Total syntheses of natural tubelactomicins B, D, and E: Establishment of their stereochemistries

Article abstract of DOI:10.1021/jo0708442

(Chemical Equation Presented) Total syntheses of the antimicrobial tricyclic 16-membered macrolides, (+)-tubelactomicin B, (+)-tubelactomicin D, and (+)-tubelactomicin E, have been accomplished for the first time with common synthetic approaches. These total syntheses established the relative and absolute configurations of the three tubelactomicins, for which planar structures had solely been reported. The total synthesis of (+)-tubelactomicin D included a newly developed stereoselective intramolecular Diels-Alder reaction for constructing the highly functionalized octahydronaphthalene substructures.

Full text of DOI:10.1021/jo0708442

Total Syntheses of Natural Tubelactomicins B, D, and E:
Establishment of Their Stereochemistries†
Kiyoto Sawamura, Keigo Yoshida, Akari Suzuki, Toru Motozaki, Ikuko Kozawa,
Takashi Hayamizu, Ryosuke Munakata, Ken-ichi Takao, and Kin-ichi Tadano*
Department of Applied Chemistry, Keio UniVersity, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
tadano@applc.keio.ac.jp
ReceiVed April 25, 2007
Total syntheses of the antimicrobial tricyclic 16-membered macrolides, (+)-tubelactomicin B,
(+)-tubelactomicin D, and (+)-tubelactomicin E, have been accomplished for the first time with com-
mon synthetic approaches. These total syntheses established the relative and absolute configurations of
the three tubelactomicins, for which planar structures had solely been reported. The total synthesis of
(+)-tubelactomicin D included a newly developed stereoselective intramolecular Diels-Alder reaction
for constructing the highly functionalized octahydronaphthalene substructures.
Introduction
(+)-Tubelactomicin A (1) (Figure 1) was isolated from the
culture broth of an actinomycete strain designated MK703-
102F1, and its structure was determined by the researchers at
the Institute of Microbial Chemistry in Japan.1b This tricyclic
16-membered macrolide 1 showed potent antimicrobial activity
against acid-fast bacteria, including drug-resistant strains.1a
Following the isolation of 1, the same group isolated and
characterized structurally similar macrolides, i.e., (+)-tubelac-
tomicin B (2), (+)-tubelactomicin D (3), and (+)-tubelactomicin
E (4), from the same microoganism.2 These antibiotics 2-4 also
showed a broad range of antimicrobial activity. The planar
structures of 2-4 were determined on the basis of spectral
1
analysis [UV, IR, H and 13C NMR]. Although their relative
and absolute stereochemistries remained undetermined, it was
considered that 2-4 possess the same stereochemistries as 1.
In 2005, we reported the total synthesis of 1, thereby establishing
the stereochemistry of the (+)-natural form.3 Tatsuta and co-
workers have also accomplished the total synthesis of 1.4 Herein,
we report the total syntheses of three other tubelactomicins, 2-4,
FIGURE 1. Structures of tubelactomicins.
thereby establishing their unknown relative and absolute ste-
reochemistries as those depicted in Figure 1.
† This paper is dedicated to the memory of the late Professor Yoshihiko Ito.
(1) (a) Igarashi, M.; Hayashi, C.; Homma, Y.; Hattori, S.; Kinoshita,
N.; Hamada, M.; Takeuchi, T. J. Antibiot. 2000, 53, 1096-1101. (b)
Igarashi, M.; Nakamura, H.; Takeuchi, T. J. Antibiot. 2000, 53, 1102-
1107.
(3) (a) Motozaki, T.; Sawamura, K.; Suzuki, A.; Yoshida, K.; Ueki, T.;
Ohara, A.; Munakata, R.; Takao, K.; Tadano, K. Org. Lett. 2005, 7, 2261-
2264. (b) Motozaki, T.; Sawamura, K.; Suzuki, A.; Yoshida, K.; Ueki, T.;
Ohara, A.; Munakata, R.; Takao, K.; Tadano, K. Org. Lett. 2005, 7, 2265-
2267.
(2) Takeuchi, T.; Igarashi, M.; Naganawa, H.; Hamada, M. Japanese
Patent JP2001-55386A, 2001.
10.1021/jo0708442 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/11/2007
J. Org. Chem. 2007, 72, 6143-6148
6143

Sawamura et al.
SCHEME 2. Synthesis of the Upper-Half Segment 5
SCHEME 1. Retrosynthetic Approach to Tubelactomicins B
(2) and D (3)
reaction of the substrate with a methyl group instead of the
(methoxymethoxy)methyl (MOM) group in 10.3a This substrate
10 for the attempted IMDA reaction would be obtained by the
(E)-selective Horner-Wadsworth-Emmons olefination of highly
oxygenated hexanal 11 and a novel (E)-trisubstituted olefin 12,
which possesses a (trimethylsilyl)acetylene group, a diethyl
methylphosphonate moiety, and an MOM-protected hydroxy-
lmethyl group. The aldehyde 11 was previously prepared from
diethyl (R)-malate3a via a stereoselective R-allylation developed
by Seebach and co-workers.7 As established in the case of the
total synthesis of 1,3b the upper- and lower-half segments, i.e.,
the combination of 5 and 7 or 6 and 8, might be connected via
a stereoselective sp2-sp2 coupling, followed by a 16-membered
macrolactonization, to construct the entire framework of 2 or
3, respectively. On the other hand, the known trans-fused
octahydronaphthalene derivative,3a which was synthesized as a
key intermediate for the total synthesis of 1, could be used for
the total synthesis of another macrolide 4 as the coupling partner
of 6 (vide infra). Following these synthetic plans, we embarked
on the total syntheses of 2-4.
We envisioned that the total syntheses of 2-4 would be
accomplished using convergent synthetic approaches similar to
that used for the total synthesis of 1. Therefore, the targeted
macrolides 2 and 3 were divided into two segments, i.e., the
upper-half segment 5 (for 2) or 63b (for 3) and the lower-half
segment 73a (for 2) or 8 (for 3) as shown in Scheme 1. The
novel upper-half segment 5 would be synthesized from 9, which
was prepared previously from methyl (R)-lactate,3b using the
analogous carbon-carbon bond extension strategy including the
Evans syn-aldol strategy5 to that used for the synthesis of another
upper-half segment 6. The novel highly oxygenated octahy-
dronaphthalene derivative 8, as the lower-half segment of 3,
would be synthesized through an endo- and π-facial selective
intramolecular Diels-Alder (IMDA) reaction6 of unsaturated
aldehyde carrying a dienyne segment, i.e., 10. We previously
observed that the structurally similar octahydronaphthalene
derivative 7 was obtained stereoselectively by the IMDA
(4) Hosokawa, S.; Seki, M.; Fukuda, H.; Tatsuta, K. Tetrahedron Lett.
2006, 47, 2439-2442.
(5) (a) Evans, D. A.; Bartroli, J.; Shih, T. L J. Am. Chem. Soc. 1981,
103, 2127-2129. (b) Gage J. R.; Evans, D. A. Org. Synth. 1989, 68, 77-
82 and 83-91.
(6) For reviews on IMDA reactions, see: (a) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L.
A., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 5, pp 153-550. (b)
Fallis, A. G. Acc. Chem. Res. 1999, 32, 464-474. (c) Bear, B. R.; Sparks,
S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820-849. (d) Marsault,
E.; Toro´, A.; Nowak, P.; Deslongchamps, P. Tetrahedron 2001, 57, 4243-
4260. (e) For a recent review on this subject, see: Takao, K.; Munakata,
R.; Tadano, K. Chem. ReV. 2005, 105, 4779-4807.
Results and Discussion
The synthesis of 5 from the known 9 is summarized
in Scheme 2. Compound 9 was converted to R-methylated
R,â-unsaturated ester 14 by diisobutylaluminum hydride
(DIBAL-H) reduction followed by a Wittig olefination of the
(7) (a) Seebach, D.; Wasmuth, D. HelV. Chim. Acta 1980, 63, 197-
200. (b) Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1984, 63, 109-
120.
6144 J. Org. Chem., Vol. 72, No. 16, 2007

Total Syntheses of Natural Tubelactomicins B, D, and E
SCHEME 3. Synthesis of the Allylic Phosphonate 12
SCHEME 4. Synthesis of the Substrate 10 and the IMDA
Reaction
resulting aldehyde 13. The ester 14 was converted to unsaturated
aldehyde 16 by a reduction-oxidation protocol via allylic
alcohol 15. The highly syn-selective boron-mediated Evans aldol
reaction of 16 and an N-propionyl Evans chiral oxazolidinone5
produced the syn-adduct 17 with excellent stereoselection.3b The
hydroxyl group in the aldol product 17 was protected as the
MOM ether, and the chiral auxiliary was reductively removed
from the resulting 18 to produce the primary alcohol 19.
Oxidation of 19 with Dess-Martin periodinane (DMP),8 fol-
lowed by Corey-Fuchs dibromoolefin formation9 of the result-
ing aldehyde 20, produced R,R-dibromoethylene derivative 21
efficiently. Base-induced elimination of hydrogen bromide from
21 provided bromoalkyne 22. Deprotection of the tert-butyl-
diphenylsilyl (TBDPS) group in 22 with HF‚pyridine, followed
by treatment of the resulting 23 with tributylstannane in the
presence of a catalytic amount of Pd(PPh3)4,10 provided (E)-
vinylstannane 5 stereoselectively.
For the synthesis of the lower-half segment 8, we first
prepared allylic phosphonate 12 from the R-hydroxymethylated
methyl acrylate 24,11 the Morita-Baylis-Hillman product of
methyl acrylate and p-formaldehyde. The synthesis of 12 from
24 is shown in Scheme 3. The allylic alcohol 24 was protected
as the MOM ether. The addition of bromine to the MOM ether
25 produced dibromide 26 in 66% yield. The de-O-MOM
derivative 27 was also produced, which was readily separated
from 26.
bromination of the resulting allylic alcohol 30 with carbon
tetrabromide in the presence of triphenylphosphine provided
allylic bromide 31. The Arbusov rearrangement of 31 with
triethyl phosphite produced functionalized diethyl allylphos-
phonate 12.
The synthesis of 8, commencing with the Horner-Wads-
worth-Emmons reaction of the known aldehyde 113a and
allylphosphonate 12, is shown in Schemes 4 and 5. From the
coupling of 11 and 12, the (E,E)-dienyne-type adduct 32 was
obtained stereoselectively. Acid hydrolysis of the silyl ether in
32, oxidation of the resulting 33 with DMP, followed by the
olefination of aldehyde 34 with Ph3PdC(Me)CO2Et produced
R,â-unsaturated ester 35 with exclusive (E)-selectivity. The (E)-
geometry of the unsaturated ester moiety of 35 was secured by
1
NOE experiment in the H NMR analysis of 35. Thus a 10%
Treatment of 26 with tetrabutylammonium fluoride (TBAF)
in HMPA provided (E)-bromoalkene 28 stereoselectively as a
result of hydrogen bromide elimination from 26. The Pd (0)-
catalyzed Sonogashira coupling of 28 and (trimethylsilyl)-
acetylene in the presence of CuI and i-Pr2NEt12 produced enyne
ester 29 in high yield. The DIBAL-H reduction of 29 and allylic
signal enhancement of the R-methyl group in the R,â-unsaturated
ester in 35 was observed when one of the allylic methylene
protons was irradiated. A reduction-oxidation strategy was used
for the conversion of 35 to the IMDA substrate 10. Thus, the
DIBAL-H reduction of 35 provided allylic alcohol 36, which
was oxidized with DMP to produce 10. The attempted IMDA
reaction of 10 proceeded at 80 °C in toluene, as observed in
the IMDA reaction of the less congested substrate, which
possessed a methyl group instead of the MOMOCH2 group in
the diene part of 10.3a The IMDA reaction produced two adducts
37 and 38 as an inseparable mixture. Thus, the mixture was
further oxidized to the respective carboxylic acids 39 and 40
by a perchlorite oxidation. The carboxylic acids 39 and 40 were
cleanly separated by chromatography on silica gel in 76% and
18% yield, respectively, for the two steps. The stereochemistry
(8) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (c) Frigerio,
M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538.
(9) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
(10) Boden, C. D. J.; Pattenden, G.; Ye. T. J. Chem. Soc., Perkin Trans.
I 1996, 2417-2419.
(11) For the preparation of 24 and bromine addition to 24, see: Ben
Ayed, T.; Amri, H.; El Gaied, M. M. Tetrahedron 1991, 47, 9621-9628.
(12) de Lera, A. R.; Iglesias, B.; Rodriguez, J.; Alvarez, R.; Lopez, S.;
Villanueva, X.; Padros, E. J. Am. Chem. Soc. 1995, 117, 8220-8231.
J. Org. Chem, Vol. 72, No. 16, 2007 6145

Sawamura et al.
SCHEME 5. Conversion of 39 to the Lower-Half Segment 8
SCHEME 6. Completion of the Total Syntheses of 2 and 3
of the major product 39 was determined to be the desired endo-
adduct unambiguously by 1H NMR analysis including detailed
NOE experiments. For the stereochemistry of the minor product
40, we assigned the exo-stereochemistry as depicted in Scheme
4 on the basis of our previous result experienced for the total
synthesis of 1.3a In the previous case,3a the ratio of the endo-
and exo-adduct was approximately 8 to 1. In the present case,
the endo/exo selectivity of the IMDA reaction of 10 was
estimated to be approximately 4:1. It is apparent that the
bulkiness of the more congested group in the diene part
diminishes the endo/exo ratio of the IMDA reaction. As we
observed in the case of 1, the π-facial selectivity in the IMDA
reaction of 10 was completely controlled.
Having achieved the synthesis of the desired IMDA adduct
39, we explored the conversion of 39 to the lower-half segment
8 as shown in Scheme 5. Protodesilylation of the C-TMS group
in 39 with TBAF and hydrolytic de-O-benzylidenation, followed
by (2-trimethylsilylethoxy)methyl (SEM) ester formation, pro-
vided 43 via 41 and 42. Selective tosylation of diol 43 and
deoxygenation of the resulting primary tosylate 44 with NaBH4
in hot DMSO provided 45. Regio- and cis-selective palladium-
catalyzed hydrostannylation of the acetylene functionality in 45
and subsequent metal-iodine exchange of the resulting vinyl-
stannane provided the lower-half segment 8 in good overall
yield.
excellent yield of 93%. Finally, acid hydrolysis of the MOM
group in 48 provided (+)-tubelactomicin B (2), which was found
to be identical with a natural sample by comparison of spectra
(1H and 13C NMR, IR), [R]D, and TLC behavior. The dextroro-
tatory property of synthetic 2 proved that the absolute stereo-
chemistry of natural 2 was as depicted. Similarly, the Stille
coupling of 6 and 8 provided (E,E)-diene 49 under the same
conditions as those used for the coupling of 5 and 7. The
Mukaiyama macrolactonization of the seco acid 50 derived
from 49 provided 51 with a lower yield of 59% for two steps.
The two-step deprotection of 51 via 52 eventually provided
(+)-tubelactomicin D (3), which was identical with a natural
sample ([R]D, 1H and 13C NMR, IR, and TLC behavior),
establishing the absolute configuration of 3.
We then explored the Stille coupling13 of 5 and 7 and also
that of 6 and 8 for the total syntheses of 2 and 3, respectively.
The reaction conditions and results of the Stille couplings and
transformation of the coupling products 46 and 49 into 2 and
3, respectively, are summarized in Scheme 6. The palladium-
catalyzed Stille coupling of 5 and 7 proceeded with CuI in the
presence of AsPh3 in DMF,14 providing (E,E)-diene 46 ef-
ficiently. Deprotection of the SEM ester in 46 with HF‚pyridine
and lactonization of the resulting seco acid 47 under the
Mukaiyama conditions (2-chloro-1-methylpyridinium iodide and
triethylamine)15 provided 16-membered macrolactone 48 in an
The total synthesis of (+)-tubelactomicin E (4) was started
with the previously reported intermediate 533a used for the total
synthesis of 1. The total synthesis of 4 from 53 is shown in
Scheme 7. The octahydronaphthalene derivative 53 was in turn
synthesized featuring an endo- and π-facial selective IMDA
reaction of a D-malic acid-derived substrate. According to the
conversion of 45 to 8, the carboxylic acid 53 was esterified
with SEMCl, and the resulting SEM ester 54 was subjected to
the palladium-catalyzed hydrostannylation, followed by tin-
iodine exchange, providing 55. The palladium-catalyzed Stille
coupling of the upper-half segment 63b and vinyl iodide 55
provided conjugated (E,E)-diene 56. Deprotection of the SEM
group in 56 and the Mukaiyama macrolactonization of the
resulting seco acid 57 provided 58, from which (+)-tubelacto-
(13) For some reviews on Stille coupling, see: (a) Stille, J. K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508-524. (b) Espinet, P.; Echavarren, A.
E. Angew. Chem., Int. Ed. 2004, 43, 4704-4734.
(14) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J. Org. Chem. 1994, 59, 5905-5911.
(15) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49-50.
6146 J. Org. Chem., Vol. 72, No. 16, 2007

Total Syntheses of Natural Tubelactomicins B, D, and E
SCHEME 7. Total Synthesis of (+)-Tubelactomicin E (4)
19.0 Hz, 1H); 13C NMR (68 MHz) δ 9.4 × 3, 11.4, 13.7 × 3,
17.1, 23.4, 25.7, 27.2, 27.4 × 3, 29.1 × 3, 39.1, 44.2, 55.6, 67.9,
85.8, 93.0, 126.5, 130.3, 132.9, 150.9; IR (neat) 3400, 2960, 1600,
1460 cm-1; HRMS calcd for C23H45O3Sn (M+- Bu) m/z 489.2391,
found 489.2392.
2-(Trimethylsilyl)ethoxymethyl (1R,2S,4aR,5R,6S,8aS)-5-Hy-
droxy-2-[(1E,3E,5S,6R,7E,12R)-12-hydroxy-6-methoxymethoxy-
5,7-dimethyltrideca-1,3,7-trienyl]-1,3,6-trimethyl-1,2,4a,5,6,7,8,-
8a-octahydronaphthalene-1-carboxylate (46). The following
reaction was carried out under argon. To a stirred solution of 5
(55.4 mg, 102 mmol) and 73a (38.5 mg, 74.0 mmol) in degassed
DMF (1 mL) was added a solution of Pd2(dba)3 (3.5 mg, 3.8 mmol),
AsPh3 (9.3 mg, 30 mmol), and CuI (2.9 mg, 15 mmol) in degassed
DMF (0.25 mL). The mixture was stirred for 45 min and then heated
at 60 °C for 2 h. After being cooled to room temperature, the
mixture was diluted with saturated aqueous NaHCO3 (20 mL) and
extracted with Et2O (3 × 10 mL). The combined organic layers
were dried and concentrated with the aid of toluene. The residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:5 to 1:3) to give 35.8 mg (75%) of 46 as a colorless oil:
TLC, Rf 0.66 (EtOAc/hexane, 2:1); [R]26.5D +216 (c 0.55, CHCl3);
1H NMR (300 MHz) δ 0.03 (s, 9H), 0.96 (t, J ) 8.3 Hz, 2H), 1.05
(d, J ) 6.4 Hz, 3H), 1.10 (d, J ) 6.6 Hz, 3H), 1.16 (s, 3H), 1.18
(d, J ) 6.2 Hz, 3H), 1.32-1.51 (m, 5H), 1.49 (s, 3H), 1.62 (s,
3H), 1.60-1.83 (m, 6H), 1.96-2.09 (m, 2H), 2.35 (d, J ) 9.6 Hz,
1H), 2.30-2.47 (m, 1H), 2.91 (m, 1H), 3.37 (s, 3H), 3.57 (d, J )
9.0 Hz, 1H), 3.68 (t, J ) 8.3 Hz, 2H), 3.78 (m, 1H), 4.44, 4.60
(2d, J ) 6.6 Hz, 1H × 2), 5.10, 5.21 (2d, J ) 6.0 Hz, 1H × 2),
5.28 (m, 1H), 5.29 (t, J ) 6.8 Hz, 1H), 5.44 (m, 1H), 5.76 (s, 1H),
5.82-5.98 (m, 2H); 13C NMR (68 MHz) δ -1.4 × 3, 11.3, 16.5,
16.8, 18.0, 18.7, 22.6, 23.5, 25.6, 27.0, 27.4, 33.3, 37.7, 39.0, 40.8.
45.5, 49.7, 54.3, 55.6, 67.8, 67.9, 79.5, 85.8, 89.5, 93.0, 121.0,
128.9, 130.6, 131.3, 132.4, 132.6, 133.0, 135.6, 175.1; IR (neat)
3420, 2950, 2930, 2880, 1730, 1710, 1460 cm-1; HRMS calcd for
C37H64O7Si (M+) m/z 648.4421, found 648.4419.
(1R,2S,4aR,5R,6S,8aS)-5-Hydroxy-2-[(1E,3E,5S,6R,7E,12R)-
12-hydroxy-6-methoxymethoxy-5,7-dimethyltrideca-1,3,7-trie-
nyl]-1,3,6-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-
carboxylic Acid (47). To a cooled (0 °C), stirred solution of 46
(35.5 mg, 54.7 mmol) in THF (1 mL) was added HF‚pyridine
complex (0.2 mL). The mixture was stirred for 21 h and quenched
with saturated aqueous NaHCO3 (4 mL) at 0 °C. This was diluted
with saturated aqueous NaHCO3 (16 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried and
concentrated with the aid of toluene. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:3) to give
24.3 mg (86%) of 47 as a colorless oil: TLC, Rf 0.51 (EtOAc/
hexane, 2:1); [R]25D +198 (c 1.02, CHCl3); 1H NMR (300 MHz) δ
1.04 (d, J ) 6.4 Hz, 3H), 1.14 (d, J ) 6.8 Hz, 3H), 1.15 (s, 3H),
1.19 (d, J ) 6.2 Hz, 3H), 1.31-1.49 (m, 5H), 1.51 (s, 3H), 1.63
(s, 3H), 1.55-1.83 (m, 6H), 1.93-2.13 (m, 2H), 2.38 (d, J ) 9.4
Hz, 1H), 2.32-2.49 (m, 1H), 2.91 (m, 1H), 3.37 (s, 3H), 3.57 (d,
J ) 9.4 Hz, 1H), 3.77-3.92 (m, 1H), 4.44, 4.60 (2d, J ) 6.7 Hz,
1H × 2), 5.28-5.52 (m, 3H), 5.75 (s, 1H), 5.85-6.02 (m, 2H);
13C NMR (68 MHz) δ 11.3, 16.6, 16.7, 18.7, 22.8, 23.1, 25.3, 26.8,
27.1, 33.5, 37.6, 38.3, 38.4, 40.8, 45.7, 49.0, 53.9, 55.6, 68.3, 79.5,
86.2, 92.9, 120.9, 129.3, 130.8, 131.5, 132.4, 132.6, 133.2, 134.7,
178.3; IR (neat) 3420, 2970, 2930, 2880, 1710, 1690, 1460, 1450
micin E (4) was synthesized by a two-step deprotection via 59.
1
The synthetic 4 was identical with a natural sample ([R]D, H
and 13C NMR, IR, and TLC behavior).
In conclusion, we have completed the total syntheses of
natural (+)-tubelactomicins B (2), D (3), and E (4) for the first
time. These total syntheses also established the relative and
absolute stereochemistries of these natural products, which had
not been determined.
Experimental Section
(1E,3S,4R,5E,10R)-10-Hydroxy-4-methoxymethoxy-3,5-di-
methyl-1-(tributylstannyl)undeca-1,5-diene (5). The following
reaction was carried out under argon. To a stirred solution of 23
(353 mg, 1.06 mmol) in THF (7 mL) were added Pd(PPh3)4 (123
mg, 0.10 mmol) and Bu3SnH (0.85 mL, 3.16 mmol). The reaction
mixture was stirred for 10 min and then concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:4 doped with Et3N) to give 504 mg (87%) of 5
as a colorless oil. 1H NMR analysis revealed the product contained
approximately 9% of the Z-isomer. This mixture was used for
subsequent steps without separation. Compound 5: TLC, Rf 0.48
(EtOAc/hexane, 1:2); [R]22.5D +58.7 (c 0.85, CHCl3); 1H NMR (300
MHz) δ 0.78-0.95 (m, 15H), 1.11 (d, J ) 6.6 Hz, 3H), 1.18 (d, J
) 6.6 Hz, 3H), 1.22-1.38, 1.40-1.54 (m, 12H), 1.22-1.54 (m,
4H), 1.48 (s, 3H), 1.60 (s, 1H), 1.88 (m, 2H), 2.41 (ddq, J ) 7.1,
9.0, 6.2 Hz, 1H), 3.38 (s, 3H), 3.63 (d, J ) 9.0 Hz, 1H), 3.84 (m,
1H), 4.45 (d, J ) 6.6 Hz, 1H), 4.62 (d, J ) 6.6 Hz, 1H), 5.32 (t,
J ) 6.6 Hz, 1H), 5.71 (dd, J ) 7.1, 19.0 Hz, 1H), 5.87 (d, J )
cm-1
.
(1S,2E,4E,6S,7R,8E,13R,16R,17S,20S,21R,22R)-21-Hydroxy-
7-methoxymethoxy-6,8,13,16,20,24-hexamethyl-14-oxatricyclo-
[14.8.0.017,22]tetracosa-2,4,8,23-tetraene-15-one (48). A solution
of 47 (20.2 mg, 38.9 µmol) in MeCN (24 mL) was added to a
refluxing solution of 2-chloro-1-methylpyridinium iodide (50.1 mg,
0.196 mmol) and Et3N (0.055 mL, 0.40 mmol) in MeCN (12 mL)
over 2.5 h by an addition funnel. The addition funnel was rinsed
with 3.5 mL of MeCN and the washing was added to the reaction
mixture. The mixture was refluxed for an additional 3.5 h. After
being cooled to room temperature, the mixture was concentrated
J. Org. Chem, Vol. 72, No. 16, 2007 6147

Sawamura et al.
in vacuo. The residue was purified by column chromatography on
2.40-2.60 (m, 2H), 2.72 (d, J ) 10 Hz, 2H), 2.84 (t, J ) 9.0 Hz,
2H), 3.89-3.93 (m, 5H), 4.71 (m, 1H), 5.28 (dd, J ) 10, 14 Hz,
1H), 5.72 (dd, J ) 5.7, 14 Hz, 1H), 5.81 (dd, J ) 4.6, 8.3 Hz, 1H),
5.89-6.00 (m, 2H), 6.09 (br s, 1H); 13C NMR (75 Hz, acetone-d6)
δ 15.9, 17.1, 19.4, 19.5, 26.1, 27.8, 29.0, 34.4, 35.9, 39.6, 41.2,
41.9, 46.5, 48.9, 50.5, 65.1, 71.4, 79.4, 81.8, 122.9, 128.7, 131.7,
134.3, 134.7, 137.0, 137.7, 144.7, 168.6, 174.4; IR (neat) 3600,
3500, 2980, 1740, 1680, 1650, 1460 cm-1; HRMS calcd for
C29H42O7 (M+) m/z 502.2930, found 502.2929.
silica gel (EtOAc/hexane, 1:4) to give 18.2 mg (93%) of 48 as a
colorless oil: TLC, Rf 0.76 (EtOAc/hexane, 1:1); [R]26 +182 (c
D
1
0.875, CHCl3); H NMR (300 MHz) δ 0.83-0.98 (m, 2H), 1.04
(d, J ) 6.2 Hz, 3H), 1.12 (s, 3H), 1.16-1.29 (m, 6H), 1.34-1.50
(m, 2H), 1.52 (s, 3H), 1.57-1.60 (m, 7H), 1.63 (s, 3H), 1.96-
2.24 (m, 2H), 2.34 (d, J ) 10.2 Hz, 1H), 2.39-2.51 (m, 1H), 2.92
(m, 1H), 3.37 (s, 3H), 3.48 (d, J ) 9.6 Hz, 1H), 4.44, 4.58 (2d, J
) 6.4 Hz, 1H × 2), 4.62-4.76 (m, 1H), 5.09 (m, 1H), 5.31 (dd, J
) 14.1, 10.2 Hz, 1H), 5.47 (dd, J ) 14.9, 6.5 Hz, 1H), 5.73 (s,
1H), 5.81-6.10 (m, 2H); 13C NMR (68 MHz) δ 11.2, 15.7, 16.7,
18.7, 19.2, 22.6, 25.3, 26.4, 26.8, 33.3, 34.8, 36.7, 38.1, 40.9, 45.6,
48.5, 54.3, 55.5, 71.2, 79.6, 88.1, 93.0, 120.5, 127.8, 130.9, 131.8,
132.8, 133.4 × 2, 135.5, 174.2; IR (neat) 3490, 2980, 2930, 2880,
1720, 1460 cm-1; HRMS (FAB) calcd for C31H48O5 (M+) m/z
500.3502, found 500.3505.
(+)-Tubelactomicin E (4). To a stirred solution of 59 (9.9 mg,
19 µmol) in MeOH (1 mL) was added 1 M aqueous NaOH (0.5
mL). The mixture was heated to 50 °C for 3 h. After being cooled
to room temperature, the mixture was acidified with 1 M aqueous
HCl to pH 2 at 0 °C. This was diluted with 1 M aqueous HCl (10
mL) and extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were dried and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (acetone/hexane,
1:1 containing 1% AcOH) to give 9.1 mg (94%) of 4 as a colorless
solid: TLC, Rf 0.27 (CHCl3/MeOH, 10:1 containing 1% AcOH),
(+)-Tubelactomicin B (2). To a cooled (0 °C), stirred solution
of 48 (17.5 mg, 34.9 µmol) in THF (0.5 mL) was added 6 M
aqueous HCl (0.5 mL). The mixture was stirred for 11 h and then
additional 6 M aqueous HCl (0.25 mL) and THF (0.5 mL) were
added. The mixture was stirred for an additional 6 h and neutralized
with saturated aqueous NaHCO3 (15 mL) at 0 °C. This was
extracted with CH2Cl2 (3 × 8 mL). The combined organic layers
were dried and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:4) to give
13.3 mg (83%) of 2 as a colorless solid: TLC, Rf 0.58 (CHCl3/
MeOH, 10:1), Rf 0.62 (EtOAc/hexane, 1:1); [R]24.5D +101(c 0.60,
0.36 (acetone/hexane, 1:1 containing 1% AcOH); [R]23.5 +94.9
D
1
(c 0.23, MeOH); H NMR (300 MHz, acetone-d6) δ 1.01-1.76
(m, 10H), 1.13 (s, 3H), 1.15 (d, J ) 6.0 Hz, 3H), 1.23 (d, J ) 6.3
Hz, 3H), 1.61 (s, 3H), 1.84 (m, 1H), 2.40 (d, J ) 10.0 Hz, 1H),
2.47-2.57 (m, 2H), 2.60-2.73 (m, 1H), 3.22 (dd, J ) 9.3, 9.3 Hz,
1H), 3.65 (dd, J ) 10.5, 6.6 Hz, 1H), 3.72 (dd, J ) 10.5, 5.1 Hz,
1H), 3.94 (d, J ) 8.4 Hz, 1H), 4.71 (m, 1H), 5.29 (dd, J ) 13.9,
10.0 Hz, 1H), 5.70 (dd, J ) 14.6, 6.2 Hz, 1H), 5.83 (s, 1H), 5.83-
6.00 (m, 3H); 13C NMR (75 MHz, acetone-d6) δ 16.1, 17.2, 19.4,
22.9, 26.0, 27.2, 28.1, 35.8, 38.5, 41.9, 46.5, 48.1, 49.1, 55.1, 67.1,
71.4, 77.4, 81.3, 122.3, 128.9, 131.8, 133.0, 134.2, 134.9, 136.9,
144.4, 168.6, 174.4 (solvent peak overlapped one carbon peak, so
one carbon was not detected); IR (KBr) 3420, 2930, 2860, 1720,
1700, 1460 cm-1; HRMS calcd for C29H42O7 (M+) m/z 502.2930,
found 502.2930.
1
MeOH); H NMR (300 MHz) δ 0.83-1.00 (m, 2H), 1.04 (d, J )
6.2 Hz, 3H), 1.12 (s, 3H), 1.18 (d, J ) 6.8 Hz, 3H), 1.21 (d, J )
6.2 Hz, 3H), 1.32-1.51 (m, 2H), 1.60 (s, 3H), 1.61-1.88 (m, 7H),
1.63 (s, 3H), 1.93-2.20 (m, 2H), 2.32-2.45 (m, 1H), 2.35 (d, J )
10.2 Hz, 1H), 2.92 (m, 1H), 3.57 (d, J ) 9.0 Hz, 1H), 4.68 (m,
1H), 5.06 (m, 1H), 5.31 (dd, J ) 14.0, 10.2 Hz, 1H), 5.48 (dd, J
) 15.0, 6.4 Hz, 1H), 5.73 (s, 1H), 5.81-5.99 (m, 2H); 13C NMR
(68 MHz) δ 11.1, 15.5, 16.7, 18.7, 19.2, 22.6, 25.3, 26.3, 26.8,
33.3, 34.8, 38.1, 40.9, 45.6, 48.5, 54.3, 71.3, 79.6, 85.3, 120.5,
127.6, 129.2, 130.8, 133.3, 133.4, 135.5, 136.2, 174.3; IR (KBr)
3420, 2980, 2930, 2880, 1720, 1705, 1460 cm-1; HRMS calcd for
C29H44O4 (M+) m/z 456.3240, found 426.3234.
Acknowledgment. We thank Dr. Masayuki Igarashi (Insti-
tute of Microbial Chemistry) for providing us the samples and
spectral copies (1H and 13C NMR, IR) of 2-4. This work was
supported by Grants-in-Aid for Scientific Research on Priority
Areas (A) “Creation of Biologically Functional Molecules
(18032069)” and, in part, by Grants-in-Aid for the 21st Century
COE program “Keio LCC” from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
(+)-Tubelactomicin D (3). To a stirred solution of 52 (40.1 mg,
77.6 µmol) in MeOH (3 mL) was added 1 M aqueous NaOH (1.5
mL). The mixture was heated at 50 °C with stirring for 6.5 h. After
being cooled to 0 °C, the mixture was acidified with 1 M aqueous
HCl to pH 2. This was diluted with H2O (4 mL) and extracted
with CH2Cl2 (3 × 3 mL). The combined organic layers were dried
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/acetone, 2:1) to give 3 (36.0
Supporting Information Available: Experimental procedures
and full spectroscopic data for all new compounds described herein
mg, 92%) as a colorless oil: TLC, Rf 0.22 (CHCl3/MeOH, 10:1
1
and copies of H and 13C NMR spectra for all new compounds,
1
containing 1% AcOH); [R]24.5 +95.7 (c 0.14, CHCl3); H NMR
D
synthetic and natural tubelactomicins B, D, and E. This material is
available free of charge via the Internet at http://pubs.acs.org.
(300 MHz, acetone-d6) δ 1.03 (d, J ) 6.4 Hz, 3H), 1.12 (s, 3H),
1.15 (d, J ) 6.0 Hz, 3H), 1.21 (d, J ) 7.3 Hz, 3H), 1.27-1.33 (m,
3H), 1.34-1.71 (m, 3H), 1.60-1.78 (m, 4H), 1.84-1.88 (m, 1H),
JO0708442
6148 J. Org. Chem., Vol. 72, No. 16, 2007