Synthesis of the L-acid (C1-C18) fragment of pamamycin-593 and De-N-methylpamamycin-579

Article abstract of DOI:10.1002/ejoc.200800600

The L-acid (C1-C18) fragment of pamamycin-593 and de-N-methylpamamycin-579, strong aerial mycelium-inducers of Streptomyces alboniger, was synthesized using a cis-selective iodoetherification and a nucleophilic addition of a cerium acetylide to an aldehyde as the key steps. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800600

FULL PAPER
DOI: 10.1002/ejoc.200800600
Synthesis of the L-Acid (C1–C18) Fragment of Pamamycin-593 and
De-N-methylpamamycin-579
Ayako Miura,[a] Shin-ya Takigawa,[a] Yukito Furuya,[a] Yusuke Yokoo,[a]
Shigefumi Kuwahara,[a] and Hiromasa Kiyota*[a]
Keywords: Pamamycins / Antibiotics / Synthesis design / Iodoetherification / Cerium acetylide
The L-acid (C1–C18) fragment of pamamycin-593 and de-N-
methylpamamycin-579, strong aerial mycelium-inducers of
Streptomyces alboniger, was synthesized using a cis-selec-
tive iodoetherification and a nucleophilic addition of a ce-
rium acetylide to an aldehyde as the key steps.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
They used 5-endo-selenoetherification to construct the three
THF rings. The total syntheses of 1 and its relatives were
also achieved by Metz’s,[4b,4c] Lee’s,[4d] Kang’s,[4e] and Han-
quet’s[4f] groups using a sulfone-guided cyclization, radical
cyclization, iodoetherification, and hydrogenation, respec-
tively, for the key THF ring formation. Synthetic ap-
proaches to the L-acid (L = large) fragments were also re-
ported by Walkup’s,[5a] Perlmutter’s (oxymercuration),[5b]
Bloch’s (Michael cyclization),[5c] Solladié’s,[5d] Hanquet’s
(hydrogenation),[4f] Nagumo’s (phenonium ion cycliza-
tion),[5e] and our groups (iodoetherification).[6] Continuing
our synthetic work of pamamycins,[6,7] we began the synthe-
sis of these new compounds 2 and 3 for further biological
studies. Here we describe an efficient and convergent syn-
thesis of the L-acid fragment 4.
Introduction
Pamamycins are a series of unique nitrogen-containing
antibiotics isolated from Streptomyces sp.[1] Among them,
pamamycin-607 (1) (Figure 1), isolated from Streptomyces
alboniger, showed aerial mycelium-inducing activity in an
aerial mycelium-less mutant of S. alboniger.[1b,1c] Recently,
its new, low-molecular-weight derivatives, pamamycin-593
(2) and de-N-methylpamamycin 579 (3), showed stronger
activity.[1c,2] The total synthesis of 1 was achieved by several
groups.[3,4] The first was reported by Thomas’ group.[4a]
Results and Discussion
In the previous paper, we prepared the C1–C18 portion
of the L-acid (Scheme 1).[6] A Julia coupling of sulfone 6,
derived from 5, with chiral aldehyde 7 afforded olefin 8.
Cis-selective iodoetherification followed by deiodination
gave the C8–C18 fragment 9.[6] However, the yields were
low in the reductive desulfonylation and deiodination steps.
Thus, we planned the new strategy in which the C15 amino
group as to be introduced stereoselectively by the reductive
amination of the corresponding keto group according to
Lee’s procedure.[4d]
The key reaction in our new synthetic plan was also a
cis-selective iodoetherification to construct both the cis-
THF rings (Figure 1).[8] The whole carbon chain would be
formed by a nucleophilic addition of an acetylide to an al-
dehyde to connect C7 and C8.
As shown in Scheme 2, our synthesis of the L-acid 4 be-
gan with the known aldehyde 5, which was our common
Figure 1. Structures of the pamamycins and our synthetic plan.
[a] Graduate School of Agricultural Sciences, Tohoku University,
1-1 Tsutsumidori-Amamiya,
Aoba-ku, Sendai 981-8555, Japan
Fax: +81-22-717-8785
E-mail: kiyota@biochem.tohoku.ac.jp
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H. Kiyota et al.
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by an NOE experiment on 12Ј. Reductive amination of the
keto group of 12 using NaBH3CN simultaneously reduced
the iodo group to give amine 14.[4d] However, the α/β (R/S)
ratio of the amino group was about 4:1. The reaction with
the corresponding deiodo ketone 13’ gave 14’ as a 3:1 α/β
mixture. Lee reported that the reductive amination of a sim-
ilar keto group proceeded stereoselectively.[4d] These iso-
mers were inseparable even after conversion to their N-Boc
and N-Boc N-methyl derivatives 15 and 16, respectively. Ac-
cordingly, the amino group was introduced by a stepwise
sequence as shown in Scheme 3. Hydride reduction of
ketone 13 afforded 17 (27%) and 8-epi-17 (59%). The ste-
reochemistry was assigned by comparison with previously
reported data.[6,7b,9,11] All other hydride reagents tested gave
mainly α-hydroxy compounds.[11] On the other hand, re-
duction by samarium(II) iodide gave predominantly 17.[12]
Compound 17 was converted to azide 18 with inversion of
configuration and reduced to 15 as a single diastereomer.
As a preliminary study, the N-methyl derivative 16 (α/β =
4:1) was subjected to the coupling reaction. Aldehyde 19,
prepared from 16, was coupled with the lithium acetylide
of 10 in 60% yield. However, the resulting mixture of four
diastereomers were inseparable, and the next Lindlar re-
duction did not proceed. Thus, the amino group was intro-
duced at a later stage of the synthesis.
Scheme 1. Our previous synthesis of the C8–C18 fragment of the
L-acid.
starting material for the synthetic studies of polynactin and
the pamamycin series.[6,9] Treatment of 5 with the Ohira–
Bestmann reagent[10] afforded alkyne 10 (C1–C7 fragment)
in 91% yield. For the C8–C18 fragment, chain elongation
of 5 by a Horner–Emmons reaction gave exclusively the 11
E-olefinic ketone with a benzyl protecting group. The corre-
sponding TBS-protected compound was prepared in a sim-
ilar way. The key iodoetherification[8] proceeded at 0 °C to
give the cis-THF 12 in 95% yield. The use of IBr as a
stronger iodonium ion donor shortened the reaction time
but lowered the yield. The stereochemistry was confirmed
Scheme 3. Coupling reaction of acetylide 10 with aldehyde 19.
The hydroxy group of 17 was protected as a TBS ether
(9),[6] and hydrogenolysis of the benzyl group afforded 22.
Oxidation of the newly formed hydroxy group led to the
Scheme 2. Synthesis of the C1–C7 and C8–C18 fragments (re-
ductive amination).
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Synthesis of L-Acid (C1–C18) Fragment of Pamamycins
C8–C15 fragment, aldehyde 23. Nucleophilic addition of
the lithium acetylide derived from 10 to aldehyde 23 was
successful using cerium trichloride, giving 24 and 8-epi-24
in a ratio of about 2:1 (Scheme 4).[13] These isomers were
separated by SiO2 column chromatography. The yield was
only 55% (with the same diastereomeric ratio) using the
lithium acetylide. Partial reduction of the triple bond of 24
was successful, giving 25.
Scheme 5. Second iodoetherification to form bis-THF framework.
5 was 1.8% over 19 steps. We have already synthesized the
S-acid[6,7] fragment (S = small), and studies towards the to-
tal synthesis are under way.
Scheme 4. Coupling reaction of acetylide 10 with aldehyde 23.
The second cis-selective iodoetherification afforded bis-
THF compound 27 (Scheme 5). In this reaction, the unde-
sired C7,8-epoxide 28 was formed in 20% via the iodonium
cation intermediate 26. The iodohydrin 27 was converted
into the corresponding epoxide 29 to confirm the configu-
ration of the 8β-hydroxy group. The trans-epoxy configura-
tion was indicated by a vicinal coupling constant of 2.2 Hz
1
between H7 and H8 in the H NMR spectrum (ca. 5 Hz is
typical of cis-epoxides). The iodo group of 27 was removed
by Bu3SnH to give 30, and the stereochemistry of the iodo-
etherification was determined by observation of strong cor-
relation between H3 and H6 in the NOESY spectrum.
As shown in Scheme 6, the secondary hydroxy group of
30 was protected with the o-fluorobenzoyl group to give 31.
We chose this group because it is removable under mildly
alkaline conditions. At first, the m-nitrobenzoyl group was
used. However, the nitro group was not stable during the
later hydrogenolysis step (azide to amine). The TBS group
was removed (32), and the 15-hydroxy group was converted
to an azido group (33). The azido group was then reduced,
and the resulting amino group was simultaneously pro-
tected with the Boc group to form 34. Hydrogenolysis of
the benzyl group (35) and successive oxidations gave the L-
Scheme 6. Synthesis of the L-acid fragment of pamamycin-593 and
acid with N,O-protecting groups 4. The overall yield from de-N-methylpamamycin-579.
Eur. J. Org. Chem. 2008, 4955–4962
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FULL PAPER
(m, 2 H), 2.04–2.31 (m, 3 H), 2.48 (t, J = 7.3 Hz, 2 H, 3-H), 3.32
(dd, J = 9.4, 6.3 Hz, 1 H, 11-H), 3.37 (dd, J = 9.4, 6.6 Hz, 1 H,
11-H), 3.66 (dt, J = 6.3, 5.2 Hz, 1 H, 9-H), 4.45 (d, J = 12.3 Hz, 1
H, CHPh), 4.52 (d, J = 12.3 Hz, 1 H, CHPh), 6.08 (dt, J = 15.9,
1.7 Hz, 1 H, 5-H) 6.83 (dt, J = 15.9, 6.9 Hz, 1 H, 6-H), 7.26–7.37
(m, 5 H, Ph) ppm. 13C NMR (150 MHz, CDCl3): δ = 12.0, 13.8,
17.7, 28.6, 29.0, 29.3, 38.0, 41.9, 71.1, 73.0, 73.0, 73.5, 127.4, 128.3,
130.1, 138.6, 147.6, 200.9 ppm. HR-FABMS (NOBA): calcd. for
C23H37O3 [M + H]+ 361.2743; found 361.2749.
Conclusions
Synthesis of the L-acid (C1–C18) fragment of pamamy-
cin-593 and de-N-methylpamamycin-579, strong aerial my-
celium inducers of Streptomyces alboniger, was achieved
using cis-selective iodoetherification and nucleophilic ad-
dition of a cerium acetylide (C1–C7) to an aldehyde (C8–
C18) fragment as the key reaction.
(5S,6S,9R,10S)-11-Benzyloxy-6,9-epoxy-5-iodo-10-methylundecan-
4-one (12): After a suspension of I2 (4.8 g, 19 mmol) and NaHCO3
(3.1 g, 38 mmol) in dry MeCN (25 mL) was stirred at 0 °C for
15 min, a solution of 11 (1.4 g, 3.8 mmol) in dry MeCN (13 mL)
was added, and the mixture was stirred for 1 d. The reaction mix-
ture was poured into saturated aqueous Na2S2O3 solution at 0 °C
and extracted with EtOAc. The combined extracts were washed
with brine, dried with MgSO4, and concentrated en vacuo. The
residue was chromatographed on silica gel. Elution with hexane/
EtOAc (10:1) gave 12 (1.5 g, 3.6 mmol, 95%) as a pale yellow oil.
Rf = 0.45 (toluene/EtOAc = 19:1). [α]2D3 = –52 (c = 0.50, Et2O). FT-
Experimental Section
General: Optical rotation values were measured with a Horiba
Sepa-300 polarimeter. FT-IR spectra were recorded as films with a
Jasco 4100 spectrometer (ATR, Zn-Se). The IR spectrum was re-
1
corded as a film with a Jasco IR Report-100 spectrometer. H and
13C NMR spectra were recorded with Varian Inova 600 (600 MHz
for 1H and 150 MHz for 13C), Inova 500 (500 MHz for 1H and
125 MHz for 13C), and Gemini 2000 (300 MHz for 1H and 75 MHz
for 13C) spectrometers in CDCl3 with tetramethylsilane as an in-
ternal standard. Mass spectra were recorded with a Jeol JMS–700
spectrometer. Merck silica gel 60 (70–230 mesh) was used for col-
umn chromatography. Merck silica gel 60 F254 (0.50 mm thickness)
was used for preparative TLC.
IR: ν = 2962 (s), 2932 (s), 2873 (s), 1707 (m), 1454 (m), 1362 (m),
˜
1
1053 (s), 734 (m), 697 (m) cm–1. H NMR (300 MHz, CDCl3): δ =
0.92 (t, J = 7.4 Hz, 3 H, 1-H), 0.93 (d, J = 6.9 Hz, 3 H, 10-Me),
1.58–1.71 (m, 3 H), 1.82–1.97 (m, 3 H), 2.20 (m, 1 H), 2.66 (t, J =
7.1 Hz, 1 H, 3-H), 2.67 (t, J = 7.1 Hz, 1 H, 3-H), 3.32 (dd, J = 6.6,
9.1 Hz, 1 H, 11-H), 3.50 (dd, J = 4.7, 9.1 Hz, 1 H, 11-H), 3.84 (dt,
J = 5.7, 8.0 Hz, 1 H, 9-H), 4.27 (m, 1 H, 5-H), 4.47 (s, 2 H, CH2Ph),
7.28–7.34 (m, 5 H, Ph) ppm. 13C NMR (150 MHz, CDCl3): δ =
13.5, 13.6, 17.4, 28.3, 31.2, 35.8, 39.2, 40.4, 72.7, 73.0, 79.3, 83.1,
127.4, 127.4, 128.3, 138.7, 204.2 ppm. HR-FABMS (NOBA): calcd.
for C19H28IO3 [M + H]+ 431.1083; found 431.1082.
(2S,3R)-3-tert-Butoxy-1-benzyloxy-2-methylhept-6-yne (10): To a
solution of dimethyl 1-diazo-2-oxopropylphosphonate (0.79 g,
4.1 mmol) and aldehyde 5 (0.80 g, 2.7 mmol) in dry MeOH (11 mL)
was added K2CO3 (0.76 g, 5.5 mmol) at 0 °C, and the mixture was
stirred for 1 d while the temperature was gradually raised to room
temperature. The reaction mixture was poured into saturated aque-
ous NH4Cl solution and extracted with Et2O. The combined ex-
tracts were washed with brine, dried with MgSO4, and concentrated
en vacuo. The residue was chromatographed on silica gel. Elution
with hexane/EtOAc (10:1) gave alkyne 10 (0.72 g, 2.5 mmol, 91%)
as a pale yellow oil. Rf = 0.53 (hexane/EtOAc = 5:1). [α]2D4 = +28.1
(6S,9R,10S)-11-Benzyloxy-6,9-epoxy-10-methylundecan-4-one (13):
A solution of 12 (200 mg, 0.47 mmol), AIBN (15 mg, 0.093 mmol),
and Bu3SnH (270 mg, 0.93 mmol) in dry CH2Cl2 (4.5 mL) was
stirred at 0 °C for 2 h. Then KF (200 mg) was added, and the mix-
ture was filtered through a Celite pad. The filtrate was concentrated
en vacuo. The residue was chromatographed on silica gel. Elution
with hexane/EtOAc (10:1 to 5:1) gave 13 (120 mg, 0.40 mmol, 85%)
as a pale yellow oil. Rf = 0.40 (hexane/EtOAc = 4:1). [α]2D5 = –4.0
(c = 1.05, Et O). FT-IR: ν = 3306 (w), 2972 (s), 2858 (w), 1455
˜
2
(w), 1389 (w), 1362 (m), 1253 (w), 1190 (m), 1099 (m), 1068 (s),
1026 (w), 734 (m), 697 (m), 624 (m) cm–1. 1H NMR (300 MHz,
CDCl3): δ = 0.91 (d, J = 7.1 Hz, 3 H, 2-Me), 1.20 (s, 9 H, tBu),
1.54–1.61 (m, 2 H), 1.92 (t, J = 2.6 Hz, 1 H, 7-H), 2.06 (m, 1 H),
2.21 (m, 2 H), 3.30 (dd, J = 9.3, 6.3 Hz, 1 H, 1-H), 3.37 (dd, J =
9.3, 6.8 Hz, 1 H, 1-H), 3.75 (dt, J = 6.3, 4.7 Hz, 1 H, 3-H), 4.47
(d, J = 11.8 Hz, 1 H, CHPh), 4.51 (d, J = 11.8 Hz, 1 H, CHPh),
7.27–7.35 (m, 5 H, Ph) ppm. 13C NMR (150 MHz, CDCl3): δ =
11.8, 14.8, 29.0, 29.7, 38.1, 68.1, 70.4, 73.0, 73.2, 73.5, 85.0, 127.4,
127.4, 128.3, 138.7 ppm. HR-FABMAS (glycerol + MeOH) calcd.
for C19H29O2 [M + H]+ 289.2168; found 289.2169.
(c = 0.50, Et O). FT-IR: ν = 2961 (s), 2874 (s), 1710 (s), 1454 (m),
˜
2
1363 (m), 1199 (w), 1073 (s), 735 (m), 697 (m) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.90 (t, J = 7.4 Hz, 3 H, 1-H), 0.94 (d, J
= 6.9 Hz, 3 H, 10-Me), 1.45 (m, 1 H, 7-H), 1.55–1.64 (m, 4 H, 2-
H, 8-H), 1.84–1.95 (m, 2 H, 8-H, 10-H), 2.05 (m, 1 H, 7-H), 2.43
(dt, J = 1.5, 7.4 Hz, 2 H, 3-H), 2.64 (dd, J = 6.3, 15.4 Hz, 1 H, 5-
H), 2.72 (dd, J = 6.6, 15.4 Hz, 1 H, 5-H), 3.34 (dd, J = 7.4, 9.1 Hz,
1 H, 11-H), 3.57 (dd, J = 4.4, 9.1 Hz, 1 H, 11-H), 3.70 (q, J =
7.1 Hz, 1 H, 9-H), 4.20 (quint, J = 6.3 Hz, 1 H, 6-H), 4.50 (s, 2 H,
CH2Ph), 7.25–7.34 (m, 5 H, Ph) ppm. 13C NMR (150 MHz,
CDCl3): δ = 13.6, 13.7, 17.0, 28.4, 31.2, 39.0, 45.6, 49.1, 73.0, 73.1,
75.1, 81.0, 127.4, 127.5, 128.3, 138.8, 209.7 ppm. HR-FABMAS
(NOBA): calcd. for C19H29O3 [M + H]+ 305.2217; found 305.2121.
(5E,9R,10S)-11-(Benzyloxy)-9-tert-butoxy-10-methylundec-5-en-4-
one (11): To a suspension of LiBr (790 mg, 9.10 mmol) in dry THF
(25 mL) was added dimethyl 2-oxopentylphosphonate (1.77 g,
9.10 mmol), Et3N (0.70 mL, 5.00 mmol), and aldehyde 5 (1.3 g,
4.6 mmol) in dry THF (15 mL). After being stirred for 4 h at room
temperature, the reaction mixture was poured into saturated aque-
ous NH4Cl solution at 0 °C and extracted with Et2O. The com-
bined extracts were washed with brine, dried with MgSO4, and con-
centrated en vacuo. The residue was chromatographed on silica gel.
Elution with hexane/EtOAc (15:1) gave enone 11 (1.4 g, 3.8 mmol,
(4S,6S,9R,10S)-11-Benzyloxy-6,9-epoxy-10-methylundecan-4-ol
(17)
a) NaBH3 Reduction: A solution of 13 (100 mg, 0.33 mmol) and
NaBH4 (15 mg, 0.40 mmol) in MeOH (20 mL) was stirred at 0 °C
for 30 min. The mixture was poured into saturated aqueous NH4Cl
83%) as a pale yellow oil. Rf = 0.40 (hexane/EtOAc = 5:1). [α]2D4
+17.4 (c = 0.60, Et O). FT-IR: ν = 2968 (s), 2874 (m), 1696 (m),
=
˜
2
1671 (m), 1627 (m), 1455 (m), 1388 (m), 1362 (m), 1192 (m), 1063 solution and extracted with EtOAc. The extract was washed with
(m), 1017 (m), 973 (m), 723 (m), 697 (m) cm–1 1H NMR
water and brine, dried with MgSO4, and concentrated. en vacuo.
(300 MHz, CDCl3): δ = 0.90 (d, J = 6.9 Hz, 3 H, 10-Me), 0.93 (t, Chromatography afforded 17 (27 mg, 0.088 mmol, 27%) and 8-epi-
J = 7.4 Hz, 3 H, 1-H), 1.19 (s, 9 H, tBu), 1.45–1.53 (m, 2 H), 1.63 17 (63 mg, 0.21 mmol, 63%) as colorless oils.
.
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Synthesis of L-Acid (C1–C18) Fragment of Pamamycins
b) SmI2 Reduction: To a solution of 13 (29 mg, 0.095 mmol) in dry
MgSO4, and concentrated en vacuo. The residue was chromato-
MeOH (0.5 mL) was added SmI2 (0.1  in THF, 5.0 mL, graphed on silica gel. Elution with hexane/EtOAc (10:1) gave 15
0.50 mmol) at 45 °C, and the mixture was stirred for 4.5 h under
argon. The reaction mixture was poured into saturated aqueous
NH4Cl solution and extracted with Et2O. The combined extracts
were washed with brine, dried with MgSO4, and concentrated en
vacuo. The residue was chromatographed on silica gel. Elution with
hexane/EtOAc (5:1) gave 17 (17 mg, 0.055 mmol, 59%) and 8-epi-
17 (6.0 mg, 0.020 mmol, 21%) as pale yellow oils. 17: Rf = 0.20
(18 mg, 0.046 mmol, 77%) as a pale yellow oil, [α]2D3 = –36 (c =
0.10, Et O). FT-IR ν = 3357 (w), 2959 (s), 2931 (s), 2871 (s), 1711
˜
2
(s), 1499 (m), 1454 (m), 1364 (s), 1249 (m), 1169 (s), 1067 (s), 735
1
(m), 697 (m) cm–1. H NMR (300 MHz, CDCl3): δ = 0.90 (t, J =
6.9 Hz, 3 H, 11-H), 0.95 (d, J = 6.9 Hz, 3 H, 2-Me), 1.26–1.63 (m,
8 H), 1.42 (s, 9 H, tBu), 1.82–1.93 (m, 2 H), 2.02 (m, 1 H), 3.37
(dd, J = 7.4, 9.1 Hz, 1 H, 1-H), 3.37 (m, 1 H), 3.61 (dd, J = 4.4,
9.1 Hz, 1 H, 1-H), 3.65 (q, J = 7.4 Hz, 1 H), 3.86 (quint, J = 6.3 Hz,
1 H), 4.51 (s, 2 H, CH2Ph), 4.56 (br. d, J = 7.4 Hz, 1 H, NH),
7.28–7.34 (m, 5 H, Ph) ppm. 13C NMR (150 MHz, CDCl3): δ =
13.7, 14.0, 18.9, 28.4, 28.5, 31.4, 38.3, 39.0, 41.3, 49.0, 73.0, 73.2,
78.7, 81.0, 127.3, 127.5, 128.3, 138.8, 155.7 ppm. HR-FABMAS
(NOBA): calcd. for C24H40NO4 [M + H]+ 406.2957; found
(hexane/EtOAc = 4:1). [α]2D3 = –6.15 (c = 1.00, Et O). FT-IR: ν =
˜
2
3432 (br., m), 2958 (s), 2932 (s), 1870 (s), 1454 (m), 1364 (m), 1072
(s), 1027 (m), 734 (m), 697 (m) cm–1. 1H NMR (300 MHz, CDCl3):
δ = 0.927 (t, J = 7.1 Hz, 3 H, 1-H), 0.934 (d, J = 6.9 Hz, 3 H, 10-
Me), 1.29–1.79 (m, 8 H), 1.86–1.99 (m, 3 H), 3.38 (dd, J = 6.7,
9.1 Hz, 1 H, 11-H), 3.55 (dd, J = 4.8, 9.1 Hz, 1 H, 11-H), 3.72 (dt,
J = 6.3, 7.4 Hz, 1 H, 4-H), 3.84 (m, 1 H, 9-H), 4.12 (q, J = 7.1 Hz, 406.2961.
1 H, 6-H), 4.50 (s, 2 H, CH2Ph), 7.23–7.34 (m, 5 H, Ph) ppm. 13C
(4S,6S,9R,10S)-11-Benzyloxy-4-tert-butyldimethylsilyloxy-6,9-ep-
NMR (150 MHz, CDCl3): δ = 13.7, 14.2, 19.0, 28.7, 30.6, 38.9,
39.4, 40.8, 68.9, 73.0, 73.1, 76.9, 81.4, 127.4, 127.5, 128.3, 138.7
ppm. HR-FABMS (NOBA): calcd. for C19H31O3 [M + H]+
307.2273; found 307.2271. HR-EIMS: calcd. for C19H30O3 [M]+
306.2195; found 306.2197. 8-Epi-17: Rf = 0.29 (hexane/EtOAc =
oxyundecane (9): A solution of 17 (15 mg, 0.048 mmol), 2,6-lutidine
(0.022 mL, 0.19 mmol), and TBSOTf (0.022 mL, 0.095 mmol) in
dry CH2Cl2 (1.0 mL) was stirred at 0 °C for 12 h, while the tem-
perature was gradually raised to room temperature. The reaction
mixture was then poured into brine and extracted with EtOAc. The
combined extracts were washed with brine, dried with MgSO4, and
concentrated en vacuo. The residue was chromatographed on silica
gel. Elution with hexane/EtOAc (10:1) gave 9 (20 mg, 0.048 mmol,
quant) as a pale yellow oil. Rf = 0.66 (hexane/EtOAc = 4:1). [α]2D4
4:1). IR: ν = 3500 (br., m), 2950 (s), 1450 (s), 1360 (s), 1280 (s)
˜
1
cm–1. H NMR (300 MHz, CDCl3): δ = 0.925 (t, J = 7.1 Hz, 3 H,
1-H), 0.93 (d, J = 6.9 Hz, 3 H, 10-Me), 1.30–1.73 (m, 8 H), 1.82–
2.06 (m, 3 H), 3.38 (dd, J = 6.7, 9.1 Hz, 1 H, 11-H), 3.53 (dd, J =
4.7, 9.1 Hz, 1 H, 11-H), 3.72 (q, J = 6.3 Hz, 1 H, 4-H), 3.84 (br. s,
1 H, OH), 4.01 (ddt, J = 7.1, 3.0, 6.8 Hz, 1 H, 6-H), 4.50 (s, 2 H,
CH2Ph), 7.23–7.34 (m, 5 H, Ph) ppm. HR-EIMS: calcd. for
C19H30O3 [M]+ 306.2195; found 306.2196.
= +8.9 (c = 1.2, CHCl3).[6] FT-IR: ν = 2955 (s), 2930 (s), 2855 (m),
˜
1461 (w), 1376 (w), 1252 (w), 1066 (m), 1005 (w), 944 (w), 834 (m),
808 (w), 773 (m), 732 (w), 696 (w) cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 0.037 (s, 3 H, SiMe), 0.043 (s, 3 H, SiMe), 0.88 (s, 9
H, tBu), 0.90 (t, J = 7.1 Hz, 3 H, 11-H), 0.95 (d, J = 6.9 Hz, 3 H,
2-Me), 1.25–1.58 (m, 8 H), 1.82–1.98 (m, 3 H), 3.34 (dd, J = 7.4,
9.1 Hz, 1 H, 1-H), 3.59 (pseudo q, J = 8.0 Hz, 1 H), 3.64 (dd, J =
4.4, 9.1 Hz, 1 H, 1-H), 3.80–3.90 (m, 2 H), 4.50 (s, 2 H, CH2Ph),
7.25–7.36 (m, 5 H, Ph) ppm. 13C NMR (125 MHz, CDCl3): δ =
13.8, 14.4, 18.1, 18.2, 25.7, 26.0, 28.9, 31.5, 40.5, 43.5, 69.7, 73.0,
73.4, 75.7, 80.6, 127.4, 127.5, 128.3, 138.9 ppm. HR-FABMS
(NOBA + NaCl): calcd. for C25H44O3SiNa [M + Na]+ 443.2957;
found 443.2959.
(2S,3R,6S,8R)-8-Azido-1-benzyloxy-3,6-epoxyundecane (18): To a
solution of 17 (23 mg, 0.073 mmol) and Et3N (0.050 mL,
0.37 mmol) in dry CH2Cl2 (0.5 mL) was added MsCl (0.030 mL,
0.37 mmol). After being stirred for 30 min, the reaction mixture
was diluted with CH2Cl2, washed with saturated aqueous NaHCO3
solution and brine, dried with Na2SO4, and concentrated en vacuo.
The residue was used in the next step without further purification.
A mixture of the crude mesylate and NaN3 (24 mg, 0.37 mmol) in
DMF (4.0 mL) was stirred for 2 d at 50 °C. The reaction mixture
was poured into saturated aqueous NaHCO3 solution and ex-
tracted with EtOAc. The combined extracts were washed with
brine, dried with MgSO4, and concentrated. en vacuo. The residue
was chromatographed on silica gel. Elution with hexane/EtOAc
(10:1) gave 18 (24.5 mg, 0.074 mmol, quant.) as a pale yellow oil.
[α]2D6 = –11 (c = 0.30, Et2O). Rf = 0.73 (toluene/EtOAc = 5:1). FT-
(2S,3R,6S,8S)-8-tert-Butyldimethylsilyloxy-3,6-epoxy-2-methylun-
decan-1-ol (22): A suspension of 9 (50 mg, 0.12 mmol) and 10%
Pd/C (25 mg) in dry MeOH (8 mL) was stirred for 15 min under
hydrogen (1 atm). The reaction mixture was filtered, and the filtrate
was concentrated en vacuo. The residue was chromatographed on
silica gel. Elution with hexane/EtOAc (10:1) gave alcohol 22
(36 mg, 0.11 mmol, 0.067 mmol, 92%) as a pale yellow oil. Rf =
0.43 (hexane/EtOAc = 4:1). [α]2D4 = +44.9 (c = 1.05, Et2O). FT-IR:
IR: ν = 2960 (m), 2933 (m), 2872 (m), 2098 (s), 1415 (w), 1254 (w),
˜
1
1094 (m), 1070 (m), 734 (m), 697 (m) cm–1. H NMR (300 MHz,
CDCl3): δ = 0.93 (t, J = 6.9 Hz, 3 H, 11-Me), 0.95 (d, J = 6.9 Hz,
3 H, 2-Me), 1.37–1.65 (m, 8 H), 1.79–2.05 (m, 3 H), 3.32–3.40 (m,
2 H), 3.60 (dd, J = 4.4, 9.1 Hz, 1 H), 3.72 (q, J = 7.4 Hz, 1 H),
3.92 (quint, J = 6.9 Hz, 1 H), 4.51 (s, 2 H, CH2Ph), 7.25–7.34 (m,
5 H, Ph) ppm. HR-FABMS (NOBA): calcd. for C19H30N3O2 [M
+ H]+ 332.2338; found 332.2341.
ν = 3461 (w), 2956 (s), 2930 (s), 2856 (m), 1462 (w), 1377 (w), 1253
˜
1
(w), 1039 (m), 939 (w), 834 (m), 807 (w), 773 (m) cm–1. H NMR
(300 MHz, CDCl3): δ = 0.04 (s, 3 H, SiMe2), 0.82 (d, J = 6.9 Hz,
3 H, 11-H), 0.89 (s, 9 H, tBu), 0.86–0.92 (m, 3 H), 1.27–1.63 (m, 9
H), 1.72 (m, 1 H), 1.88–2.07 (m, 2 H), 3.52–3.63 (m, 4 H), 3.80 (m,
1 H), 3.97 (pseudo quint, J = 7.4 Hz, 1 H). 13C NMR (150 MHz,
CDCl3): δ = 13.7, 14.3, 18.0, 18.1, 25.9, 30.6, 30.8, 40.6, 41.0, 43.2,
68.8, 69.5, 76.6, 85.8 ppm. HR-FABMS (NOBA): calcd. for
C18H39O3Si [M + H]+ 331.2667; found 331.2669.
(2S,3R,6S,8R)-1-Benzyloxy-8-tert-butoxycarbonylamino-3,6-epoxy-
undecane (15): A suspension of 18 (20 mg, 0.060 mmol) and Pd/
BaSO4 (30 mg) in dry MeOH (1.0 mL) was stirred for 10 h under
hydrogen (1 atm). The reaction mixture was filtered, and the filtrate
was concentrated en vacuo. The residue was used in the next step
without further purification. A solution of the crude amine, Et3N
(2R,3R,6S,8S)-8-tert-Butyldimethylsilyloxy-3,6-epoxy-2-methylun-
decanal (23): A suspension of 22 (22 mg, 0.060 mmol), Dess–Mar-
(0.025 mL, 0.18 mmol), and Boc2O (52 mg, 0.24 mmol) in CH2Cl2 tin periodinane (40 mg, 0.094 mmol), and NaHCO3 (20 mg,
(2.0 mL) was stirred at 20 °C for 1 d. The reaction mixture was 0.24 mmol) in dry Et2O (2.5 mL) was stirred at 0 °C for 30 min.
poured into saturated aqueous NH4Cl solution and extracted with
EtOAc. The combined extracts were washed with brine, dried with
The reaction mixture was poured into saturated aqueous NaHCO3
solution and extracted with Et2O. The combined extracts were
Eur. J. Org. Chem. 2008, 4955–4962
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4959

H. Kiyota et al.
FULL PAPER
washed with saturated aqueous NaHCO3 solution and brine, dried
with MgSO4, and concentrated en vacuo. The residue was chro-
matographed on silica gel. Elution with hexane/EtOAc (20:1) gave
aldehyde 23 (17 mg, 0.053 mmol, 88%) as a pale yellow oil. Rf =
1 H), 3.72–3.84 (m, 2 H), 3.92–4.01 (m, 2 H), 4.44–4.53 (m, 3 H),
5.49–5.52 (m, 2 H), 7.28–7.38 (m, 5 H, Ph) ppm. 13C NMR
(150 MHz, CDCl3): δ = –4.7, –4.3, 12.3, 13.6, 14.1, 14.4, 18.0, 18.1,
22.7, 24.7, 24.1, 25.9, 29.0, 30.6, 31.0, 31.2, 31.6, 38.2, 40.6, 43.3,
44.2, 69.5, 71.0, 71.5, 73.0, 73.3, 73.4, 76.6, 82.2, 127.4, 127.5,
0.43 (hexane/EtOAc = 4:1). FT-IR (film): ν = 2950 (s), 2700 (m,
˜
1
H–CO), 1725 (s, C=O), 1460 (s), 1370 (s), 1250 (s) cm–1. H NMR 128.3, 129.6, 132.1, 138.7 ppm. HR-FABMS (NOBA): calcd. for
(300 MHz, CDCl3): δ = 0.037 (s, 3 H, SiMe), 0.043 (s, 3 H, SiMe),
0.88 (s, 9 H, tBu), 0.89 (t, J = 7.4 Hz, 3 H, 11-H), 1.06 (d, J =
7.1 Hz, 3 H, 2-Me), 1.23–1.66 (m, 8 H), 1.92–2.07 (m, 2 H), 2.43
(pseudo quint, J = 7.1 Hz, 1 H), 3.80–3.98 (m, 3 H), 9.77 (d, J =
2.5 Hz, 1 H, 1-H) ppm. HR-FABMS (glycerol): calcd. for
C18H37O3Si [M + H]+ 329.2512; found 329.2514.
C37H67O5Si [M + H]+ 619.4758; found 619.4761.
(2S,3R,6S,7S,8S,9R,10R,13S,15S)-1-Benzyloxy-15-tert-butyldimeth-
ylsilyloxy-3,6:10,13-diepoxy-7-iodo-2,9-dimethyloctadecan-8-ol (27):
To a suspension of I2 (57 mg, 0.23 mmol) and NaHCO3 (38 mg,
0.45 mmol) in dry MeCN (1.0 mL) was added 26 (28 mg,
0.045 mmol) in dry MeCN (1.0 mL) at 0 °C, and the mixture was
stirred for 20 min at 0 °C. Then the reaction mixture was poured
into saturated aqueous Na2S2O3 solution and extracted with Et2O.
The combined extracts were washed with brine, dried with MgSO4,
and concentrated en vacuo. The residue was chromatographed on
silica gel. Elution with hexane/EtOAc (10:1) gave 27 (22 mg,
0.032 mmol, 72%) as a pale yellow oil. Rf = 0.29 (hexane/EtOAc
(2S,3R,8S,9S,10R,13S,15S)-1-Benzyloxy-3-tert-butoxy-15-tert-bu-
tyldimethylsilyloxy-10,13-epoxy-2,9-dimethyloctadec-6-yn-8-ol (24):
To a solution of alkyne 10 (260 mg, 0.90 mmol) in dry THF
(5.0 mL) was added BuLi (1.6  in hexane, 0.53 mL) at –70 °C, and
the mixture was stirred for 1 h at –78 °C under argon. This mixture
was then added to a suspension of dry CeCl3 (240 mg, 0.91 mmol)
in dry THF (2.0 mL), and the mixture was stirred for an additional
1 h at –78 °C. To this mixture was added aldehyde 23 (110 mg,
0.33 mmol) in dry THF (3.0 mL), and the mixture was stirred for
6 h. The reaction mixture was poured into saturated aqueous
NH4Cl solution and extracted with Et2O. The combined extracts
were washed with brine, dried with MgSO4, and concentrated en
vacuo. The residue was chromatographed on silica gel. Elution with
hexane/EtOAc (15:1) gave 24 (134 mg, 0.217 mmol, 65%) and 8-
epi-24 (66 mg, 0.107 mmol, 32%) as pale yellow oils. 24: Rf = 0.31
= 5:1). [α]2D3 = +26 (c = 0.35, Et O). FT-IR: ν = 3411 (w), 2956 (s),
˜
2
2928 (s), 2855 (s), 1461 (m), 1377 (w), 1254 (m), 1066 (m), 952 (w),
835 (m), 807 (w), 774 (m), 733 (w) and 697 (w) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 0.05 (s, 6 H, SiMe2), 0.86–0.91 (m, 3 H),
0.88 (s, 9 H, tBu), 0.96 (d, J = 6.9 Hz, 3 H), 0.99 (d, J = 6.9 Hz, 3
H), 1.26–1.59 (m, 8 H), 1.64–2.18 (m, 8 H), 3.41 (dd, J = 6.9,
9.3 Hz, 1 H), 3.61 (dd, J = 4.9, 9.3 Hz, 1 H), 3.71–3.93 (m, 6 H),
4.21 (pseudo dt, J = 8.8, 3.3 Hz, 1 H), 4.38 (pseudo dd, J = 8.8,
2.2 Hz, 1 H), 4.51 (s, 2 H,CH2 Ph), 7.28–7.35 (m, 5 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = –4.8, –4.5, 10.9, 13.6, 14.3, 17.9, 18.0,
25.8, 28.0, 29.0, 31.3, 31.9, 38.2, 40.5, 41.6, 43.2, 44.5, 69.6, 73.0,
73.1, 73.8, 76.1, 77.6, 81.8, 82.6, 127.4, 127.6, 128.4 ppm. HR-
FABMS (NOBA + NaCl): calcd. for C33H57O5SiNaI [M + Na]+
711.2918; found 711.2917.
(hexane/Et2O = 3:1). [α]2D4 = +38 (c = 0.20, Et O). FT-IR: ν = 3488
˜
2
(w), 2958 (s), 2360 (s), 2337 (m), 1461 (w), 1363 (w), 1254 (w), 1193
(w), 1069 (m), 835 (m), 775 (w), 698 (w) cm–1. 1H NMR (300 MHz,
CDCl3): δ = 0.062 (s, 3 H, SiMe), 0.078 (s, 3 H, SiMe), 0.88 (s, 9
H, tBu), 0.86–0.92 (m, 9 H), 1.20 (s, 9 H), 1.26–1.63 (m, 10 H),
1.81 (m, 1 H), 1.91–2.00 (m, 2 H), 2.08 (m, 1 H), 2.17–2.39 (m, 2
H), 3.29 (dd, J = 6.6, 9.1 Hz, 1 H, 1-H), 3.39 (dd, J = 6.6, 9.1 Hz,
1 H, 1-H), 3.68–3.70 (m, 2 H), 3.75–3.83 (m, 2 H), 3.91–4.04 (m,
2 H), 4.34 (s, 2 H), 4.49 (s, 2 H), 7.29–7.35 (m, 5 H, Ph) ppm. 13C
NMR (150 MHz, CDCl3): δ = –4.6, –4.4, 12.0, 13.8, 14.3, 15.3,
18.0, 18.1, 26.0, 29.0, 30.2, 30.4, 30.7, 38.1, 40.5, 43.3, 43.9, 67.6,
69.5, 70.7, 73.0, 73.2, 73.4, 79.0, 82.1, 86.4, 127.4, 127.4, 128.3,
138.7 ppm. HR-FABMS (NOBA + NaCl): calcd. for C37H64O5S-
iNa [M + Na]+ 639.4421; found 639.4423. 8-epi-24: Rf = 0.23 (hex-
(2S,3R,6S,7S,8R,9R,10R,13S,15S)-1-Benzyloxy-15-tert-butyldimeth-
ylsilyloxy-3,6:7,8:10,13-triepoxy-2,9-dimethyloctadecane (29): A
suspension of 27 (6.1 mg, 0.0087 mmol) and K2CO3 (12 mg,
0.087 mmol) in dry MeOH (0.6 mL) was stirred at 20 °C for 2 h,
and the reaction mixture was poured into water and extracted with
EtOAc. The combined extracts were washed with brine, dried with
MgSO4, and concentrated en vacuo. The residue was chromato-
graphed on silica gel. Elution with hexane/EtOAc (10:1) gave 29
(3.5 mg, 0.0062 mmol, 72%) as a pale yellow oil. Rf = 0.31 (hexane/
EtOAc = 5:1). 1H NMR (300 MHz, CDCl3): δ = 0.04 (s, 6 H,
SiMe), 0.87–0.91 (m, 3 H), 0.88 (s, 9 H, tBu), 0.96 (d, J = 6.6 Hz,
3 H), 0.98 (d, J = 6.0 Hz, 3 H), 1.26–1.36 (m, 4 H), 1.39 (m, 4 H),
1.52–1.64 (m, 4 H), 1.80–1.98 (m, 4 H), 2.77 (dd, J = 2.2, 7.1 Hz,
1 H), 2.91 (dd, J = 2.2, 3.6 Hz, 1 H), 3.39 (dd, J = 7.1, 9.1 Hz, 1
H), 3.47 (dd, J = 4.4, 9.1 Hz, 1 H), 3.67 (m, 1 H), 3.72–3.91 (m, 3
H), 3.97 (m, 1 H), 4.51 (s, 2 H), 7.28–7.34 (m, 5 H, Ph) ppm. 13C
NMR (150 MHz, CDCl3): δ = –4.6, –4.4, 13.2, 13.5, 14.4, 18.1,
18.1, 25.9, 26.8, 28.6, 29.0, 31.5, 38.8, 40.5, 41.1, 43.4, 59.1, 56.0,
69.7, 73.0, 73.2, 75.9, 77.8, 80.9, 81.4, 127.4, 127.5, 128.3, 138.8
ppm. HR-FABMS (NOBA): calcd. for C33H57O5Si [M + H]+
561.3975; found 561.3981.
ane/Et O = 3:1). FT-IR: ν = 3438 (w), 2957 (s), 2360 (s), 2339 (m),
˜
2
1456 (m), 1362 (m), 1253 (m), 1193 (m), 1066 (s), 835 (m), 775 (w),
697 (w) cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.05 (s, 6 H), 0.88
(s, 9 H), 0.86–0.94 (m, 9 H), 1.19 (s, 9 H), 1.26–1.72 (m, 10 H),
1.87–2.12 (m, 3 H), 2.17–2.38 (m, 2 H), 3.28 (dd, J = 6.6, 9.3 Hz,
1 H, 1-H), 3.38 (dd, J = 6.9, 9.3 Hz, 1 H, 1-H), 3.60 (m, 1 H),
3.670 (m, 1 H), 3.79 (m, 1 H), 3.99 (m, 1 H), 4.19 (s, 1 H), 4.39 (d,
J = 8.2 Hz, 1 H), 4.48 (s, 2 H), 7.29–7.35 (m, 5 H, Ph) ppm.
(2S,3R,6Z,8S,9S,10R,13S,15S)-1-Benzyloxy-3-tert-butoxy-15-tert-
butyldimethylsilyloxy-10,13-epoxy-2,9-dimethyloctadec-6-en-8-ol
(25): A suspension of 24 (25 mg, 0.040 mmol) and Lindlar catalyst
(42 mg) in dry MeOH (0.5 mL) was stirred for 15 min under hydro-
gen (1 atm). The reaction mixture was filtered, and the filtrate was
concentrated en vacuo. The residue was chromatographed on silica
gel. Elution with toluene/EtOAc (20:1) gave 25 (24 mg,
0.039 mmol, 98%) as a pale yellow oil. Rf = 0.34 (hexane/EtOAc
(2S,3R,6S,8R,9S,10R,13S,15S)-1-Benzyloxy-15-tert-butyldimethyl-
silyloxy-3,6:10,13-diepoxy-2,9-dimethyloctadecan-8-ol (30): A solu-
tion of 27 (70 mg, 0.10 mmol), AIBN (8.3 mg, 0.051 mmol), and
Bu3SnH (0.054 mL, 0.20 mmol) in dry CH2Cl2 (1.2 mL) was stirred
= 5:1). [α]2D3 = +34 (c = 0.50, Et O). FT-IR: ν = 3516 (w), 2958 (s),
˜
2
2934 (s), 2856 (m), 1461 (w), 1362 (w), 1253 (w), 1194 (w), 1071 at 0 °C. for 2 h. KF (70 mg) was then added, and the mixture was
1
(m), 946 (w), 835 (m), 774 (m), 734 (w), 697 (w) cm–1. H NMR extracted with Et2O. The combined extracts were washed with
(300 MHz, CDCl3): δ = 0.89 (s, 9 H), 0.81–0.92 (m, 9 H), 1.19 (s, brine, dried with MgSO4, and concentrated en vacuo. The residue
9 H), 1.26–1.63 (m, 12 H), 1.80–2.16 (m, 4 H), 3.30 (dd, J = 6.6, was chromatographed on silica gel. Elution with hexane/EtOAc
9.1 Hz, 1 H), 3.39 (dd, J = 6.3, 9.1 Hz, 1 H), 3.61 (q, J = 5.5 Hz,
(10:1) gave 30 (49 mg, 0.083 mmol, 82%) as a pale yellow oil. Rf =
4960
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4955–4962

Synthesis of L-Acid (C1–C18) Fragment of Pamamycins
0.43 (hexane/EtOAc = 3:1). [α]2D2 = +25 (c = 0.45, Et O). FT-IR: ν
(t, J = 7.8 Hz, 1 H) ppm. HR-FABMS (NOBA): calcd. for
˜
2
= 3502 (w), 2956 (s), 2932 (s), 2855 (m), 1460 (w), 1375 (w), 1252
(w), 1065 (m), 943 (w), 835 (m), 808 (w), 774 (m), 733 (w), 697 (w)
C34H48FO6 [M + H]+ 571.3435; found 571.3442.
(2S,3R,6S,7S,8R,9R,10R,13S,15R)-15-Azido-1-benzyloxy-
3,6:10,13-diepoxy-2,9-dimethyloctadecan-8-yl o-Fluorobenzoate
(33): To a solution of 32 (11 mg, 0.018 mmol) and Et3N (0.051 mL,
0.37 mmol) in dry CH2Cl2 (2 mL) at 0 °C was added MsCl
(0.014 mL, 0.18 mmol), and the mixture was stirred for 13 h. The
mixture was then diluted with CH2Cl2, washed with saturated
aqueous NaHCO3 solution and brine, dried with Na2SO4, and con-
centrated en vacuo. The residual crude mesylate was used in the
next step without further purification. A solution of the crude mes-
ylate and NaN3 (15 mg, 0.23 mmol) in DMF (2 mL) was stirred at
50 °C for 2 d. The reaction mixture was then quenched with satu-
rated aqueous NaHCO3 solution and extracted with EtOAc. The
combined extracts were washed with brine, dried with MgSO4, and
concentrated en vacuo. The residue was chromatographed on silica
gel. Elution with hexane/EtOAc (10:1) gave 33 (11 mg, 0.018 mmol,
1
cm–1. H NMR (600 MHz, CDCl3): δ = 0.05 (s, 6 H, SiMe), 0.87
(d, J = 8.4 Hz, 3 H, 9-Me), 0.88 (t, J = 7.2 Hz, 3 H, 18-H), 0.88
(s, 9 H, tBu), 0.95 (d, J = 6.6 Hz, 3 H), 1.26–1.34 (m, 3 H, 17-H),
1.42 (m, 2 H, 16-H), 1.47 (m, 1 H), 1.52–1.70 (m, 8 H, 14-H), 1.73
(m, 1 H), 1.89 (m, 1 H, 2-H), 1.91–2.02 (m, 2 H), 3.34 (dd, J = 7.7,
9.1 Hz, 1 H, 1-H), 3.50 (br. s, OH), 3.62 (dd, J = 4.4, 9.1 Hz, 1 H,
1-H), 3.71 (q, J = 7.8 Hz, 1 H, 3-H), 3.73 (dd, J = 8.4, 6.6 Hz, 1
H, 10-H), 3.80 (quint, J = 6.3 Hz, 1 H, 15-H), 3.91 (m, 1 H, 8-H),
3.92 (m, 1 H, 13-H), 4.06 (dq, J = 8.4, 6.6 Hz, 1 H, 6-H), 4.50 (s,
2 H, CH2Ph), 7.27–7.34 (m, 5 H, Ph) ppm. 13C NMR (150 MHz,
CDCl3): δ = –4.7, –4.4, 13.0, 13.7, 14.4, 18.0, 18.1, 25.9, 28.7, 30.1,
31.2, 31.5, 39.1, 39.2, 40.6, 43.1, 43.3, 69.5, 71.3, 73.0, 73.3, 76.3,
76.9, 80.7, 82.5, 127.4, 127.5, 128.3, 138.9 ppm. HR-FABMS
(NOBA): calcd. for C33H59O5Si [M + H]+ 563.4132; found
563.4133.
99%) as a pale yellow oil. Rf = 0.54 (hexane/EtOAc = 3:1). [α]2D1
=
–4.4 (c = 0.64, Et O). FT-IR: ν = 2962 (m), 2872 (m), 2359 (s),
˜
2
(2S,3R,6S,7S,8R,9R,10R,13S,15S)-1-Benzyloxy-15-tert-butyldimeth-
ylsilyloxy-3,6:10,13-diepoxy-2,9-dimethyloctadecan-8-yl o-Fluoro-
benzoate (31): To a solution of 30 (7.5 mg, 0.013 mmol), o-fluoro-
benzoic acid (18 mg, 0.13 mmol), and DMAP (15 mg, 0.13 mmol)
in dry CH2Cl2 (1 mL) was added DCC (52 mg, 0.25 mmol) at 0 °C,
and the mixture was stirred at room temperature for 8 h. The reac-
tion mixture was filtered, and the filtrate was washed with saturated
aqueous NH4Cl solution, saturated aqueous NaHCO3 solution,
and brine, dried with MgSO4, and concentrated en vacuo. The resi-
due was chromatographed on silica gel. Elution with hexane/EtOAc
(10:1) gave 31 (8.0 mg, 0.012 mmol, 92%) as a pale yellow oil. Rf
= 0.51 (hexane/EtOAc = 4:1). [α]2D5 = +10 (c = 0.57, Et2O). FT-IR:
2101 (s), 1717 (m), 1613 (w), 1488 (w), 1455 (w), 1298 (m), 1250
(w), 1078 (w) and 758 (w) cm–1. 1H NMR (300 MHz, CDCl3): δ =
0.91 (t, J = 6.9 Hz, 3 H, 18-H), 0.94 (d, J = 6.9 Hz, 3 H), 1.01 (d,
J = 7.1 Hz, 3 H), 1.34–1.61 (m, 12 H), 1.76–2.02 (m, 6 H), 3.37
(dd, J = 7.4, 9.1 Hz, 2 H, 1 H), 3.38 (m, 1 H), 3.60 (dd, J = 4.4,
9.1 Hz, 1 H), 3.63–3.76 (m, 2 H), 3.82–3.94 (m, 2 H), 4.50 (s, 2 H,
CH2Ph), 5.53 (dt, J = 2.7, 6.8 Hz, 1 H, 8-H), 7.13 (m, 1 H), 7.19
(m, 1 H), 7.33 (d, J = 4.4 Hz, 1 H), 7.47–7.54 (m, 5 H), 7.94 (m, 1
H) ppm. HR-FABMS (NOBA): calcd. for C34H47FN3O5 [M +
H]+ 596.3500; found 596.3496.
(2S,3R,6S,7S,8R,9R,10R,13S,15R)-1-Benzyloxy-15-tert-butoxycar-
bonylamino-3,6:10,13-diepoxy-2,9-dimethyloctadecan-8-yl o-Fluoro-
benzoate (34): A suspension of 33 (13 mg, 0.021 mmol), 10% Pd/C
(22 mg), and Boc2O (9.1 mg, 0.042 mmol) in dry MeOH (1.0 mL)
was stirred for 2 h under hydrogen (1 atm). The reaction mixture
was filtered, and the filtrate was concentrated en vacuo. The residue
was chromatographed on silica gel. Elution with hexane/EtOAc
(5:1) gave 34 (14 mg, 0.021 mmol, 98%) as a pale yellow oil. Rf =
ν = 2956 (s), 2931 (s), 2855 (s), 1715 (s), 1613 (m), 1456 (m), 1299
˜
(s), 1249 (s), 1127 (m), 1076 (s), 836 (m), 775 (m), 757 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.05 (s, 6 H, SiMe), 0.87 (s, 9 H,
tBu), 0.91 (t, J = 7.1 Hz, 3 H), 0.97 (d, J = 6.9 Hz, 3 H), 1.04 (d,
J = 6.9 Hz, 3 H), 1.29–1.66 (m, 12 H), 1.84–2.00 (m, 6 H), 3.38
(dd, J = 7.4, 9.3 Hz, 1 H), 3.63 (dd, J = 4.7, 6.9 Hz, 1 H), 3.67–
3.74 (m, 2 H), 3.81–3.95 (m, 3 H), 4.53 (s, 2 H, CH2Ph), 5.54 (m,
1 H, 8-H), 7.12–7.25 (m, 6 H), 7.37 (d, J = 4.4 Hz, 1 H), 7.54 (m,
1 H), 7.97 (dt, J = 1.9, 7.7 Hz, 1 H) ppm. HR-EIMS: calcd. for
C40H61FO6Si [M]+ 684.4221; found 684.4222.
0.37 (hexane/EtOAc = 3:1). [α]2D7 = –4.7 (c = 0.36, Et O). FT-IR: ν
˜
2
= 3388 (w), 2963 (m), 2872 (m), 1709 (s), 1613 (m), 1488 (w), 1455
(w), 1364 (m), 1298 (m), 1249 (m), 1078 (m), 805 (m), 757 (m), 697
1
(m) cm–1. H NMR (500 MHz, CDCl3): δ = 0.89 (t, J = 7.3 Hz, 3
(2S,3R,6S,7S,8R,9R,10R,13S,15S)-1-Benzyloxy-3,6:10,13-diepoxy-
15-hydroxy-2,9-dimethyloctadecan-8-yl o-Fluorobenzoate (32): A
15 mL Falcon tube equipped with a magnetic stir bar was charged
with 31 (8.0 mg, 0.013 mmol) in dry MeCN (1 mL). To the solution
was added HF (40 % aqueous HF/MeCN = 1:19, 0.050 mL) at
0 °C, and the mixture was stirred at room temperature for 15 h.
Then the reaction mixture was quenched with saturated aqueous
NaHCO3 solution and extracted with EtOAc. The combined ex-
tracts were washed with brine, dried with MgSO4, and concentrated
en vacuo. The residue was chromatographed on silica gel. Elution
H, 18-H), 0.93 (d, J = 6.3 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.25–
1.62 (m, 10 H), 1.41 (s, 9 H, tBu), 1.81–2.05 (m, 8 H), 3.34 (dd, J
= 7.3, 8.7 Hz, 1 H), 3.56 (m, 1 H), 3.60 (dd, J = 4.4, 8.8 Hz, 1 H),
3.64–3.71 (m, 2 H), 3.82 (quint, J = 6.3 Hz, 1 H), 3.90 (quint, J =
6.3 Hz, 1 H), 4.49 (s, 2 H), 4.51 (br. s, 1 H), 5.53 (m, 1 H, 8-H),
7.12 (dd, J = 8.3, 10.3 Hz, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.26 (s,
2 H), 7.33 (d, J = 4.4 Hz, 3 H), 7.49 (m, 1 H), 7.94 (m, 1 H) ppm.
HR-FABMS (NOBA): calcd. for C39H57FNO7 [M + H]+ 670.4119;
found 670.4121.
with hexane/EtOAc (3:1) gave 32 (5.3 mg, 0.0093 mmol, 73%) as a (2S,3R,6S,7S,8R,9R,10R,13S,15R)-15-tert-Butoxycarbonylamino-
pale yellow oil. Rf = 0.54 (hexane/EtOAc = 1:1). [α]2D6 = –6.0 (c =
3,6:10,13-diepoxy-1-hydroxy-2,9-dimethyloctadecan-8-yl o-Fluoro-
0.37, Et O). FT-IR: ν = 3525 (w), 2961 (s), 2871 (s), 1714 (s), 1613 benzoate (35): A suspension of 34 (6.1 mg, 0.0091 mmol) and
˜
2
(m), 1488 (m), 1455 (m), 1378 (w), 1299 (s), 1250 (m), 1128 (m), Pd(OH)2 (5.0 mg) in dry MeOH (0.50 mL) was stirred overnight
1
1079 (m), 758 (m) cm–1. H NMR (300 MHz, CDCl3): δ = 0.91 (t, under hydrogen (1 atm). The reaction mixture was filtered, and the
J = 6.8 Hz, 3 H, 18-H), 0.93 (d, J = 7.3 Hz, 3 H), 1.01 (d, J = filtrate was concentrated en vacuo to give alcohol 35 (4.2 mg,
6.8 Hz, 3 H), 1.30–1.71 (m, 12 H), 1.85–1.96 (m, 6 H), 2.82 (br. s,
1 H), 3.34 (t, J = 8.8 Hz, 1 H), 3.60 (dd, J = 4.4, 8.8 Hz, 1 H), 3.66
(quint, J = 7.3 Hz, 2 H), 3.83 (br. s, 1 H), 3.87 (quint, J = 6.3 Hz,
0.0072 mmol, 80%) as a pale yellow oil. Rf = 0.31 (hexane/EtOAc
= 1:1). [α]2D0 = +3.8 (c = 0.20, Et O). FT-IR: ν = 3391 (w), 2961
˜
2
(s), 1711 (s), 1613 (w), 1507 (w), 1488 (w), 1456 (m), 1365 (w), 1298
1 H), 4.03 (m, 1 H), 4.50 (s, 2 H, CH2Ph), 5.56 (t, J = 6.3 Hz, 1 (m), 1250 (m), 1172 (w), 1080 (w) and 758 (w) cm–1. 1H NMR
H, 8-H), 7.12 (dd, J = 8.8, 10.3 Hz, 1 H), 7.19 (t, J = 7.8 Hz, 1 H),
(300 MHz, CDCl3): δ = 0.81 (d, J = 6.9 Hz, 3 H 18-H), 0.90 (t, J
7.20–7.40 (m, 4 H), 7.33 (d, J = 4.4 Hz, 1 H), 7.50 (m, 1 H), 7.94 = 7.1 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H), 1.23–1.65 (m, 10 H), 1.42
Eur. J. Org. Chem. 2008, 4955–4962
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4961

H. Kiyota et al.
FULL PAPER
(s, 9 H, tBu), 1.72 (m, 1 H), 1.81–2.02 (m, 7 H), 3.36 (br. s, 1 H),
3.59–3.72 (m, 5 H), 3.82 (quint, J = 6.9 Hz, 1 H), 3.96 (quint, J =
6.9 Hz, 1 H), 4.59 (m, 1 H), 5.57 (m, 1 H, 8-H), 7.12 (m, 1 H), 7.20
(m, 1 H), 7.48 (m, 1 H), 7.96 (dt, J = 1.9, 7.7 Hz, 1 H) ppm. HR-
FABMS (NOBA): calcd. for C32H51FNO7 [M + H]+ 580.3650;
found 580.3647.
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b) S. Kondo, K. Yasui, M. Katayama, S. Marumo, T. Kondo,
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bonylamino-3,6:10,13-diepoxy-8-o-fluorobenzoyloxy-2,9-dimethyl-
octadecanoic Acid (4): A mixture of 35 (8.7 mg, 0.015 mmol) and
Dess–Martin periodinane (9.5 mg, 0.023 mmol) in dry CH2Cl2
(1.5 mL) was stirred at 0 °C for 12 h. The reaction mixture was
then filtered, and the filtrate was washed with saturated aqueous
Na2S2O3 solution and brine, dried with MgSO4, and concentrated
en vacuo. The residue was used in the next step without further
purification. A mixture of the crude aldehyde, 2-methylbut-2-ene
(7.0 mg, 0.10 mmol), 80% NaClO2 (6.0 mg, 0.053 mmol), and
NaH2PO4·2H2O (5.5 mg, 0.035 mmol) in tBuOH/H2O (4:1,
0.15 mL) was stirred at room temperature for 1.5 h. The mixture
was then diluted with EtOAc, washed with saturated aqueous
NH4Cl solution and brine, dried with MgSO4, and concentrated en
vacuo. The residue was chromatographed on a TLC plate. Develop-
ment with hexane/EtOAc (1:1) gave 4 (2.8 mg, 0.0047 mmol, 31%)
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as a pale yellow oil. FT-IR: ν = 3327 (w), 2961 (s), 1711 (s), 1613
˜
(w), 1488 (w), 1456 (m), 1366 (w), 1299 (m), 1250 (m), 1170 (w),
1128 (w), 1080 (w) and 758 (w) cm–1. 1H NMR (300 MHz, CDCl3):
δ = 0.89 (t, J = 7.1 Hz, 3 H, 18-H), 1.01 (d, J = 6.9 Hz, 3 H), 1.18
(d, J = 6.9 Hz, 3 H), 1.23–1.65 (m, 10 H), 1.42 (s, 9 H, tBu), 1.81–
2.10 (m, 7 H), 2.43 (m, 1 H), 3.63 (br. s, 2 H), 3.81 (m, 1 H), 3.95
(m, 1 H), 4.08 (m, 1 H), 4.50 (br. s, 1 H), 5.60 (br. s, 1 H), 7.12 (m,
1 H), 7.20 (m, 1 H), 7.51 (m, 1 H), 7.96 (dt, J = 1.9, 7.7 Hz, 1 H)
ppm. HR-FABMS (NOBA): calcd. for C32H49FNO8 [M + H]+ 594,
3442; found 594.3448.
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We thank Prof. Masahiro Natsume (Tokyo Univ. of Agriculture &
Technology, Japan) for providing the spectroscopic data for the pa-
mamycins. We also appreciate the assistance of Mrs. Teiko Yamada
(Tohoku Univ.) in measuring NMR and mass spectra. Financial
support by a grant-in-aid from the Japan Society for the Promotion
of Science (No. 09760108, 11760083, 17580092, and 19580120), the
Agricultural Chemical Research Foundation, Intelligent Cosmos
Foundation, and the Naito Foundation is gratefully acknowledged.
Received: June 20, 2008
Published Online: September 2, 2008
4962
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4955–4962