, 58.20; H, 9.09.
5-O-(ter t-Bu tyldim eth ylsilyl)-6,7-O-isopr opyliden e-4-th io-
2,3,4-t r id eoxy-D-a r a bin o-h ep t on ic Acid 1,4-Th iola ct on e
(4b). The above hydrogenation procedure to 4a was employed,
with unsaturated thiolactone 3b (2.20 g, 9.55 mmol), 10% Pd
on carbon (270 mg), and NaOAc (85 mg) in dry THF (50 mL).
After flash chromatographic purification (1:1 EtOAc:hexanes),
the saturated thiolactone intermediate (2.0 g, 90% yield) was
obtained as white crystals: mp 118-120 °C; 1H NMR (300 MHz,
CDCl3) δ 4.25 (ddd, J ) 7.5, 7.0, 3.9 Hz, 1H), 4.09 (m, 1H), 3.95
(m, 2H), 3.77 (dd, J ) 7.2, 3.9 Hz, 1H), 2.91 (d, J ) 3.6 Hz, 1H),
2.5-2.8 (m, 2H), 2.1-2.5 (m, 2H), 1.42 (s, 3H), 1.34 (s, 3H). This
intermediate was subjected to the same protection protocol as
that utilized to afford 4a , employing 2 × 3.88 g (2 × 25.77 mmol)
of TBSCl and 2 × 1.75 g (2 × 25.77 mmol) of imidazole in
anhydrous DMF (30 mL) for 48 h. After flash chromatography
(7:3 hexanes/EtOAc), protected thiolactone 4b (1.93 g, 65%) was
2-O-(ter t-Bu tyld im eth ylsilyl)-4,5-d id eoxy-D-th r eo-h exu -
r on ic Acid 6,3-La cton e (5a ). Gen er a l P r oced u r e. Protected
lactone 4a (2.8 g, 8.5 mmol) was dissolved in 10 mL of 70%
aqueous acetic acid, and the resulting solution was allowed to
react at 50 °C. The reaction was monitored by TLC and was
judged complete after 8 h. The solution was then quenched with
saturated NaHCO3, and the resulting mixture was extracted
with EtOAc (3 × 30 mL). The combined organic layers were
dried (MgSO4) and concentrated to give a crude residue that was
purified by flash chromatography (9:1 EtOAc/MeOH). There was
obtained a pure terminal diol intermediate (2.34 g, 95%) as a
white solid: mp 81-83 °C; 1H NMR (300 MHz, CDCl3) δ 4.68
(td, J ) 7.2, 4.2 Hz, 1H), 3.86 (m, 4H), 2.85 (bs, 1H), 2.56 (m,
2H), 2.17 (m, 3H), 0.91 (s, 9H), 0.15 (s, 6H). This partially
deprotected lactone was then dissolved in CH2Cl2 (16 mL) and
treated with a 0.65 M aqueous NaIO4 solution (16 mL) and
chromatography grade SiO2 (16 g). The resulting heterogeneous
mixture was vigorously stirred at room temperature until
complete consumption of the starting material (about 20 min,
monitoring by TLC). The slurry was filtered under suction and
the silica thoroughly washed with CH2Cl2 and EtOAc. The
filtrates were evaporated to afford aldehyde 5a (1.77 g, 85%) as
colorless crystals: mp 60-61 °C; [R]20D -97.8 (c 2.7, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 9.67 (d, J ) 1.3 Hz, 1H), 4.88 (ddd, J
) 8.1, 5.4, 2.6 Hz, 1H), 4.04 (dd, J ) 2.6, 1.3 Hz, 1H), 2.57 (m,
2H), 2.37 (m, 1H), 2.19 (m, 1H), 0.95 (s, 9H), 0.12 (s, 6H); 13C
NMR (75.4 MHz, CDCl3) δ 201.9, 176.5, 79.6, 79.2, 27.7, 25.5 (3
C), 23.2, 18.0, -4.7, -5.2. Anal. Calcd for C12H22O4Si: C, 55.78;
H, 8.58. Found: C, 55.65; H, 8.63.
obtained as an oil: [R]20 -57.3 (c 3.3, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 4.14 (ddd, J ) 9.9, 5.7, 4.8 Hz, 1H), 4.02 (m,
2H), 3.93 (dd, J ) 5.4, 4.8 Hz, 1H), 3.84 (m, 1H), 2.61 (m, 2H),
2.29 (m, 1H), 2.09 (m, 1H), 1.42 (s, 3H), 1.33 (s, 3H), 0.89 (s,
9H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ
207.8, 109.2, 77.8, 74.7, 66.4, 54.9, 42.3, 28.5, 26.5, 25.8 (3 C),
25.1, 18.3, -3.6, -3.9. Anal. Calcd for C16H30O4SSi: C, 55.45;
H, 8.73. Found: C, 55.39; H, 8.88.
4-[(ter t-Bu toxyca r bon yl)a m in o]-5-O-(ter t-bu tyld im eth -
ylsilyl)-6,7-O-isop r op ylid en e-2,3,4-tr id eoxy-D-a r a bin o-h ep -
ton ic Acid 1,4-La cta m (4c). The above hydrogenation proce-
dure to transform 3a into 4a was adopted, with unsaturated
lactam 3c (2.0 g, 6.38 mmol), 10% Pd on carbon (210 mg), and
NaOAc (88 mg) in dry THF (30 mL). After flash chromato-
graphic purification (6:4 hexanes:EtOAc), there was obtained a
saturated lactam intermediate (1.85 g, 92%) as a white solid:
mp 99-103 °C; 1H NMR (300 MHz, CDCl3) δ 4.31 (ddd, J ) 5.7,
5.4, 3.9 Hz, 1H), 4.05 (m, 2H), 3.97 (ddd, J ) 5.5, 4.8, 1.2 Hz,
1H), 3.69 (q, J ) 5.7 Hz, 1H), 3.54 (d, J ) 6.3 Hz, 1H), 2.71 (dt,
J ) 17.1, 10.5 Hz, 1H), 2.32 (ddd, J ) 17.7, 6.0, 4.8 Hz, 1H),
2.10 (m, 2H), 1.48 (s, 9H), 1.36 (s, 3H), 1.30 (s, 3H). This
intermediate was subjected to the same protection protocol as
that utilized to afford 4a , employing 2 × 2.65 g (2 × 17.58 mmol)
of TBSCl and 2 × 1.20 g (2 × 17.62 mmol) of imidazole in dry
DMF (20 mL) for 48 h. After flash chromatographic purification
(7:3 hexanes/EtOAc), protected lactam 4c (2.37 g, 94%) was
2-O-(ter t-Bu tyldim eth ylsilyl)-3,4,5-tr ideoxy-3-th io-D-th r eo-
h exu r on ic Acid 6,3-Th iola cton e (5b). The title compound
was prepared following the two-step procedure described to
transform 4a into 5a , starting with 1.90 g (5.48 mmol) of
protected thiolactone 4b. The first deprotection step afforded
1.60 g (95% yield) of a partially deprotected thiolactone as white
1
crystals: mp 77-79 °C; H NMR (300 MHz, CDCl3) δ 4.13 (m,
1H), 3.92 (m, 1H), 3.69 (m, 3H), 2.92 (bs, 2H), 2.57 (m, 2H), 2.20
(m, 1H), 2.00 (m, 1H), 0.86 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H).
This intermediate was transformed into aldehyde 5b by the
same oxidative protocol as that used to afford 5a . 5b (1.29 g,
90%) was obtained as an oil: [R]20 -109.8 (c 1.1, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 9.50 (d, J ) 1.5 Hz, 1H), 4.06 (m,
1H), 3.98 (dd, J ) 6.9, 1.8 Hz, 1H), 2.50 (m, 2H), 2.20 (m, 1H),
2.00 (m, 1H), 0.82 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR
(75.4 MHz, CDCl3) δ 208.0, 201.9, 79.9, 53.4, 42.0, 28.5, 25.8 (3
C), 18.3, -3.5, -3.9. Anal. Calcd for C12H22O3SSi: C, 52.52;
H, 8.08. Found: C, 52.56; H, 8.21.
obtained as a pale yellow oil: [R]20 +21.3 (c 0.8, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 4.14 (ddd, J ) 8.1, 3.6, 1.2 Hz, 1H),
4.04 (dd, J ) 8.4, 3.3 Hz, 1H), 4.02 (dd, J ) 8.4, 6.3 Hz, 1H),
3.90 (m, 1H), 3.66 (dd, J ) 8.1, 6.3 Hz, 1H), 2.51 (m, 1H), 2.33
(m, 1H), 2.11 (m, 1H), 1.93 (m, 1H), 1.46 (s, 9H), 1.24 (s, 3H),
1.20 (s, 3H), 0.80 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR
(75.4 MHz, CDCl3) δ 174.4, 149.8, 109.8, 82.3, 75.2, 71.1, 68.6,
60.2, 31.8, 29.4, 28.0 (3 C), 26.2, 25.4 (3 C), 24.9, 17.6, -4.2,
-5.0. Anal. Calcd for C21H39NO6Si: C, 58.71; H, 9.15; N, 3.26.
Found: C, 58.79; H, 9.20; N, 3.12.
2-O-(ter t-Bu t yld im et h ylsilyl)-3,4,5-t r id eoxy-3-a m in o-D-
th r eo-h exu r on ic Acid 6,3-La cta m (5c). The title compound
was prepared following the two-step procedure described to
transform 4a into 5a , starting with 2.30 g (5.35 mmol) of
protected lactam 4c. The first deprotection step afforded 1.44
g (93%) of a partially deprotected lactam as white crystals: mp
1
5-O-(ter t-Bu t yld im et h ylsilyl)-6,7-O-isop r op ylid en e-2,3-
d id eoxy-L-a r a bin o-h ep ton ic Acid 1,4-La cton e (en t-4a ). The
above hydrogenation-protection procedure to 4a was adopted
with 2.2 g (10.27 mmol) of unsaturated lactone ent-3a to afford
94-96 °C; H NMR (300 MHz, CDCl3) δ 4.20 (bs, 2H), 3.91 (m,
1H), 3.74 (m, 1H), 3.5-3.7 (m, 3H), 3.32 (m, 2H), 2.17 (m, 1H),
1.95 (m, 1H), 0.90 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3 H). This
intermediate was transformed into aldehyde 5c (1.15 g, 90%)

Notes
J . Org. Chem., Vol. 62, No. 13, 1997 4517
as an oil: [R]20D -64.5 (c 2.2, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 9.65 (s, 1H), 6.62 (bs, 1H), 3.91 (m, 2H), 2.25 (m, 3H), 2.02 (m,
1H), 0.94 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (75.4 MHz,
CDCl3) δ 202.2, 178.2, 80.3, 55.2, 29.5, 25.6 (3 C), 22.5, 18.0,
-4.6, -5.1. Anal. Calcd for C12H23NO3Si: C, 55.99; H, 9.01;
N, 5.44. Found: C, 56.08; H, 9.12; N, 5.31.
2-O-(ter t-Bu tyld im eth ylsilyl)-4,5-d id eoxy-L-th r eo-h exu -
r on ic Acid 6,3-La cton e (en t-5a ). The above two-step proce-
dure to 5a was adopted, with 2.5 g (7.56 mmol) of lactone ent-
4a , to afford 1.6 g (82%) of pure aldehyde ent-5a as a glassy
solid: [R]20D +96.3 (c 2.4, CHCl3). 1H and 13C NMR spectra fully
coincided with those of its enantiomer 5a . Anal. Calcd for
mmol). An unsaturated intermediate formed as a 9:1 Z/ E
isomeric mixture (1.24 g, 65%) as an oil: 1H NMR (300 MHz,
CDCl3, Z isomer) δ 5.54 (dt, J ) 11.4, 6.9 Hz, 1H), 5.29 (bt, J )
11.4 Hz, 1H), 4.49 (t, J ) 8.1 Hz, 1H), 3.88 (bq, J ) 8.1 Hz, 1H),
2.62 (ddd, J ) 16.8, 9.3, 5.1 Hz, 1H), 2.53 (ddd, J ) 16.8, 9.9,
7.2 Hz, 1H), 1.9-2.3 (m, 2H), 1.68 (m, 2H), 1.2-1.4 (m, 16H),
0.87 (m, 12H), 0.07 (s, 3H), 0.03 (s, 3H). Hydrogenation and
BF3 etherate-promoted deprotection of this intermediate finally
gave a crude residue, which was subjected to flash chromato-
graphic purification (8:2 hexanes/EtOAc) to furnish pure thio-
muricatacin [(R,R)-1b] (0.84 g, 94%) as colorless crystals: mp
40-42 °C; [R]20D -39.1 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 3.98 (ddd, J ) 7.5, 6.3, 4.8 Hz, 1H), 3.77 (ddd, J ) 8.8, 4.8, 4.5
Hz, 1H), 2.73 (ddd, J ) 16.8, 7.5, 5.4 Hz, 1H), 2.56 (ddd, J )
16.8, 9.0, 7.8 Hz, 1H), 2.32 (dddd, J ) 13.2, 7.8, 6.3, 5.4 Hz, 1H),
2.17 (dddd, J ) 13.2, 9.0, 7.5, 7.5 Hz, 1H), 1.71 (bs, 1H), 1.50
(m, 2H), 1.1-1.4 (m, 20H), 0.88 (t, J ) 6.9 Hz, 3H); 13C NMR
(75.4 MHz, CDCl3) δ 208.0, 74.3, 56.9, 42.0, 36.4, 31.9, 29.6, 29.5,
29.4 (3C), 29.3, 28.9, 28.5, 25.6, 22.6, 14.1. Anal. Calcd for
C
12H22O4Si: C, 55.78; H, 8.58. Found: C, 55.70; H, 8.61.
2-O-(ter t-Bu tyldim eth ylsilyl)-3,4,5-tr ideoxy-3-th io-L-th r eo-
h exu r on ic Acid 6,3-Th iola cton e (en t-5b). The above two-
step procedure to 5b was adopted, with 1.7 g (4.90 mmol) of
thiolactone ent-4b, to afford 1.19 g (88%) of pure aldehyde ent-
5b as an oil: [R]20 +107.3 (c 1.1, CHCl3). 1H and 13C NMR
D
spectra fully coincided with those of its enantiomer 5b. Anal.
Calcd for C12H22O3SSi: C, 52.52; H, 8.08. Found: C, 52.48; H,
7.89.
C
17H32O2S: C, 67.95; H, 10.73. Found: C, 67.90; H, 10.78.
(-)-Aza m u r ica ta cin [(R,R)-1c]. The above procedure to
2-O-(ter t-Bu t yld im et h ylsilyl)-3,4,5-t r id eoxy-3-a m in o-L-
th r eo-h exu r on ic Acid 6,3-La cta m (en t-5c). The above two-
step procedure to 5c was adopted, with 2.5 g (5.82 mmol) of
lactam ent-4c, to afford 1.23 g (82%) of pure aldehyde ent-5c as
(R,R)-1a was adopted, starting with aldehyde 5c (1.0 g, 3.89
mmol). An unsaturated intermediate formed as a 9:1 Z/E
isomeric mixture (0.92 g, 60%) as an oil: 1H NMR (300 MHz,
CDCl3, Z-isomer) δ 5.75 (bs, 1H), 5.53 (m, 1H), 5.24 (m, 1H),
4.20 (t, J ) 8.7 Hz, 1H), 3.52 (m, 1H), 2.32 (m, 2H), 2.05 (m,
2H), 1.69 (m, 1H), 1.27 (m, 17H), 0.88 (m, 12H), 0.06 (s, 3H),
0.03 (s, 3H). Hydrogenation and BF3 etherate-promoted depro-
tection of this intermediate finally gave a crude residue, which
was subjected to flash chromatographic purification (9:1 EtOAc/
MeOH) to furnish pure azamuricatacin [(R,R)-1c] (0.61 g, 93%)
an oil: [R]20 +65.8 (c 2.1, CHCl3). 1H and 13C NMR spectra
D
fully coincided with those of its enantiomer 5c. Anal. Calcd
for C12H23NO3Si: C, 55.99; H, 9.01; N, 5.44. Found: C, 55.75;
H, 9.12; N, 5.60.
(-)-Mu r ica ta cin [(R,R)-1a ]. Gen er a l P r oced u r e. n-Bu-
tyllithium (7.2 mL of a 1.6 M solution in hexanes, 11.5 mmol)
was added to a solution of undecyl triphenylphosphonium
bromide (5.9 g, 11.9 mmol) in anhydrous THF (30 mL) at -80
°C. After 3 h, aldehyde 5a (1.7 g, 6.58 mmol), previously
dissolved in 30 mL of anhydrous THF, was added to this red-
orange solution at -80 °C. The resulting solution was allowed
to warm to room temperature, and after 3 days, the reaction
was concentrated under vacuum, poured into water, and ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were dried (MgSO4) and concentrated to provide a crude residue
that was purified by flash chromatography (8:2 hexanes/EtOAc).
There was obtained a 9:1 Z/E mixture of an olefin intermediate
(1.57 g, 60%) as an oil: 1H NMR (300 MHz, CDCl3, Z-isomer) δ
5.52 (m, 1H), 5.39 (t, J ) 8.7 Hz, 1H), 4.51 (dd, J ) 8.7, 4.2 Hz,
1H), 4.45 (m, 1H), 2.56 (ddd, J ) 17.5, 10.2, 7.5 Hz, 1H), 2.43
(ddd, J ) 17.5, 9.6, 6.3 Hz, 1H), 2.0-2.3 (m, 4H), 1.26 (m, 16H),
0.87 (m, 12H), 0.07 (s, 3H), 0.05 (s, 3H). A solution of this
unsaturated compound (1.5 g, 3.78 mmol) in dry THF (30 mL)
was subjected to catalytic hydrogenation with 10% Pd on carbon
(124 mg) in the presence of NaOAc (52 mg) at room temperature
for 24 h. The catalyst was then removed by filtration and the
filtrate concentrated to give a crude residue, which was subjected
to flash chromatographic purification (8:2 hexanes/EtOAc). This
material (1.4 g, 3.51 mmol, 93%) was dissolved in dry CHCl3
(20 mL), and BF3 etherate (0.86 mL, 7.02 mmol) was added
dropwise to the stirring solution at ambient temperature. After
8 h, the reaction was quenched with solid NaHCO3, and the
resulting mixture was concentrated under vacuum to afford a
crude residue, which was purified by flash chromatography (6:4
hexanes/EtOAc). There was obtained pure muricatacin [(R,R)-
1a ] (0.9 g, 90%) as colorless crystals: mp 71-73 °C; [R]20D -23.1
as a white solid: mp 63-65 °C; [R]20D -13.3 (c 0.3, MeOH); [R]20
D
-9.2 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.30 (bs, 1H),
3.54 (q, J ) 7.0 Hz, 1H), 3.38 (m, 1H), 2.37 (m, 2H), 2.26 (bs,
1H), 2.16 (m, 1H), 1.78 (m, 1H), 1.47 (m, 2H), 1.2-1.4 (m, 20H),
0.88 (t, J ) 7.2 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 178.2,
75.5, 59.1, 33.5, 31.9, 30.3, 29.6 (3 C), 29.5 (3 C), 29.3, 25.3, 23.8,
22.7, 14.1. Anal. Calcd for C17H33NO2: C, 72.04; H, 11.73; N,
4.94. Found: C, 72.10; H, 11.75; N, 4.81.
(+)-Mu r ica ta cin [(S,S)-1a ]. The above three-step procedure
to (R,R)-1a was adopted, with aldehyde ent-5a (1.5 g, 5.8 mmol),
to afford pure muricatacin [(S,S)-1a ] (0.87 g, 53%) as a white
solid: mp 73-74 °C; [R]20D +23.0 (c 1.6, CHCl3); 1H and 13C NMR
spectra fully coincided with those of its enantiomeric counterpart
(R,R)-1a . Anal. Calcd for
C17H32O3: C, 71.79; H, 11.34.
Found: C, 71.53; H, 11.45. Reported data: mp 65 °C, [R]25D +25
(c 1.7, MeOH) (ref 6b); mp 73-74 °C, [R]D +23.02 (c 1.26, CHCl3)
(ref 6c); mp 67-68 °C, [R]D +22.6 (CHCl3) (ref 6d); mp 72 °C,
[R]D +23.6 (c 1.50, CHCl3) (ref 6e); mp 65-66 °C, [R]23D +23.6 (c
1.6, CHCl3) (ref 6f).
(+)-Th iom u r ica t a cin [(S,S)-1b ]. The above three-step
procedure to (R,R)-1b was adopted, with aldehyde ent-5b (1.1
g, 4.0 mmol), to afford pure thiomuricatacin [(S,S)-1b] (0.7 g,
58%) as a glassy solid: [R]20 +36.2 (c 1.8, CHCl3). 1H and 13C
D
NMR spectra fully coincided with those of its enantiomeric
counterpart (R,R)-1b. Anal. Calcd for C17H32O2S: C, 67.95; H,
10.73. Found: C, 67.85; H, 10.82.
(+)-Aza m u r ica ta cin [(S,S)-1c]. The above three-step pro-
cedure to (R,R)-1c was adopted, with aldehyde ent-5c (1.0 g, 3.89
mmol), to afford pure azamuricatacin [(S,S)-1c] (0.64 g, 58%)
as a white solid: mp 63-64 °C; [R]20D +14.0 (c 0.4, MeOH); [R]20
D
1
(c 1.5, CHCl3); H NMR (300 MHz, CDCl3) δ 4.42 (td, J ) 7.2,
+10.3 (c 0.4, CHCl3). 1H and 13C NMR spectra fully coincided
with those of its enantiomeric counterpart (R,R)-1c. Anal. Calcd
for C17H33NO2: C, 72.04; H, 11.73; N, 4.94. Found: C, 71.95;
H, 11.81; N, 4.90.
4.5 Hz, 1H), 3.58 (m, 1H), 2.63 (ddd, J ) 17.7, 9.9, 5.4 Hz, 1H),
2.54 (dt, J ) 17.7, 9.0, 1H), 2.0-2.3 (m, 2H), 1.86 (d, J ) 5.7
Hz, 1H), 1.4-1.6 (m, 2H), 1.1-1.4 (m, 20H), 0.87 (t, J ) 6.9 Hz,
3H); 13C NMR (75.4 MHz, CDCl3) δ 177.2, 82.9, 73.7, 33.0, 31.9,
29.6 (3 C), 29.5 (3 C), 29.3, 28.7, 25.4, 24.1, 22.7, 14.1. Anal.
Calcd for C17H32O3: C, 71.79; H, 11.34. Found: C, 71.75; H,
Ack n ow led gm en t. Financial support from the Con-
siglio Nazionale delle Ricerche (CNR), Italy, and Min-
istero dell’Universita` e della Ricerca Scientifica e Tec-
nologica (MURST), Italy, is gratefully acknowledged.
11.41. Reported data: mp 72 °C; [R]24 -22.9 (c 1.1, CHCl3)
D
(ref 6a); mp 73-74 °C, [R]D -23.14 (c 2.36, CHCl3) (ref 6c); mp
67-68 °C, [R]D -23.3 (c 1.8, CHCl3) (ref 6d).
(-)-Th iom u r ica ta cin [(R,R)-1b]. The above procedure to
(R,R)-1a was adopted, starting with aldehyde 5b (1.27 g, 4.62
J O970205Z