Synthetic studies on (-)-lemonomycin: An efficient asymmetric synthesis of lemonomycinone amide

Article abstract of DOI:10.1021/jo8027449

Asymmetric synthesis of lemonomycinone amide (2) was accomplished from readily accessible starting materials. Enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester (11) by 5-tert- butyldimethylsilyloxy-2,4-dimethoxy-3-methylbenzyl bromide (10) in the presence of Corey-Lygo's phase transfer catalyst [O-(9)-ally-N-(9-anthracenylmethyl) cinchonidium bromide, 0.1 equiv] afforded, after chemoselective hydrolysis of the imine function (THF/H₂O/AcOH), the substituted L-tert-butyl phenylalanate 13 in 85% yield. A Pictet-Spengler reaction of 14 with benzyloxyacetaldehyde (15) provided the 1,3-cisdisubstituted tetrahydroisoquinoline 16 in 85% yield as a single diastereomer. Coupling of hindered secondary amine 16 with amino acid 9 was accomplished under carefully controlled conditions to furnish the amide 22, which was in turn converted to hemiaminal 24. A hafnium triflate catalyzed conversion of hemiaminal to α-amino thioether followed by a silver tetrafluoroborate promoted intramolecular Mannich reaction of 26 afforded the tetracycle 27 in excellent overall yields. Debenzylation of 27 [Pd(OH)₂, H₂, MeOH, 0°C], removal of N-Boc function (aqueous 3 N HCl, MeOH/H₂O), and oxidation of hydroquinone to quinone [(NH₄)₂Ce(NO ₃)₆, H₂O, rt] afforded the lemonomycinone amide 2 in 76% yield over three steps

Full text of DOI:10.1021/jo8027449

Synthetic Studies on (-)-Lemonomycin: An Efficient Asymmetric
Synthesis of Lemonomycinone Amide
Yan-Chao Wu,† Guillaume Bernadat,† Ge´raldine Masson,† Ce´dric Couturier,†
Thierry Schlama,§,‡ and Jieping Zhu*,†
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France, and RHODIA,
Centre de Recherches et de Technologie de Lyon (CRTL), aVenue des Fre`res Perret, BP 62,
F-69192 Saint-Fons Cedex, France
zhu@icsn.cnrs-gif.fr
ReceiVed December 23, 2008
Asymmetric synthesis of lemonomycinone amide (2) was accomplished from readily accessible starting
materials. Enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester (11) by 5-tert-
butyldimethylsilyloxy-2,4-dimethoxy-3-methylbenzyl bromide (10) in the presence of Corey-Lygo’s phase
transfer catalyst [O-(9)-ally-N-(9′-anthracenylmethyl) cinchonidium bromide, 0.1 equiv] afforded, after
chemoselective hydrolysis of the imine function (THF/H2O/AcOH), the substituted L-tert-butyl phenylalanate
13 in 85% yield. A Pictet-Spengler reaction of 14 with benzyloxyacetaldehyde (15) provided the 1,3-cis-
disubstituted tetrahydroisoquinoline 16 in 85% yield as a single diastereomer. Coupling of hindered secondary
amine 16 with amino acid 9 was accomplished under carefully controlled conditions to furnish the amide 22,
which was in turn converted to hemiaminal 24. A hafnium triflate catalyzed conversion of hemiaminal to
R-amino thioether followed by a silver tetrafluoroborate promoted intramolecular Mannich reaction of 26
afforded the tetracycle 27 in excellent overall yields. Debenzylation of 27 [Pd(OH)2, H2, MeOH, 0 °C], removal
of N-Boc function (aqueous 3 N HCl, MeOH/H2O), and oxidation of hydroquinone to quinone [(NH4)2Ce(NO3)6,
H2O, rt] afforded the lemonomycinone amide 2 in 76% yield over three steps.
Introduction
of Streptomyces candidus (LL-AP191).2 However, its structure
was not elucidated until 2000 by He and co-workers at Wyeth-
Ayerst.3 Lemonomycin exhibited potent antibiotic activities
against methicillin-resistant Staphylococcus aureus (MRSA),
Bacillus subtilis, and vancomycin-resistant Enterococcus fae-
cium (VREF).4 It is also cytotoxic against a human colon tumor
cell line (HCT-116). The broad spectra of antibiotic activities
in conjunction with its fascinating molecular architecture have
(-)-Lemonomycin (1, Figure 1) is a tetrahydroisoquinoline
alkaloid1 that was isolated in 1964 from the fermentation broth
† Institut de Chimie des Substances Naturelles.
‡ RHODIA.
§ Present address: Novartis Pharma AG, Chemical & Analytical Development
(CHAD), CH-4002 Basel, Switzerland.
(1) For a comprehensive review of the chemistry and biology related to the
antitumor antibiotic tetrahydroisoquinoline alkaloids, see: Scott, J. D.; Williams,
R. M. Chem. ReV. 2002, 102, 1669–1730. For a recent review on the syntheses
of naphthyridinomycin and lemonomycin, see: Siengalewicz, P.; Rinner, U.;
Mulzer, J. Chem. Soc. ReV. 2008, 37, 2676–2690.
(2) Whaley, H. A.; Patterson, E. L.; Dann, M.; Shay, A. J.; Porter, J. N.
Antimicrob. Agents Chemother. 1964, 8, 83–86.
(3) He, H.; Shen, B.; Carter, G. T. Tetrahedron Lett. 2000, 41, 2067–2071.
(4) Zhu, J. Expert. Opin. Ther. Pat. 1999, 9, 1005–1019.
2046 J. Org. Chem. 2009, 74, 2046–2052
10.1021/jo8027449 CCC: $40.75 2009 American Chemical Society
Published on Web 02/05/2009

Synthetic Studies on (-)-Lemonomycin
SCHEME 1. Retrosynthetic Analysis of 1 and 2
FIGURE 1. Structures of lemonomycin and lemonomycinone amide.
made lemonomycin an attractive synthetic target. Stoltz and co-
workers reported the first and only total synthesis of (-)-
lemonomycin in 2003,5 whereas Magnus’s group reported the
synthesis of racemic lemonomycinone amide (2) in 2005.6
Fukuyama,7 Williams,8 and Mulzer9 have also developed
efficient strategies for the access of the advanced tetracyclic
core of lemonomycin. In connection with our ongoing program
dealing with the synthesis of tetrahydroisoquinoline-containing
alkaloids,10 we have been interested in the synthesis of lem-
onomycin.11 Since the quinone and the hemiaminal moiety of
this alkaloid were labile to many reaction conditions, they were
thought to be installed at latter stages of the synthesis.
Consequently, tetracyclic core 3 was considered as a key
intermediate in our synthesis (Scheme 1). For the construction
of the 3,8-diazabicycle [3.2.1]-octane ring system of 3, an
intramolecular nucleophilic addition to the incipient N-acylimin-
ium intermediate was sought.12 However, cyclization of 411 and
5
13 using tethered malonate and allylsilane as nucleophiles was
unsuccessful in our initial studies. The seminal contribution of
Hiemstra14 and Magnus6 on the use of enolsilane as nucleophile
for trapping the N-acyliminium intermediate,15 as well as our
own work on the application of such strategy for the synthesis
of (-)-quinocarcin,16 prompted us to examine the cyclization
of 6.17 Compound 6 should be accessible from aminoalcohol
7, which in turn could be prepared by coupling of tetrahy-
droisoquinoline 8 and amino acid 9. We report herein the
realization of this strategy for the synthesis of (-)-lemonomycin
precursor 3 and lemonomycinone amide (2).
Results and Discussion
Synthesis of substituted tetrahydroisoquinoline 8 is shown
in Scheme 2. 5-tert-Butyldimethylsilyloxy-2,4-dimethoxy-3-
methylbenzyl bromide (10) was prepared from 2,6-dimethoxy-
toluene in seven steps with 61% overall yield (see Supporting
Information).18 Enantioselective alkylation of N-(diphenyl-
methylene)glycine tert-butyl ester (11) by 10 in the presence
of Corey-Lygo’s phase transfer catalyst19,20 (12, O-(9)-allyl-N-
(9′-anthracenylmethyl) cinchonidium bromide, 0.1 equiv) af-
forded, after chemoselective hydrolysis of the imine function
(THF/H2O/AcOH), the amino ester 13 in 85% yield. The
absolute configuration of 13 was deduced on the basis of the
Corey-Lygo empiric model and was confirmed by Trost’s
method (Supporting Information).21 The ee of 13 was deter-
mined to be higher than 98%. Removal of the silyl ether from
13 gave free amino phenol 14 in 92% yield. A slow addition of
(5) Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125,
15000–15001.
(6) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005, 127, 12476–12477.
(7) Fukuyama, T.; Rikimaru, K.; Mori, K.; Kan, T. Chem. Commun. 2005,
394–396.
(8) Vincent, G.; Chen, Y.; Lane, J. W.; Williams, R. M. Heterocycles 2007,
72, 385–398.
(9) Siengalewicz, P.; Brecker, L.; Mulzer, J. Synlett 2008, 2443–2446.
(10) (a) Chen, X. C.; Chen, J. C.; De Paolis, M.; Zhu, J. J. Org. Chem. 2005,
70, 4397–4408. (b) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem.
Soc. 2006, 128, 87–89. (c) Chen, J. C.; Chen, X. C.; Willot, M.; Zhu, J. Angew.
Chem., Int. Ed. 2006, 45, 8028–8032. (d) Chen, X. C.; Zhu, J. Angew. Chem.,
Int. Ed. 2007, 46, 3962–3965.
(11) Couturier, C.; Schlama, T.; Zhu, J. Synlett 2006, 1691–1694.
(12) For recent reviews, see: (a) Hiemstra, H.; Speckamp, W. N. In
ComprehensiVe Organis Synthesis; Trost, B., Fleming, I., Heathcock, C. H., Eds.;
Pergmon: Oxford, 1991; Vol. 2, pp 1047-1082. (b) Maryanoff, B. E.; Zhang,
H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431–
1628. (c) Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104, 2311–2352.
(13) Cedric Couturier, PhD thesis, Ecole Polytechnique, 17 October 2005.
Cyclization using allylsilane as internal nucleophile wherein an amide group in
5 was replaced by aminonitrile function has been successfully applied to the
synthesis of advanced lemonomycin intermediate and quinocarcin; see ref 9 and
Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796–16797.
(14) Hiemstra, H.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1988, 53,
3884–3886.
(17) For an example using amino thioether as a precursor of N-acyliminium,
see: Padwa, A.; Waterson, A. G. Tetrahedron 2000, 56, 10159–10173.
(18) (a) Godfrey, I. M.; Sargent, M. V.; Elix, J. A. J. Chem. Soc., Perkin
Trans. 1 1974, 1353–1354. (b) Luly, J. R.; Rapoport, H. J. Org. Chem. 1981,
46, 2745–2752. (c) Fukuyama, T.; Sachleben, R. A. J. Am. Chem. Soc. 1982,
104, 4957–4958. (d) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A.
J. Am. Chem. Soc. 1990, 112, 3712–3713.
(19) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–
12415.
(15) For intermolecular reaction of enolsilane and N-acyliminium, see: Shono,
T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103, 1172–1176.
(16) Wu, Y.-C.; Liron, M.; Zhu, J. J. Am. Chem. Soc. 2008, 130, 7148–
7152.
(20) (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595–
8598. (b) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518–525.
(21) (a) Ott, R.; Sauber, K. Tetrahedron Lett. 1972, 3873–3878. (b) Trost,
B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59, 4202–4205.
J. Org. Chem. Vol. 74, No. 5, 2009 2047

Wu et al.
SCHEME 2. Synthesis of Tetrahydroisoquinoline 8
SCHEME 3. Synthesis of Amino Acid 9
SCHEME 4. Synthesis of the Core Structure of
Lemonomycin and Lemonomycinone Amide
a dichloromethane solution of benzyloxyacetaldehyde (15) to
the reaction mixture containing 14, acetic acid (1.1 equiv), and
4 Å molecular sieves in dichloromethane provided the
Pictet-Spengler adduct 16 in 85% yield as a single diastere-
omer. The 1,3-cis relative stereochemistry of 16 was deduced
from the observed NOE correlation between H1 and H3
(Supporting Information) and is in accordance with literature
precedents.10,22 A tert-butoxycarbonylation of the secondary
amine followed by benzylation of phenol (BnBr, Cs2CO3, DMF)
in the presence of a catalytic amount of sodium iodide converted
16 to 17 in excellent overall yield. Transesterification of a tert-
butyl ester to a methyl ester with concurrent removal of the
N-Boc function from 17 was realized in one operation (MeOH/
SOCl2) to afford the desired tetrahydroisoquinoline 8 in 92%
yield.
Synthesis of amino acid 9 is depicted in Scheme 3. The (S)-
methyl 2-(N,N-di-Boc-amino)-5-hydroxypentanoate (20) was
prepared from L-glutamic acid (18) in four steps with 73%
overall yield.23 N-Monodeprotection of 20 (CeCl3 ·7H2O, NaI,
MeCN) followed by silylation of the primary hydroxy group
provided compound 21 in 79% yield. It has to be noted that
lactonization of 20 was not observed under these mild condi-
(22) For 1,3-cis selective Pictet-Spengler reactions, see: (a) Massiot, G.;
Mulamba, T. J. Chem. Soc., Chem. Commun. 1983, 1147–1149. (b) Bailey, P. D.;
Hollinshead, S. P.; McLay, N. R.; Morgan, K.; Palmer, S. J.; Prince, S. N.;
Reynolds, C. D.; Wood, S. D. J. Chem. Soc., Perkin Trans. 1 1993, 431–439.
(c) Myers, A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon, S. J. Am.
Chem. Soc. 1999, 121, 8401–8402. (d) Myers, A. G.; Kung, D. W. J. Am. Chem.
Soc. 1999, 121, 10828–10829.
(23) (a) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.; Martin,
V. S. J. Org. Chem. 1998, 63, 3741–3744. (b) Jia, Y.; Zhu, J. J. Org. Chem.
2006, 71, 7826–7834.
tions. Finally, hydrolysis of 21 with lithium hydroxide afforded
amino acid 9 in 97% yield.
With the tetrahydroisoquinoline 8 and amino acid 9 in hands,
synthesis of lemonomycinone amide was realized as shown in
Scheme 4. Coupling of hindered secondary amine 8 with amino
acid 9 was accomplished by a one-pot temperature-controlled
peptide coupling strategy. Thus, esterification of 9 with 1-hy-
2048 J. Org. Chem. Vol. 74, No. 5, 2009

Synthetic Studies on (-)-Lemonomycin
SCHEME 5. Conformational Consideration on the
Formation of 25 and 27
SCHEME 6. Hydrogenolysis of 27: Unexpected Observation
droxy-7-azabenzotriazol (HOAt) (HATU, DIPEA, DMF, 0 °C)
afforded the transient activated ester, which underwent ami-
nolysis with amine 8 at room temperature to produce the amide
22 in 84% yield (92% based on conversion) without detectable
epimerization. Reduction of methyl ester 22 with lithium
borohydride gave primary alcohol 23, which upon Swern
oxidation afforded directly the hemiaminal 24 as a mixture of
two diastereomers (ratio 3/2).
Treatment of 24 with EtSH under our recently developed
conditions [0.1 equiv of Hf(OTf)4, CH2Cl2, rt]24 afforded amino
thioether 25 in 86% yield, with concurrent removal of O-TBS
function as a single diastereomer. The stereoselective formation
of 25 with a Ca,Cb-cis relative stereochemistry indicated that
conformer A (Scheme 5), wherein the Ca substituent adopted a
pseudoaxial position, was the low-energy conformation of the
N-acyliminium intermediate resulting from 24. Such spatial
arrangement minimized indeed the unfavorable allylic A1,2
strain25 encountered in the alternative conformation wherein the
Ca substitutent was in a pseudoequatorial position. Although
the selectivity observed in the formation of 25 is of no
consequence, it did provide an important hint that the subsequent
intramolecular Mannich reaction of 26 could be a conforma-
tionally favored process.26 Indeed, if the N-acyliminium inter-
mediate resulting from 26 has the same conformational pref-
erence, then the desired cyclization would be expected to be
facile via conformer B (Scheme 5).
Chemoselective Swern oxidation of 25 followed by silyl enol
ether formation (TIPSOTf, Et3N, Et2O, room temperature)
afforded compound 26 as a single diastereomer in 92% overall
yield. The intramolecular Mannich reaction of 26 in the presence
of silver tetrafluoroborate furnished tetracyclic aldehyde 27 as
a single diastereomer in 87% yield. Removal of two O-Bn
functions in compound 27 under carefully controlled hydro-
genolysis conditions [Pd(OH)2/C, MeOH, 0 °C] afforded
tetracyclic alcohol 3 in 94% yield. Compound 3 was properly
protected for the further elaboration to (-)-lemonomycin. In
the present study, we converted 3 to lemonomycinone amide
(2) following literature precedents.6 Thus, treatment of 3 under
mild acidic conditions followed by oxidation with ammonium
cerium(VI) nitrate afforded 2 in 81% yield.
under the basic hydrogenolysis conditions, compound 3 with
an exo-aldehyde function is partially epimerized to endo-
aldehyde 29. Although 29 might be thermodynamically less
stable than 3 for steric reasons, the formation of hemiacetal
might drive the equilibrium toward the final formation of 28.
This epimerization was, however, effectively suppressed when
the reaction was carried out at 0 °C. We have also performed
O-debenzylation in the presence of Pd/C (H2, MeOH, rt).
However, under these conditions, aldehyde was reduced to
primary alcohol, as was confirmed by its further conversion to
quinone 30 following a N-deprotection/oxidation sequence (78%
yield over three steps).
Conclusions
In summary, we describe concise syntheses of advanced
intermediate 3 for lemonomycin and lemonomycinone amide 2
with an overall yield of 15% and 12%, respectively, starting
from readily accessible 2,6-dimethoxytoluene. Key steps in-
cluded (a) enantioselective alkylation of glycine template for
the synthesis of non-proteinogenic amino acid, (b) epimerization-
free coupling of hindered secondary amine with amino acid,
(c) hafnium triflate catalyzed conversion of highly functionalized
aminal to amino thioether, and (d) intramolecular Mannich
reaction for the construction of bridged bicyclic ring system.
We assumed that formation of hemiacetal 28 from 27 could
have an important implication in designing a synthetic strategy
for bioxalomycin,27 and we are currently exploiting opportunities
offered by this serendipity.
Experimental Section
(1R,3S)-tert-Butyl 1-((Benzyloxy)methyl)-1,2,3,4-tetrahydro-8-
hydroxy-5,7-dimethoxy-6-methylisoquinoline-3-carboxylate (16).
To a solution of amino phenol 14 (250.0 mg, 800.0 µmol) in 8 mL
of dichloromethane were added acetic acid (AcOH, 51 µL, 880.0
µmol) and 4 Å molecular sieves sequentially at room temperature.
It is interesting to note that hydrogenolysis of 27 in the
presence of Pearlman’s catalyst has to be carried out at 0 °C.
Indeed, performing this transformation at room temperature
under otherwise identical conditions led to the formation of
hemiacetal 28 in 85% yield (Scheme 6). We hypothesized that
(27) For total synthesis of bioxalomycin, see: (a) Evans, D. A.; Illig, C. R.;
Saddler, J. C. J. Am. Chem. Soc. 1986, 108, 2478–2479. (b) Fukuyama, T.; Li,
L.; Laird, A. A.; Frank, R. K. J. Am. Chem. Soc. 1987, 109, 1587–1589. (c)
(24) Wu, Y.-C.; Zhu, J. J. Org. Chem. 2008, 73, 9522–9524.
(25) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289–296.
(26) Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 1949–1964.
¨
Kaniskan, H. U.; Garner, P. J. Am. Chem. Soc. 2007, 129, 15460–15461.
J. Org. Chem. Vol. 74, No. 5, 2009 2049

Wu et al.
The mixture was degassed with argon and added slowly to a solution
of benzyloxyacetaldehyde (15, 136.7 mg, 880.0 µmol) in 4 mL of
dichloromethane over 12 h. The mixture was stirred at room
temperature for 24 h, filtered though celite, and saturated aqueous
sodium bicarbonate solution (NaHCO3, 20 mL) was added. The
two layers were separated, and the aqueous layer was extracted
with dichloromethane (20 mL × 3). The combined organic extracts
were dried over anhydrous sodium sulfate, filtered, and concen-
trated. The residue was purified by flash column chromatography
(gradient elution 0.5% f 5% methanol in dichloromethanes) to
provide tetrahydroisoquinoline 16 (302.7 mg) in 85% yield. Pale
yellow foam; [R]27D -114.6° (c 2.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.32-7.25 (m, 5 H), 6.49 (br, 1 H), 4.58 (d, 1 H, J )
12.0 Hz), 4.53 (d, 1 H, J ) 12.0 Hz), 4.49 (br, 1 H), 4.10 (dd, 1 H,
J ) 9.0, 4.5 Hz), 3.75-3.72 (m, 4 H), 3.66 (s, 3 H), 3.38 (dd, 1 H,
J ) 11.0, 2.5 Hz), 3.18 (dd, 1 H, J ) 15.5, 2.5 Hz), 2.56 (dd, 1 H,
J ) 15.5, 11.0 Hz), 2.22 (s, 3 H), 1.51 (s, 9 H); 13C NMR (75
MHz, CDCl3) δ 172.3, 149.1, 144.1, 142.8, 138.0, 128.2, 127.53,
127.50, 127.46, 125.1, 122.0, 120.5, 81.3, 73.5, 73.1, 60.5, 60.3,
55.4, 53.4, 28.0, 27.9, 9.4 ppm; FTIR (film) 2977, 2934, 1730, 1455,
1412, 1367, 1280, 1248, 1192, 1156, 1110, 1059, 1004, 847, 739,
698 cm-1; HRMS (TOF MS ES+) m/z calcd for C25H34NO6 [M +
H]+ 444.2386, found 444.2394.
4.50-4.47 (m, 2 H), 4.18-4.08 (m, 1 H), 3.84-3.65 (m, 8 H),
3.53-3.47 (m, 1 H), 2.83-2.77 (m, 1 H), 2.26 (s, 3 H), 1.52 (s, 9
H), 1.50 and 1.48 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 171.6
(171.4), 154.2 (154.1), 151.2 (151.1), 150.0, 144.4 (144.3), 138.1
(137.9), 137.6 (137.2), 127.9 (d), 127.5 (127.4), 127.3, 127.2, 127.0
(126.9), 126.7 (126.6), 124.1 (123.9), 121.4, 80.3 (80.1), 79.8 (79.6),
77.2, 74.3, 73.8, 72.1 (71.8), 60.2 (59.6), 56.1 (55.6), 49.1 (48.3),
27.8, 27.5 (27.3), 23.7, 8.9 ppm; FTIR (film) 2974, 2934, 1737,
1693, 1454, 1412, 1390, 1365, 1315, 1253, 1152, 1136, 1114, 1067,
1028, 1006, 966, 851, 736, 697 cm-1; HRMS (TOF MS ES+) m/z
calcd for C37H47NO8Na [M + Na]+ 656.3199, found 656.3157.
(1R,3S)-Methyl 8-(Benzyloxy)-1-((benzyloxy)methyl)-1,2,3,4-tet-
rahydro-5,7-dimethoxy-6-methylisoquinoline-3-carboxylate (8). To
a solution of protected tetrahydroisoquinoline 17 (127.7 mg, 2.0
mmol) in 5 mL of methanol was added sulfonyl chloride (SOCl2,
0.1 mL) at 0 °C. The mixture was stirred at reflux for 4 h and
concentrated, and 50 mL of ethyl acetate and 20 mL of saturated
aqueous sodium bicarbonate solution were added. The two layers
were separated, and the aqueous layer was extracted with ethyl
acetate (30 mL × 3). The combined organic layers were washed
with brine, dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was purified by column chromatography
(gradient elution 10% f 30% ethyl acetate in heptanes) to afford
(1R,3S)-Di-tert-butyl 8-(Benzyloxy)-1-((benzyloxy)methyl)-3,4-
dihydro-5,7-dimethoxy-6-methylisoquinoline-2,3(1H)-dicarboxy-
late (17). To a solution of amine 16 (769.8 mg, 1.7 mmol) in
acetonitrile (ACN, 43 mL) were added N,N-diisopropylethylamine
(DIPEA, 30.0 µL, 0.2 mmol) and di-tert-butyldicarbonate (Boc2O,
401.7 mg, 1.8 mmol) sequentially at 0 °C. The mixture was stirred
at room temperature for overnight, and 100 mL of ethyl acetate
and 50 mL of water were added. The two layers were separated,
and the aqueous layer was extracted with ethyl acetate (50 mL ×
3). The combined organic layers were washed with brine, dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by column chromatography (gradient elution
10% f 25% ethyl acetate in heptanes) to afford (1R,3S)-di-tert-
butyl 1-((benzyloxy)methyl)-3,4-dihydro-8-hydroxy-5,7-dimethoxy-
6-methylisoquinoline-2,3(1H)-dicarboxylate (849.2 mg) in 90%
yield. White solids; mp ) 35-36 °C; [R]27D -4.0° (c 9.1, CHCl3);
1H NMR (300 MHz, CDCl3, 1.6:1 mixture of rotamers, the major
rotamer was listed) δ 7.40-7.15 (m, 5 H), 6.39 (s, 1 H), 5.75 (dd,
1 H, J ) 9.0, 4.5 Hz), 4.63 (d, 1 H, J ) 11.7 Hz), 4.52 (d, 1 H, J
) 11.7 Hz), 4.14 (dd, 1 H, J ) 12.0, 6.9 Hz), 3.96 (dd, 1 H, J )
8.4, 4.5 Hz), 3.77 (s, 3 H), 3.66 (dd, 1 H, J ) 9.0, 8.4 Hz), 3.65 (s,
3 H), 3.43 (dd, 1 H, J ) 15.3, 6.9 Hz), 2.61 (dd, 1 H, J ) 15.3,
12.0 Hz), 2.22 (s, 3 H), 1.48 (s, 9 H), 1.45 (s, 9 H); 13C NMR (75
MHz, CDCl3, the major rotamer was listed) δ 172.3, 154.7, 148.5,
145.4, 142.6, 137.7, 128.1, 127.5, 127.4, 123.6, 122.4, 120.6, 81.1,
80.8, 73.1, 72.7, 61.0, 60.4, 55.9, 48.7, 28.2, 27.9, 23.8, 9.5 ppm;
FTIR (film) 2976, 2864, 1732, 1684, 1455, 1414, 1392, 1365, 1348,
1317, 1253, 1150, 1111, 1057, 1004, 848, 750, 697 cm-1; HRMS
(TOF MS ES+) m/z calcd for C30H41NO8Na [M + Na]+ 566.2730,
found 566.2723.
tetrahydroisoquinoline 8 (90.6 mg) in 92% yield. Pale yellow foam;
1
[R]26 -49.5° (c 1.7, CHCl3); colorless oil; H NMR (300 MHz,
D
CDCl3, 1.6:1 mixture of rotamers, the major rotamer was listed) δ
7.41-7.25 (m, 10 H), 5.08 (d, 1 H, J ) 11.1 Hz), 4.89 (d, 1 H, J
) 11.1 Hz), 4.48 (s, 2 H), 4.43 (dd, 1 H, J ) 7.8, 2.1 Hz), 4.18
(dd, 1 H, J ) 8.4, 2.1 Hz), 3.84 (s, 3 H), 3.79 (s, 3 H), 3.72 (s, 3
H), 3.66 (dd, 1 H, J ) 8.4, 7.8 Hz), 3.50 (dd, 1 H, J ) 10.8, 3.0
Hz), 3.26 (dd, 1 H, J ) 15.9, 3.0 Hz), 2.69 (dd, 1 H, J ) 15.9,
10.8 Hz), 2.27 (s, 3 H); 13C NMR (75 MHz, CDCl3, the major
rotamer was listed) δ 173.3, 152.1, 150.0, 148.5, 145.3, 138.3,
137.4, 128.2, 128.0, 127.9, 127.7, 127.2, 127.1, 126.9, 124.6, 123.4,
74.3, 73.6, 72.7, 60.0, 59.9, 54.5, 53.6, 51.8, 27.6, 9.1 ppm; FTIR
(film) 3365, 2934, 2858, 1738, 1454, 1409, 1335, 1280, 1255, 1196,
1110, 1061, 1028, 1002, 735, 697 cm-1; HRMS (TOF MS ES+)
m/z calcd for C29H33NO6Na [M + Na]+ 514.2206, found 514.2219.
Amide Ester 22. To a solution of tetrahydroisoquinoline 8 (800.0
mg, 1.6 mmol) and (S)-5-tert-butyl-dimethylsilyloxy-2-(N-Boc-
amino)pentanoic acid (9, 678.7 mg, 2.0 mmol) in 8 mL of DMF,
DIPEA (1.3 mL, 8.1 mmol) were added 3H-1,2,3-triazolo-[4,5-
b]pyridin-3-ol (HOAt, 265.8 mg, 2.0 mmol) and O-(7-azabenzop-
triazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphat
(HATU, 742.6 mg, 2.0 mmol) sequentially at 0 °C. The mixture
was stirred at 0 °C for overnight, stirred at room tempera-
ture for 36 h, and ethyl acetate (50 mL) and water (20 mL) were
added sequentially. The two layers were separated, and the
aqueous layer was extracted with ethyl acetate (50 mL × 3).
The combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by column chromatography (gradient elution 10%
f 30% ethyl acetate in heptanes) to afford amide ester 22 (1.1
To a mixture of (1R,3S)-di-tert-butyl 1-((benzyloxy)methyl)-3,4-
dihydro-8-hydroxy-5,7-dimethoxy-6-methylisoquinoline-2,3(1H)-
dicarboxylate (840.7 mg, 1.5 mmol), cesium carbonate (Cs2CO3,
658.2 mg, 2.0 mmol), and sodium iodine (NaI, 22.7 mg, 0.15 mmol)
in 6 mL of N,N-dimethyl formamide (DMF) was added benzyl
bromide (BnBr, 225 µL, 1.8 mmol) at room temperature. The
mixture was stirred at room temperature for 6 h, and 50 mL of
ethyl acetate and 30 mL of water were added. The two layers were
separated, and the aqueous layer was extracted with ethyl acetate
(50 mL × 3). The combined organic layers were washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by column chromatography (gradient elution
1% f 20% ethyl acetate in heptanes) to afford protected tetrahy-
1
g) in 84% yield. Yellow oil; [R]25 +2.1° (c 1.4, CHCl3); H
D
NMR (300 MHz, CDCl3, 6.2:1 mixture of rotamers, the major
rotamer was listed) δ 7.63-7.17 (m, 10 H), 5.91 (t, 1 H, J )
6.0 Hz), 5.21 (d, 1 H, J ) 10.8 Hz), 5.09-4.83 (m, 3 H),
4.55-4.40 (m, 3 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.68 (s, 3 H),
3.60-3.43 (m, 5 H), 2.77 (dd, 1 H, J ) 15.3, 12.0 Hz), 2.23 (s,
3 H), 1.90-1.70 (m, 2 H), 1.68-1.47 (m, 2 H), 1.33 (s, 9 H),
0.89 (s, 9 H), 0.03 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 174.2,
172.6, 155.1, 151.5, 150.7, 144.8, 138.0, 137.9, 128.3, 128.2,
127.7, 127.6, 127.5, 127.2, 126.9, 125.3, 121.5, 79.1, 74.8, 73.1,
72.4, 62.9, 60.9, 60.3, 55.2, 52.2, 51.6, 50.6, 29.8, 28.8, 28.3,
26.0, 23.6, 18.3, 9.4, -5.3 ppm; FTIR (film) 2930, 2856, 1750,
1705, 1645, 1497, 1455, 1418, 1365, 1254, 1172, 1094, 1066,
1008, 835, 299, 735, 698 cm-1; HRMS (TOF MS ES+) m/z calcd
for C45H64N2O10NaSi [M + Na]+ 843.4228, found 843.4232.
droisoquinoline 17 (926.6 mg) in 98% yield. Colorless oil; [R]27
D
-17.3° (c 7.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.52-7.15
(m, 10 H), 6.04 and 5.83 (t, 1 H, J ) 5.0 Hz), 5.12-5.01 (m, 2 H),
2050 J. Org. Chem. Vol. 74, No. 5, 2009

Synthetic Studies on (-)-Lemonomycin
Amide Alcohol 23. To a solution of amide ester 22 (50.0 mg,
60.9 µmol) in 6 mL of tetrahydrofuran (THF) were added lithium
borohydride (LiBH4, 5.6 mg, 243.6 µmol) and methanol (10 µL,
243.6 µmol) sequentially at 0 °C. The mixture was stirred at room
temperature for 8 h, and ethyl acetate (20 mL) and water (10 mL)
were added sequentially. The two layers were separated, and the
aqueous layer was extracted with ethyl acetate (30 mL × 3). The
combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by column chromatography (gradient elution 10% f
50% ethyl acetate in heptanes) to afford amide alcohol 23 (45.0
mg) in 93% yield. Pale foam; [R]25D +1.7° (c 0.3, CHCl3); 1H NMR
(300 MHz, CDCl3, 1:1 mixture of rotamers) δ 7.60-7.10 (m, 10
H), 6.30 (dd, 1 H, J ) 9.0, 5.1 Hz), 5.42 (d, 1 H, J ) 8.4 Hz), 5.21
(d, 1 H, J ) 11.1 Hz), 4.99 (d, 1 H, J ) 11.1 Hz), 4.93-4.82 (m,
1 H), 4.68-4.33 (m, 3 H), 3.80 (d, 1 H, J ) 3.9 Hz), 3.67 (s, 6 H),
3.65-2.71 (m, 6 H), 2.22 (s, 3 H), 1.90-1.52 (m, 4 H), 1.44 (s, 9
H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ
174.7, 173.5, 150.0, 144.7, 136.9, 128.5, 128.4, 128.34, 128.30,
128.2, 128.1, 128.0, 127.8, 127.7, 127.4, 122.9, 79.5, 75.0, 73.3,
71.1, 66.2, 62.7, 60.7, 60.3, 52.8, 51.4, 47.3, 30.0, 28.9, 28.4, 25.9,
22.5, 18.3, 9.4, -5.4 ppm; FTIR (film) 2928, 2856, 1709, 1633,
1497, 1454, 1414, 1365, 1251, 1169, 1097, 1007, 835, 776, 734,
698 cm-1; HRMS (TOF MS ES+) m/z calcd for C44H64N2O9NaSi
[M + Na]+: 815.4279, found 815.4279.
18.4, 9.4, -5.3 ppm; FTIR (film) 2927, 2855, 1693, 1651, 1454,
1392, 1365, 1335, 1291, 1255, 1163, 1097, 1057, 1006, 939, 910,
834, 774, 752, 734, 697 cm-1; HRMS (TOF MS ES+) m/z calcd
for C44H62N2O9NaSi [M + Na]+ 813.4122, found 813.4102.
Thioaminal 25. To a solution of hemiaminal 24 (66.7 mg, 84.3
µmol) and ethanethiol (EtSH, 630 µL, 8.4 mmol) in 1 mL of
dichloromethane was added hafnium trifluoromethanesulfonate
[Hf(OTf)4, 6.5 mg, 8.4 µmol] at 0 °C. The mixture was stirred at
room temperature for 4 h, and dichloromethane (20 mL) and water
(10 mL) were added sequentially. The two layers were separated,
and the aqueous layer was extracted with dichloromethane (20 mL
× 3). The combined organic layers were washed with brine, dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by column chromatography (gradient elution
10% f 80% ethyl acetate in heptanes) to afford thioaminal 25 (53.3
1
mg) in 86% yield. Foam; [R]25 +44.2° (c 1.2, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.28-7.03 (m, 10 H), 5.67-5.41 (m, 2 H),
4.91 (s, br, 2 H), 4.41-4.24 (m, 3 H), 3.74 (s, 3 H), 3.70-3.56
(m, 7 H), 3.43-3.35 (m, 1 H), 2.92-2.87 (m, 2 H), 2.69-2.38
(m, 4 H), 2.17 (s, 3 H), 1.42 (s, 9 H), 1.28-1.19 (m, 5 H); 13C
NMR (75 MHz, CDCl3, the major rotamer was listed) δ 169.1,
150.5, 144.8, 138.6, 137.2, 128.6, 128.4, 128.3, 127.9, 127.8, 127.7,
127.4, 127.1, 126.7, 123.7, 81.7, 74.6, 72.7, 61.1, 60.3, 57.6, 57.3,
56.2, 54.2, 49.5, 33.7, 31.9, 29.7, 28.3, 26.8, 22.7, 14.9, 9.4 ppm;
FTIR (film) 2929, 1693, 1651, 1455, 1413, 1385, 1311, 1257, 1161,
1117, 1058, 1008, 735, 697, 668 cm-1; HRMS (TOF MS ES+)
m/z calcd for C40H52N2O8NaS [M + Na]+ 743.3342, found
743.3335.
Hemiaminal 24. To a solution of oxalyl chloride (85 µL, 974.7
µmol) in 3 mL of dichloromethane, dimethyl sulfoxide (DMSO,
175 µL, 2.4 mmol) was added at -78 °C. The mixture was stirred
at -78 °C for 30 min, and then amide alcohol 23 (386.5 mg, 487.3
µmol) in a solution of dichloromethane (1 mL) was added. The
obtained mixture was stirred at -78 °C for 30 min, and added
dropwise with triethylamine (Et3N, 409 µL, 2.9 mmol). The mixture
was stirred at -78 °C for 30 min, stirred at 0 °C for 30 min, and
10 mL of water was added. The two layers were separated, and
the aqueous layer was extracted with dichloromethane (50 mL ×
3). The combined organic layers were washed with brine, dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by column chromatography (gradient elution
5% f 25% ethyl acetate in heptanes) to afford hemiaminal 24
(350.0 mg, 91% yield) as foam in a 3:2 mixture of diastereomers.
trans-Isomer 24a: foam; [R]25D +8.5° (c 4.0, CHCl3); colorless
oil; 1H NMR (500 MHz, CDCl3) δ 7.35-7.27 (m, 5 H), 7.20-7.19
(m, 3 H), 7.05-7.03 (m, 2 H), 6.66 (d, 1 H, J ) 1.0 Hz), 5.57 (t,
1 H, J ) 3.0 Hz), 5.01 (d, 1 H, J ) 11.5 Hz), 4.98 (d, 1 H, J )
11.5 Hz), 4.78 (t, 1 H, J ) 8.5 Hz), 4.45 (dd, 1 H, J ) 11.5, 4.0
Hz), 4.32 (s, 2 H), 3.84 (d, 1 H, J ) 5.0 Hz), 3.82 (s, 3 H), 3.68
(s, 3 H), 3.66 (d, 1 H, J ) 5.0 Hz), 3.46 (dd, 1 H, J ) 9.5, 3.0 Hz),
3.40 (dd, 1 H, J ) 14.5, 4.0 Hz), 3.28 (dt, 1 H, J ) 9.5, 3.0 Hz),
2.62 (dd, 1 H, J ) 14.5, 11.5 Hz), 2.26 (s, 3 H), 2.13-1.76 (m, 2
H), 1.73-1.60 (m, 2 H), 1.48 (s, 9 H), 0.91 (s, 9 H), 0.07 (s, 6 H);
13C NMR (75 MHz, CDCl3, the major rotamer was listed) δ 167.9,
156.3, 151.4, 150.4, 144.4, 138.4, 137.2, 128.5, 128.4, 128.3,
128.14, 128.09, 127.6, 127.3, 124.6, 124.5, 82.5, 81.4, 74.7, 73.0,
72.3, 63.3, 62.6, 60.9, 60.3, 58.5, 57.0, 50.6, 49.0, 28.3, 26.0, 25.4,
18.4, 9.4, -5.3 ppm; FTIR (film) 2928, 2855, 1697, 1651, 1454,
1392, 1366, 1336, 1255, 1164, 1100, 1061, 1006, 835, 775, 735,
698 cm-1; HRMS (TOF MS ES+) m/z calcd for C44H62N2O9NaSi
[M + Na]+ 813.4122, found 813.4141.
Silyl Enol Ether 26. To a solution of oxalyl chloride (93 µL,
1.1 mmol) in 2 mL of dichloromethane was added dimethyl
sulfoxide (183 µL, 2.5 mmol) at -78 °C. The mixture was stirred
at -78 °C for 30 min, and amide thioaminal 25 (153.0 mg, 212.0
µmol) in a solution of dichloromethane (1 mL) was added. The
obtained mixture was stirred at -78 °C for 30 min, and triethy-
lamine (445.1 µL, 3.2 mmol) was added dropwise. The mixture
was stirred at -78 °C for 30 min and stirred at 0 °C for 30 min,
and 10 mL of water was added. The two layers were separated,
and the aqueous layer was extracted with dichloromethane (30 mL
× 3). The combined organic layers were washed with brine, dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by column chromatography (gradient elution
10% f 80% ethyl acetate in heptanes) to afford the aldehyde (143.4
mg) in 94% yield. Colorless oil; [R]27D +49.2° (c 0.4, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 9.73 (s, 1 H), 7.25-7.05 (m, 10 H),
5.70-5.41 (m, 2 H), 4.91 (s, br, 2 H), 4.37-4.20 (m, 3 H), 3.73
(s, 3 H), 3.59-3.40 (m, 6 H), 2.94-2.89 (m, 4 H), 2.60-2.50 (m,
4 H), 2.16 (s, 3 H), 1.41 (s, 9 H), 1.26 (t, 3 H, J ) 7.4 Hz); 13C
NMR (75 MHz, CDCl3, the major rotamer was listed) δ 201.7,
167.8, 150.4, 144.8, 138.5, 137.3, 137.0, 128.6, 128.4, 128.2, 127.9,
127.7, 127.3, 127.0, 126.5, 124.6, 123.6, 81.6, 74.6, 72.7, 72.2,
61.0, 60.3, 49.3, 42.8, 31.8, 29.6, 29.3, 28.2, 26.7, 22.6, 14.8, 14.0,
9.4 ppm; FTIR (film) 2922, 1725, 1694, 1651, 1454, 1415, 1385,
1310, 1259, 1162, 1118, 699, 668 cm-1; HRMS (TOF MS ES+)
m/z calcd for C41H53N2O9NaS [M + MeOH + Na]+ 773.3448,
found 773.3442.
To a solution of this aldehyde (83.8 mg, 116.6 µmol) in 2 mL
of diethyl ether (Et2O) were added triethylamine (Et3N, 82 µL, 582.8
µmol) and triisopropylsilyl trifluoromethanesulfonate (TIPSOTf, 63
µL, 233.1 µmol) sequentially at 0 °C. The mixture was stirred at
room temperature for 12 h and quenched with saturated aqueous
sodium bicarbonate solution (10 mL). The two layers were
separated, and the aqueous layer was extracted with ethyl acetate
(30 mL × 3). The combined organic layers were washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by column chromatography (gradient elution
1% f 20% ethyl acetate in heptanes) to afford silyl enol ether 26
cis-Isomer 24b: foam; [R]25 +10.5 ° (c 5.0, CHCl3); colorless
D
oil; 1H NMR (300 MHz, CDCl3) δ 7.40-7.09 (m, 10 H), 5.98-5.55
(m, 2 H), 5.01 (d, 1 H, J ) 10.8 Hz), 4.95 (d, 1 H, J ) 10.8 Hz),
4.51-4.32 (m, 3 H), 3.93-3.75 (m, 4 H), 3.68 (s, 3 H), 3.62 (t, 2
H, J ) 6.0 Hz), 3.49 (dd, 1 H, J ) 9.3, 3.0 Hz), 3.38 (dd, 1 H, J
) 12.3, 3.6 Hz), 3.08 (dd, 1 H, J ) 15.0, 3.6 Hz), 3.28 (dd, 1 H,
J ) 15.0, 12.3 Hz), 2.25 (s, 3 H), 2.16-1.55 (m, 4 H), 1.49 (s, 9
H), 0.90 (s, 9 H), 0.06 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ
167.9, 151.3, 150.4, 144.7, 138.0, 137.2, 128.5, 128.4, 128.1, 127.9,
127.6, 127.4, 127.3, 126.9, 124.6, 124.0, 81.2, 74.7, 73.0, 72.3,
63.3, 62.6, 60.9, 60.3, 57.0, 55.9, 49.0, 29.7, 28.3, 26.0, 25.9, 25.4,
(100.0 mg) in 98% yield. Colorless oil; [R]27 +62.0° (c 0.5,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.29-7.02 (m, 10 H), 6.28
(d, 1 H, J ) 11.7 Hz), 5.74 (t, 1 H, J ) 4.8 Hz), 5.68 (d, 1 H, J )
J. Org. Chem. Vol. 74, No. 5, 2009 2051

Wu et al.
2.7 Hz), 5.46-5.05 (m, 1 H), 4.95-4.85 (m, 2 H), 4.49-4.30 (m,
3 H), 3.73 (s, 3 H), 3.58-3.40 (m, 6 H), 3.16-2.43 (m, 6 H), 2.16
(s, 3 H), 1.41 (s, 9 H), 1.29-0.97 (m, 30 H); 13C NMR (75 MHz,
CDCl3, the major rotamer was listed) δ 175.4, 167.8, 154.1, 151.2,
150.4, 144.8, 141.3, 138.6, 137.2, 128.5, 128.2, 127.9, 127.7, 127.3,
127.0, 124.5, 123.9, 108.5, 81.3, 72.7, 72.4, 61.0, 60.3, 59.5, 57.4,
49.3, 33.8, 28.1, 26.9, 24.4, 22.6, 17.7, 14.7, 11.9, 9.4 ppm; FTIR
(film) 2927, 2865, 1693, 1656, 1454, 1413, 1384, 1307, 1248, 1165,
1117, 1009, 883, 696, 668 cm-1; HRMS (TOF MS ES+) m/z calcd
for C47H72N2O8NaSiS [M + Na]+ 875.4676, found 875.4693.
Tetracyclic Aldehyde 27. To a solution of silyl enol ether 26
(57.8 mg, 66.0 µmol) in 3 mL of THF was added silver
tetrafluoroborate (AgBF4, 23.1 mg, 118.9 µmol) at room temper-
ature. The mixture was stirred at room temperature for 8 h, and
saturated aqueous sodium bicarbonate solution (10 mL) and ethyl
acetate (20 mL) were added sequentially. The two layers were
separated, and the aqueous layer was extracted with ethyl acetate
(20 mL × 3). The combined organic layers were washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by column chromatography (gradient elution
10% f 40% ethyl acetate in heptanes) to afford tetracyclic aldehyde
(gradient elution 50% f 100% ethyl acetate in heptanes) to afford
tetracyclic alcohol 3 (22.4 mg) in 94% yield. Foam; [R]25D -101.7°
(c 2.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.74 (s, 1 H), 5.93
(s, 1 H), 5.63 (s, br, 1 H), 4.74 (s, 1 H), 4.67 (s, br, 1 H), 3.97 (dd,
1 H, J ) 13.0, 3.5 Hz), 3.78 (s, 3 H), 3.68 (s, 3 H), 3.66-3.60 (m,
1 H), 3.33 (t, 1 H, J ) 8.0 Hz), 3.07 (dd, 1 H, J ) 13.0, 2.5 Hz),
2.61 (dd, 1 H, J ) 14.5, 7.0 Hz), 2.57-2.47 (m, 1 H), 2.41-2.37
(m, 1 H), 2.24 (s, 3 H), 2.21 (m, 1 H), 1.43 (s, 9 H) ppm; 13C
NMR (75 MHz, CDCl3) δ 199.0, 170.1, 148.3, 144.6, 142.2, 124.0
(d), 123.5, 117.9, 81.6, 66.2, 61.2, 60.8, 60.4, 51.9, 50.8, 32.5, 28.2,
25.3, 21.0, 14.2, 9.7 ppm; FTIR (film) 3382, 2974, 2937, 1678,
1658, 1643, 1454, 1393, 1414, 1368, 1319, 1286, 1249, 1161, 1006,
913, 731 cm-1; HRMS (TOF MS ES+) m/z calcd for C24H32N2O8Na
[M + Na]+ 499.2056. Found 499.2052.
Lemonomycinone Amide (2). To a solution of tetracyclic
alcohol 3 (28.1 mg, 58.9 µmol) in 1.5 mL of methanol was added
hydrochloric acid (HCl, 12 M, 0.5 mL) at 0 °C. The mixture was
stirred at room temperature for 3 h, and concentrated. The residue
was diluted with water (1.0 mL), and ammonium cerium(IV) nitrate
(129.2 mg, 235.6 µmol) was added at room temperature. The
mixture was stirred at room temperature for 3 h, purified on reve-
rse phase HPLC, and lyophilized to afford lemonomycinone amide
27 (37.8 mg) in 87% yield. White foam; [R]27 -41.5 ° (c 0.5,
D
(2, 18.1 mg) in 81% yield. Orange foam; UV ) 267.8; [R]25
CHCl3); colorless oil; 1H NMR (500 MHz, CDCl3) δ 9.56 (s, 1H)
7.38-7.02 (m, 10 H), 5.43 (s, br, 1 H), 4.99 (d, 1 H, J ) 11.0 Hz),
4.96 (d, 1 H, J ) 11.0 Hz), 4.63 (s, br, 1 H), 4.57 (s, br, 1 H), 4.29
(d, 1 H, J ) 11.5 Hz), 4.24 (d, 1 H, J ) 11.5 Hz), 4.12 (dd, 1 H,
J ) 9.5, 3.5 Hz), 3.81 (s, 3 H), 3.69 (s, 3 H), 3.66-3.57 (m, 1 H),
3.34 (dd, 1 H, J ) 9.5, 2.0 Hz), 3.08 (t, 1 H, J ) 8.0 Hz), 2.92 (dd,
1 H, J ) 13.5, 2.0 Hz), 2.71 (t, 1 H, J ) 13.5 Hz), 2.42-2.32 (m,
1 H), 2.27 (s, 3 H), 2.04 (t, 1 H, J ) 11.0 Hz), 1.43 (s, 9 H); 13C
NMR (75 MHz, CDCl3, the major rotamer was listed) δ 198.9,
167.9, 150.9, 150.3, 144.2, 138.1, 136.9, 128.4, 128.2, 128.1, 127.8,
127.4, 126.4, 124.6, 124.3, 81.0, 74.4, 72.9, 71.4, 60.7, 60.1, 57.5,
56.8, 49.9, 48.5, 32.2, 28.0, 25.2, 9.3 ppm; FTIR (film) 2936, 2922,
2868, 2852, 1726, 1700, 1663, 1660, 1456, 1454, 1411, 1367, 1316,
1288, 1259, 1160, 1110, 1057, 1010, 801, 754, 698 cm-1; HRMS
(TOF MS ES+) m/z calcd for C38H44N2O8Na [M + Na]+ 679.2995,
found 679.3026.
D
1
-72.9° (c 0.8, D2O); H NMR (500 MHz, D2O) δ 5.13 (d, 1 H, J
) 4.5 Hz), 5.04 (s, br, 1 H), 4.38 (s, 1 H), 4.31 (d, 1 H, J ) 6.5
Hz), 4.09 (dd, 1 H, J ) 12.0, 3.5 Hz), 3.84 (dt, 1 H, J ) 11.5, 3.0
Hz), 3.85 (s, 3 H); 3.51 (dd, 1 H, J ) 12.0, 2.0 Hz), 2.93 (dd, J )
16.5, 3.0 Hz, 1 H), 2.81-2.77 (m, 1 H), 2.48-2.43 (m, 2 H), 2.26
(dt, 1 H, J ) 14.5, 6.5 Hz), 1.96 (s, 3 H) ppm; 13C NMR (75 MHz,
D2O) δ 187.0, 181.5, 167.2, 155.8, 142.7, 136.5, 131.2, 89.9, 61.5,
61.0, 59.6, 58.7, 55.0, 52.3, 41.5, 31.5, 23.5, 8.7 ppm; FTIR (D2O):
3372, 1670, 1649, 1452, 1208 cm-1; HRMS (TOF MS ES+) m/z
calcd for C18H23N2O7 [M + H]+ 379.1505. Found 379.1511.
Acknowledgment. Financial support from CNRS is gratefully
acknowledged. Y.C.W thanks a postdoctoral fellowship from
ICSN and C.C. thanks Rhodia for a doctoral fellowship.
Tetracyclic Alcohol 3. To a solution of tetracyclic aldehyde 27
(32.8 mg, 50.0 µmol) in 3 mL of methanol was added palladium
hydroxide [Pd(OH)2, moist, Pd content 20%, 10 mg] at 0 °C. The
mixture was stirred at 0 °C under an atmosphere of hydrogen for
6 h, filtered through a plug of Celite, washed with methanol, and
concentrated. The residue was purified by column chromatography
Supporting Information Available: Experimental proce-
1
dures, characterization data, and copies of H and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO8027449
2052 J. Org. Chem. Vol. 74, No. 5, 2009