Total synthesis of leustroducsin B

Article abstract of DOI:10.1021/jo8005599

(Chemical Equation Presented) Leustroducsin B was synthesized via a convergent route based on division of the leustroducsin molecule into three segments A, B, and C. Two coupling reactions (Julia coupling reaction and Nozaki-Hiyama-Kishi (NHK) reaction) w

Full text of DOI:10.1021/jo8005599

Total Synthesis of Leustroducsin B
Kazuyuki Miyashita,*,†,‡ Tomoyuki Tsunemi,† Takafumi Hosokawa,† Masahiro Ikejiri,† and
Takeshi Imanishi*,†
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamadaoka, Suita, Osaka 565-0871,
Japan, and Faculty of Pharmacy, Osaka Ohtani UniVersity, 3-11-1 Nishikiori-kita, Tondabayashi,
Osaka 584-8540, Japan
miyasik@osaka-ohtani.ac.jp; imanishi@phs.osaka-u.ac.jp
ReceiVed March 18, 2008
Leustroducsin B was synthesized via a convergent route based on division of the leustroducsin molecule
into three segments A, B, and C. Two coupling reactions (Julia coupling reaction and Nozaki-Hiyama-Kishi
(NHK) reaction) were employed for coupling of segments A and B: segment A1 for the Julia coupling
reaction was prepared by a combination of Sharpless asymmetric epoxidation and an epoxide-cleavage
reaction with an organoaluminum reagent, while segment A2 for the NHK reaction was synthesized from
optically active alcohol that had previously been prepared by lipase-catalyzed kinetic resolution. Segment
B, whose structure was modified with some functional groups, was synthesized from (R)-malic acid by
a combination of Wittig reaction and Sharpless asymmetric dihydroxylation, and segment C, containing
a cyclohexane moiety, was prepared by asymmetric Diels-Alder reaction. Segment B was first coupled
with segment A1 via the Julia coupling reaction, but the yield was low due to unexpected epimerization.
The NHK reaction of segment A2 proceeded to give the coupling product in good yield. This product
was coupled with segment C via Wittig and Stille coupling reactions, and finally, phosphorylation was
carried out by partial hydrolysis of a cyclic phosphate to give leustroducsin B.
Introduction
compared to that against PP1 among reported PP inhibitors,
making compound 3 an attractive synthetic target.4 Conse-
quently, a number of synthetic studies on fostriecin (3), including
some by our group, have been reported.5,6 As expected based
on its structural similarity to fostriecin (3), the hydrated analogue
of leustroducsins, leustroducsin H (1h), is also known to be a
potent PP2A inhibitor, suggesting a relationship between the
Leustroducsins A-C (1a-c), shown in Figure 1, were
isolated from the culture broth of Streptomyces platensis SANK
60191 by Sankyo’s groups in 1993.1,2 These compounds have
been found to show various biological activities, including
induction of a colony-stimulating factor by NF-κB activation,
thrombopoiesis, anti-infective activity, and antimetastatic activ-
ity.3 An analogous natural product, fostriecin (3), has also
attracted much attention due to its superior specific inhibitory
activity against serine/threonine protein phosphatase (PP) 2A
(3) (a) Kohama, T.; Katayama, T.; Inukai, M.; Maeda, H.; Shiraishi, A.
Microbiol. Immunol. 1994, 38, 741–745. (b) Kohama, T.; Maeda, H.; Imada
Sakai, J.; Shiraishi, A.; Yamashita, K. J. Antibiot. 1996, 49, 91–94. (c) Koishi,
R.; Serizawa, N.; Kohama, T. J. Interferon Cytokine Res. 1998, 18, 863–869.
(d) Koishi, R.; Yoshimura, C.; Kohama, T.; Serizawa, N. J. Interferon Cytokine
Res. 2002, 22, 343–350. (e) Recent review: Shimada, K.; Koishi, R.; Kohama,
T. Annu. Rep. Sankyo Res. Lab 2004, 56, 11–28.
† Osaka University.
‡ Osaka Ohtani University.
(1) (a) Kohama, T.; Enokita, R.; Okazaki, T.; Miyaoka, H.; Torikata, A.;
Inukai, M.; Kaneko, I.; Kagasaki, T.; Sakaida, Y.; Satoh, A.; Shiraishi, A. J.
Antibiot. 1993, 46, 1503–1511. (b) Kohama, T.; Nakamura, T.; Kinoshita, T.;
Kaneko, I.; Shiraishi, A. J. Antibiot. 1993, 46, 1512–1519.
(2) (a) Shibata, T.; Kurihara, S.; Yoda, K.; Haruyama, H. Tetrahedron 1995,
51, 11999–12012. (b) Matsuhashi, H.; Shimada, K. Tetrahedron 2002, 58, 5619–
5626.
(4) Reviews: (a) de Jong, R. S.; de Vries, E. G. E.; Mulder, N. H. Anti-
Cancer Drugs 1997, 8, 413–418. (b) McCluskey, A.; Sim, A. T. R.; Sakoff,
J. A. J. Med. Chem. 2002, 45, 1151–1175. (c) Lewy, D. S.; Gauss, C. M.; Soenen,
D. R.; Boger, D. L. Curr. Med. Chem. 2002, 9, 2005–2032. (d) Honkanen, R. E.;
Golden, T. Curr. Med. Chem. 2002, 9, 2055–2075. (e) Honkanen, R. E. Handb.
Exp. Pharmacol. 2005, 167, 295–317. (f) Colby, D. A.; Chamberlin, A. R. Mini-
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5360 J. Org. Chem. 2008, 73, 5360–5370
10.1021/jo8005599 CCC: $40.75 2008 American Chemical Society
Published on Web 06/13/2008

Total Synthesis of Leustroducsin B
leustroducsin B (1b), dividing the structure into three segments
A, B, and C, as shown in Figure 3.
In our consideration of the synthesis of segment A of
leustroducsin (1), we noted that the most significant difference
between leustroducsins (1) and fostriecin (3) was the additional
stereogeniccenteratC(4)in1.Forthisreason,theHorner-Emmons
reaction used our synthesis of fostriecin (3) was not suitable
due to the possibility of epimerization of the C(4) stereogenic
center.
We decided to examine two coupling reactions, the Julia
coupling reaction12 and the Nozaki-Hiyama-Kishi (NHK)
reaction,13 for the coupling of segment A with segment B (6).
Segment A1 (4), the substrate for the Julia coupling reaction,
was to be prepared from trans-2-penten-1-ol (9) by Sharpless
asymmetric epoxidation followed by an epoxide cleavage
reaction with an alkynylaluminum reagent, while segment A2
(5), the substrate for the NHK reaction with segment B, was to
be synthesized from optically active alcohol 10, which had
already been prepared by Panek’s group from ethylmalonate
11 using lipase-catalized kinetic resolution as a key step.14
Segment B (6), which contains a 2-aminoethyl group (another
characteristic structural difference from fostriecin (3)) was to
be obtained from (R)-malic acid (13): (1) the 2-aminoethyl group
was to be introduced by a Wittig reagent with a lactone structure
and (2) Sharpless asymmetric dihydroxylation of the resulting
olefin 12 was to give the desired hydoxyl groups in a
stereoselective manner. Segment B (6) was expected to serve
as a common intermediate for the Julia and NHK substrate.
The structure of the right side of leustroducsins (1), the
olefinic moiety, is largely different from that of fostriecin (3).
However, we expected that the coupling of segment B (6) with
segment C (7) could be achieved basically using the same
reaction, the Stille coupling reaction. Segment C (7) was to be
synthesized by homologation of optically active 3-cyclohexen-
ecarboxylic acid (14), which was to be obtained by Diels-Alder
reaction of 15 with 1,3-butadiene.
FIGURE 1. Structures of leustroducsins (1), phoslactomycin B (2),
and fostriecin (3).
biological activity of leustroducsins and the PP2A-specific
inhibitory activity.7 Synthetic studies on this type have been
reported by two groups in Japan. In 2003, Fukuyama and co-
workers reported the first total synthesis of leustroducsin B (1b),8
while in 2006, Kobayashi and co-workers successfully synthe-
sized the analogous natural product, phoslactomycin B (2).9,10
In this paper, we describe details of our total synthesis of
leustroducsin B (1b).11
In our previous paper, we described the total synthesis of
fostriecin (3) via a convergent route.5 When planning the
synthetic strategy, we paid particular attention to the possibility
of synthesizing various derivatives, including not only analogous
natural products but also artificial derivatives, using the same
synthetic strategy. On the basis of this, fostriecin (3) was
synthesized via a convergent route in which the molecule was
constructed from three segments A′, B′, and C′, as shown in
Figure 2. We also utilized this strategy in the synthesis of
Results and Discussion
Synthesis of Segment A. Compound 4 (segment A1 for the
Julia coupling reaction) was synthesized from trans-2-penten-
1-ol (9) as follows (Scheme 1). Sharpless asymmetric epoxi-
dation of 9 with L-(+)-DIPT furnished epoxyalcohol 16 with
greater than 20:1 stereoselectivity (determined after being
derived from MTPA ester). The stereochemistry of the product
16 was assigned to be 2S and 3S from experimental prediction
reported by Sharpless and co-workers,15 but was eventually
determined by comparison of the [R]D value with that of
authentic sample.16 Cleavage of the epoxide bond of 16 with
an alkynylaluminum reagent prepared from 1717 in cyclohexane
yielded 1,2-diol 18a as the major product, accompanying
regioisomeric 1,3-diol 18b. The reaction in toluene gave similar
results, but with a slightly improved yield. The structures of
18a and 18b were confirmed by transformation into the cyclic
(5) (a) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T.
Chem. Commun. 2002, 742–743. (b) Miyashita, K.; Ikejiri, M.; Kawasaki, H.;
Maemura, S.; Imanishi, T. J. Am. Chem. Soc. 2003, 125, 8238–8243.
(6) Reviews: (a) See ref 4c. (b) Shibasaki, M.; Kanai, M. Heterocycles 2005,
66, 727–741. (c) Miyashita, K.; Ikejiri, M.; Tsunemi, T.; Matsumoto, A.;
Imanishi, T. J. Synth. Org. Chem., Jpn. 2007, 65, 874–887.
(7) (a) Shibata, T.; Kurihara, S.; Oikawa, T.; Ohkawa, N.; Shimazaki, N.;
Sasagawa, K.; Kobayashi, T.; Kohama, T.; Asai, F.; Shiraishi, A.; Sugimura, Y.
J. Antibiot. 1995, 48, 1518–1520. (b) Kawada, M.; Kawatsu, M.; Masuda, T.;
Ohba, S.; Amemiya, M.; Kohama, T.; Ishizuka, M.; Takeuchi, T. Int. Immu-
nopharmacol. 2003, 3, 179–188.
(8) Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125,
4048–4049.
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2006, 45, 3320–3323. (b) Nonaka, H.; Maeda, N.; Kobayashi, Y. Tetrahedron
Lett. 2007, 48, 5601–5604.
(10) (a) Fushimi, S.; Nishikawa, S.; Shimazu, A.; Seto, H. J. Antibiot. 1989,
42, 1019–1025. (b) Fushimi, S.; Furihata, K.; Seto, H. J. Antibiot. 1989, 42,
1026–1036. (c) Ozasa, T.; Suzuki, K.; Sasamata, M.; Tanaka, K.; Kobori, M.;
Kadota, S.; Nagai, K.; Saito, T.; Watanabe, S.; Iwanami, M. J. Antibiot. 1989,
42, 1331–1338. (d) Ozasa, T.; Tanaka, K.; Sasamata, M.; Kaniwa, H.; Shimizu,
M.; Matsumoto, H.; Iwanami, M. J. Antibiot. 1989, 42, 1339–1343. (e) Tomiya,
T.; Uramoto, M.; Isono, K. J. Antibiot. 1990, 43, 118–121. (f) Usui, T.; Marriott,
G.; Inagaki, M.; Swarup, G.; Osada, H. J. Biochem. 1999, 125, 960–965.
(11) A portion of this work appeared in our preliminary communication :
Miyashita, K.; Tsunemi, T.; Hosokawa, T.; Ikejiri, M.; Imanishi, T. Tetrahedron
Lett. 2007, 48, 3829–3833.
(12) Review: Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–
2585.
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ReV. 1999, 99, 991–1046.
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(15) Sharpless, K. B.; Katsuki, T. J. Am. Chem. Soc. 1980, 102, 5974–5976.
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Chem. 1987, 629–632. (b) Honda, M.; Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1984, 25, 3857–3860.
(17) Organ, M. G.; Bratovanov, S. Tetrahedron Lett. 2000, 41, 6945–6949.
J. Org. Chem. Vol. 73, No. 14, 2008 5361

Miyashita et al.
FIGURE 2. Total synthesis of fostriecin (3) from a previous study.5
FIGURE 3. Retrosynthetic analysis of leustroducsins (1).
carbonates, 19a and 19b, the IR spectra of which showed
maximum absorption at 1807 and 1756 cm-1 corresponding to
5-membered and 6-membered cyclic carbonates, respectively.
The 1,2-diol 18a was protected to give p-anisilidene acetal 20
as a diastereomeric mixture (ca. 2:3), and reduction of the triple
bond of 20 was carried out without separation. Hydrogenation
with Lindlar catalyst afforded a mixture of a saturated compound
and the desired (Z)-olefinic compound 21, which was hard to
separate. We then employed activated Zn as an alternative
method for the reaction,18 which proceeded smoothly to give
21 in good yield. Reductive cleavage of the acetal bond of 21
with DIBAl-H took place regioselectively at -100 °C to yield
primary alcohol 22, and reaction of 22 with thiol 23 under
Mitsunobu conditions afforded sulfide 24, which was oxidized
to give segment A1 (4) for the Julia coupling reaction.
Aldehyde 5, corresponding to segment A2 for the NHK
reaction, was prepared from known alcohol 10 as shown in
Scheme 2.14 Oxidation of 10 and subsequent treatment with
Wittig reagent19 afforded cis-unsaturated ester 26. The ester
group of 26 was reduced with DIBAl-H, and the hydroxyl group
of the resultant 27 was protected with a MPM group, yielding
28. The TBS group of 28 was removed by acidic treatment to
give 29, which was oxidized with Dess-Martin periodinane to
yield the desired segment A2 (5) for the NHK reaction.
Synthesis of Segment B (6). Segment B (6) was synthesized
as shown in Scheme 3. Oxidation of alcohol 3020 followed by
in situ treatment with Wittig reagent 31,21 containing a γ-lactone
structure, afforded (E)-olefin 12 stereoselectively. The lactone
moiety of 12 was reduced with DIBAl-H to give hydroxyalde-
(19) Ando, K. J. Org. Chem. 1997, 62, 1934–1939.
(20) (a) Hanessian, S.; Ugolini, A.; Dube´, D.; Glamyan, A. Can. J. Chem.
1984, 62, 2146–2147. (b) Mori, K.; Takigawa, T.; Matsuo, T. Tetrahedron 1979,
35, 933–940.
(18) Aerssens, M. H. P. J.; van der Heiden, R.; Heus, M.; Brandsma, L.
Synth. Commun. 1990, 20, 3421–3425.
5362 J. Org. Chem. Vol. 73, No. 14, 2008

Total Synthesis of Leustroducsin B
SCHEME 1. Synthesis of Segment A1
SCHEME 2. Synthesis of Segment A2
and the differences in the 1H NMR chemical shifts (∆δ) of the
(S)- and (R)-monoesters are summarized in Figure 4. Thus, the
stereochemistry at C(9) was unambiguously shown to have an
(R)-configuration, which implies that the configuration at C(8)
is also R.
Finally, compound 36 was transformed into segment B (6)
as follows. The Vic-diol moiety of 36 was protected with an
acetonide group to give bisacetonide 37. The terminal acetonide
group of 37 was then selectively removed by zinc nitrate
treatment, giving diol 38, the primary hydroxyl group of which
was selectively protected with a MPM group via cyclic stannane
to give 39. Finally, the secondary hydroxyl group of 39 was
protected with a TBS group to give segment B (6).
FIGURE 4. ∆δ () ∆δS - ∆δR) values (ppm) for MTPA esters of 36.
Synthesis of Segment C (7). Several methods including
opticalresolutionbyrecrystallization24 andasymmetricDiels-Alder
reaction25–28 have been reported to give optically active 3-cy-
clohexenecarboxylic acid (14). However, the recrystallization
procedure was found to be inefficient, and expensive chiral
auxiliaries, sometimes with unnatural stereochemistry, are
required to obtain the (R)-isomer 14 by asymmetric Diels-Alder
reaction. On the basis of the report by Raw and Jang of an
effective asymmetric Diels-Alder reaction with a crotonic acid
derivative containing an (R)-benzyloxazolidinone structure as
a chiral auxiliary,29 we applied this reaction to acrylic acid
derivative 15 (Scheme 4). The Diels-Alder reaction of 15 with
hyde 32, which was protected with a TBDPS group, affording
aldehyde 33. After reduction of 33, the hydroxyl group of the
resulting 34 was protected with a benzoyl group to give olefin
35. Sharpless asymmetric dihydroxylation of 35 with the
(DHQD)2PHAL22 ligand furnished diol 36 as a single isomer
in good yield. The stereochemistry of 36 was expected to be as
shown based on experimental prediction proposed by Sharpless
and co-workers22 and also from our previous result,5 but was
determined by modified Mosher’s method.23 Diol 36 was
transformed into (S)- and (R)-MTPA monoesters, respectively,
(24) Schwartz, H. M.; Wu, W.-S.; Marr, P. W.; Jones, J. B. J. Am. Chem.
Soc. 1978, 100, 5199–5203.
(21) (a) Fizar, S.; Hudson, R. F.; Salvadori, G. HelV. Chim. Acta 1963, 46,
1580. (b) Couturier, M.; Dory, Y. L.; Rouillard, F.; Deslongchamps, P.
Tetrahedron 1998, 54, 1529.
(25) Poll, T.; Sobczak, A.; Hartmann, H.; Helmchen, G. Tetrahedron Lett.
1985, 26, 3095–3098.
(22) Review: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483–2547.
(26) Marshall, J. A.; Xie, S. J. Org. Chem. 1995, 60, 7230–7237.
(27) Smith, A. B., III; Hale, K. J.; Laalso, L. M.; Chen, K.; Rie´ra, A
Tetrahedron Lett. 1989, 30, 6963–6966.
(23) (a) Kusumi, T.; Ohtani, I.; Inouye, Y.; Kakisawa, H. Tetrahedron Lett.
1988, 29, 4731–4734. (b) Takano, S.; Takahashi, M.; Yanase, M.; Sekiguchi,
Y.; Iwabuchi, Y.; Ogasawara, K. Chem. Lett. 1988, 1827–1828.
(28) Srakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741–1744.
(29) Raw, A. S.; Jang, E. B. Tetrahedron 2000, 56, 3285–3290.
J. Org. Chem. Vol. 73, No. 14, 2008 5363

Miyashita et al.
SCHEME 3. Synthesis of Segment B
SCHEME 4. Synthesis of Segment C
butadiene afforded 40 as a single diastereomer. The chiral
auxiliary was removed by hydrolysis, and the resulting car-
boxylic acid 14 was converted to lactone 42 by iodolactonization
and subsequent reduction of 41 with silane.30 After reduction
with DIBAl-H, dibromomethylenation of 43 by Wittig reaction
afforded 44, which was treated with n-butyllithium and tribu-
tyltin chloride without protecting the hydroxyl group to furnish
acetylene 45. This was reduced by hydozirconation to give cis-
olefin 46, which was finally esterified with carboxylic acid
4731to afford segment C (7). It is notable that various
segments C for other leustroducsins and phoslactomycins can
be synthesized by using different types of carboxylic acid in
the last step.
Coupling Reaction of Segment B (6) with Segment A. As
is obvious from the structure of segment B (6), it can be coupled
with either segment A or C by selective removal of one of the
two terminal protecting groups (the benzoyl group and the MPM
group). In view of the stability of the diene moiety of
leustroducsins (1) and the diversity of the acyloxy side chain
on the cyclohexane structure, segment A, rather than segment
C, was initially used for the coupling reaction. For the Julia
coupling reaction of segment B (6) with segment A1 (4), segment
B (6) was transformed into aldehyde 49 in good yield by
selective removal of the terminal benzoyl group by methanolysis
and oxidation with TPAP (Scheme 5).
Although the Julia coupling reaction of 49 with segment A1
(4) using NaHMDS as a base afforded olefin 50 in 49% yield,
it was found that unexpected epimerization at C(5) took place,
resulting in the formation of a diastereomeric mixture. The
mechanism of epimerization at C(5) is thought to be as shown
in Figure 5: elimination of the p-methoxybenzyloxy group
followed by re-addition of the p-methoxybenzyloxy anion to
vinylsulfone.32 On the basis of this, we attempted the reaction
using a different base (LiHMDS). Interestingly, no epimerization
was observed with this base, but the yield decreased consider-
ably. This is probably due to the lower nucleophilicity of the
lithium salt of the p-methoxybenzyloxy anion compared to the
corresponding sodium salt. It is also noteworthy that the (R)-
(30) Martin, S.; Dappen, M. S.; Dupre´, B.; Murphy, C. J.; Colapret, J. A. J.
Org. Chem. 1989, 54, 2209–2216.
(32) Evans and co-workers reported that similar epimerization took place in
the Julia coupling reaction of a sulfone derivative with an oxygen atom of a
tetrahydrofuran ring at the ꢀ-position: Evans, D. A.; Rajapakse, H. A.; Chiu,
A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4573–4576.
(31) Sonnet, P. E.; Gazzillo, J. A.; Dudley, R. L.; Boswell, R. T. Chem.
Phys. Lipids 1990, 54, 205–214.
5364 J. Org. Chem. Vol. 73, No. 14, 2008

Total Synthesis of Leustroducsin B
SCHEME 5. Julia Coupling Reaction of Segment A1 with
Segment B
SCHEME 6. NHK Reaction of Segment A2 with Segment B
diastereomer was obtained as a major product when KHMDS
was used as a base, although the yield was much lower. The
(S)-isomer 50 obtained with LiHMDS was transformed into triol
51 by removal of all MPM groups under oxidative conditions.
Synthesis of Leustroducsin B (1b). Before construction of
the entire carbon skeleton of leustroducsin B (1b) by coupling
with segment C (7), the amino group at C(25) was introduced
as follows (Scheme 7). Triol 51 was oxidized with TEMPO,
affording lactone-aldehyde 55 in a one-pot reaction. Compound
55 was subjected to the Wittig reaction, affording (Z)-iodom-
ethylene 56 as a major product. After removal of two silyl
groups of 56 to give 57, both hydroxyl groups were again
protected with a TBS group, and the primary hydroxyl group
was regenerated by careful acidic hydrolysis, giving the alcohol
58. An azide group was introduced via standard protocols, and
the resulting azide 59 was reduced and protected with an Alloc
group to give 60 in a one-pot reaction. Acidic treatment resulted
in simultaneous removal of the acetonide and TBS groups to
afford triol 61, which was then coupled with segment C (7)
under Pd(0)-catalyzed conditions, producing 62, which contains
the entire carbon skeleton of leustroducsin B (1b).
As the desired product 50 was obtained only in low yield
under Julia reaction conditions, we attempted the NHK reaction
(Scheme 6). In this case, aldehyde 49 was treated with iodoform
and CrCl2 to give trans-iodomethylene 52,33 which was coupled
with segment A2 (5) under NHK reaction conditions. The
reaction took place smoothly but with unfavorable stereoselec-
tivity, affording product 53 as a mixture of diastereomers which
was separable by flash chromatography. The stereochemistry
of 53 was determined by transformation of 53a into triol 51,
which was identical with the compound derived from the product
of the Julia coupling reaction. This result showed that the desired
(S)-isomer 53a was the minor product of the NHK reaction. It
was also found that oxidation of the diastereomeric mixture of
53 and subsequent reduction of the resulting ketone 54 with
L-selectride gave the (R)-isomer 53b stereoselectively.34 This
stereochemical outcome, with preferential formation of the (R)-
isomer 53b, is thought to be affected by the neighboring
stereogenic center in ketone 54, and may be explained by
consideration of the Felkin-Anh model shown in Figure 6. The
(R)-isomer 53b was converted into the desired (S)-isomer 53a
by the Mitsunobu reaction. Overall, the NHK reaction was
concluded to be more effective than the Julia coupling reaction
for coupling of segment A with segment B.
FIGURE 6. Stereoselectivity for reduction of ketone 54.
The final stage, regioselective introduction of the phosphate
function, was achieved via a cyclic phosphate, using a method
we developed and employed in the total synthesis of fostriecin.5b
The hydroxyl group at C(11) was regioselectively protected with
a TBS group at -78 °C, giving diol 63. Formation of a cyclic
phosphate triester followed by partial hydrolysis of 64 success-
fully produced 65a, a fully protected form of leustroducsin B
(1b), as a major product, accompanied by C(8) O-phosphate
65b and cyclic phosphate diester 65c (65a:65b:65c ) 71:22:
7). The structures of these compounds 65a-c were confirmed
by comparison of their characteristic 31P NMR chemical shifts,
as shown in Scheme 7.5b As it was difficult to separate these
phosphate diesters 65 at this stage, the final transformations were
FIGURE 5. Possible mechanism for epimerization at C(5).
J. Org. Chem. Vol. 73, No. 14, 2008 5365

Miyashita et al.
SCHEME 7. Total Synthesis of Leustroducsin B: Final Steps
carried out with the unseparated mixture. First, the TBS group
of 65 was deprotected, and then the allyl protecting groups were
removed.35 The resulting product was purified by PTLC to
afford leustroducsin B (1b), the [R]D value and 1H and 13C NMR
data for which were identical with those of authentic sample.
products and hybrid analogues of fostriecin (3) and leustroduc-
sins (1), and would contribute to studies in chemical biology
and medicinal chemistry, particularly in the area of serine/
threonine protein phosphatases.
Experimental Section
Conclusion
(2R,3R,5R)-5-tert-Butyldimethylsiloxy-2-(2-tert-butyldiphenyl-
siloxyethyl)-2,3-isopropylidenedioxy-6-(4-methoxybenzyloxy)-1-
hexanol (48). To a stirred solution of 6 (870 mg, 1.05 mmol) in
methanol (10 mL) was added K2CO3 (436 mg, 3.15 mmol), and
the reaction was stirred at room temperature for 4 h. After filtration,
the resulting filtrate was diluted with ether, washed with water and
saturated NaCl solution, dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (ethyl acetate-hexane ) 1:6) to give 48
A total synthesis of leustroducsin B (1b) was achieved via a
convergent route involving a three-segment coupling process,
employing a strategy that was basically the same as that used
for our total synthesis of fostriecin (3). This synthetic strategy
provides an efficient method for synthesis not only of fostriecin-
type natural products but also of various derivatives, including
compounds lacking sections of the structure of the parent natural
(621 mg, 86%) as a colorless oil: [R]21 -2.92 (c 1.92, CHCl3);
D
(33) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–
7410.
IR νmax (KBr) 3382, 2930, 1462 cm-1; 1H NMR (270 MHz, CDCl3)
δ 0.05 (3H, s), 0.08 (3H, s), 0.90 (9H, s), 1.05 (9H, s), 1.29 (3H,
s), 1.34 (3H, s), 1.48-1.82 (4H, m), 2.65 (1H, br s), 3.34 (1H, dd,
J ) 5, 10 Hz), 3.40 (1H, dd, J ) 5, 10 Hz), 3.52 (1H, m), 3.76
(1H, m), 3.80 (3H, s), 3.89-4.00 (2H, m), 4.22 (1H, d, J ) 9 Hz),
4.52 (2H, s), 6.88 (2H, d, J ) 9 Hz), 7.26 (2H, d, J ) 9 Hz),
7.35-7.46 (6H, m), 7.64-7.70 (4H, m); 13C NMR (67.8 MHz,
(34) Although we examined reductions of the corresponding ketone including
asymmetric reductions, the results were unsatisfactory.
(35) When deprotection procedures were carried out in reverse (allyl
protecting groups followed by the TBS group), in the same sequence as used in
our fostriecin synthesis, purification was more difficult and we were unable to
isolate pure leustroducsin B.
(36) Goering, H. L.; Serres, C., Jr. J. Am. Chem. Soc. 1952, 74, 5908–5912.
5366 J. Org. Chem. Vol. 73, No. 14, 2008

Total Synthesis of Leustroducsin B
CDCl3) δC -4.9, -4.1, 18.1, 19.0, 25.9 (3C), 26.8 (3C), 27.0, 28.5,
34.3, 34.6, 55.2, 59.8, 64.7, 68.7, 72.9, 74.8, 76.6, 83.1, 107.5, 113.7
(2C), 127.7 (2C), 127.7 (2C), 129.3 (2C), 129.7, 129.7, 130.4, 133.1,
133.2, 135.5 (2C), 135.6 (2C), 159.1; mass (FAB) m/z 723 (M +
H+); HRMS calcd for C41H63O7Si2 723.4113, found 723.4094.
(2R,4R,5R,6E,8S,9S,10Z)-2-tert-Butyldimethylsiloxy-5-(2-tert-
butyldiphenylsiloxyethyl)-9-ethyl-4,5-isopropylidenedioxy-8,12-
bis(4-methoxybenzyloxy)-6,10-dodecadiene (50). To a stirred
solution of 48 (53 mg, 0.073 mmol) in CH2Cl2 (0.8 mL) were added
molecular sieves 4A (110 mg), N-methylmorpholine -N-oxide (26
mg, 0.110 mmol), and tetrapropylammonium perruthenate (2.1 mg,
8 mol%) at room temperature, and the reaction was stirred at the
same temperature for 2 h. After filtration, the reaction mixture was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (ethyl acetate-hexane
) 1:8) to give 49 (49 mg, 95%). To a stirred solution of 49 (49
mg, 0.068 mmol) and the segment A1 (4) (79 mg, 0.136 mmol) in
THF (0.7 mL) was added sodium bis(trimethylsilyl)amide (1.1 M
in THF, 123 µL, 0.136 mmol) at -78 °C, and the reaction was
stirred at the same temperature for 1 h. After being warmed to 0
°C for 1 h, the reaction mixture was diluted with ether, washed
with saturated NH4Cl solution, saturated NaHCO3 solution, water,
and saturated NaCl solution, dried over MgSO4, and concentrated
under reduced pressure. The resulting residue was purified by silica
gel column chromatography (ethyl acetate-hexane ) 1:8) to give
50 (37 mg, 49%) as a colorless oil: [R]22D +58.6 (c 0.55, CHCl3);
IR νmax (KBr) 2851, 1685, 1650, 1613, 1511, 1460 cm-1; 1H NMR
(270 MHz, CDCl3) δ 0.03 (3H, s), 0.04 (3H, s), 0.75 (3H, t, J )
7 Hz), 0.85 (9H, s), 1.03, (9H, s), 1.03-1.13 (1H, m), 1.26 (3H,
s), 1.29 (3H, s), 1.43-1.56 (2H, m), 1.62-1.79 (2H, m), 1.96 (1H,
dt, J ) 5, 12 Hz), 2.32-2.43 (1H, m), 3.38 (2H, ddd, J ) 5, 10,
13 Hz), 3.51 (1H, dd, J ) 6, 8), 3.75-4.10 (7H, m), 3.79 (6H, s),
3.80 (3H, s), 4.24 (1H, d, J ) 12 Hz), 4.33 (1H, d, J ) 12 Hz),
4.35 (1H, d, J ) 12 Hz), 4.47 (1H, d, J ) 12 Hz), 4.49 (2H, d, J
) 12 Hz), 5.16 (1H, t, J ) 11 Hz), 5.40 (1H, d, J ) 15 Hz), 5.53
(1H, dd, J ) 8, 15 Hz), 5.61 (1H, td, J ) 6, 11 Hz), 6.79 (2H, d,
J ) 9 Hz), 6.84 (2H, d, J ) 9 Hz), 6.89 (2H, d, J ) 9 Hz), 7.05
(2H, d, J ) 9 Hz), 7.19 (2H, d, J ) 9 Hz), 7.26-7.37 (8H, m),
7.61-7.65 (4H, m); 13C NMR (67.8 MHz, CDCl3) δC: -4.7, -4.1,
11.8, 18.2, 19.2, 24.3, 26.0 (3C), 26.7, 27.0 (3C), 28.4, 33.9, 36.9,
44.6, 55.3, 55.3, 55.3, 60.7, 66.3, 68.6, 69.7, 71.7, 72.9, 74.9, 79.4,
82.2, 82.8, 107.8, 113.5 (2C), 113.6 (2C), 113.6 (2C), 127.5 (2C),
127.5 (2C), 128.2, 128.5, 129.1 (2C), 129.2 (2C), 129.2 (2C), 129.4
(2C), 130.3, 130.5, 130.6, 132.9, 133.7, 133.8, 134.6, 135.3 (2C),
135.4 (2C), 158.7, 158.9, 159.0; mass (FAB) m/z 1110 (M + Na+);
HRMS calcd for C65H90O10Si2Na 1109.5970, found 1109.5970.
Reactions with lithium and potassium bis(trimethylsilyl)amide
were also carried out similarly.
(2R,4R,5R,6E,8S,9S,10Z)-2-tert-Butyldimethylsiloxy-5-(2-tert-
butyldiphenylsiloxyethyl)-9-ethyl-4,5-isopropylidenedioxy-6,10-
dodecadiene-1,8,12-triol (51). To a stirred solution of 50 (349 mg,
0.321 mmol) in CH2Cl2 (3 mL) containing water (0.3 mL) was
added DDQ (291 mg, 1.28 mmol) at room temperature, and the
reaction was stirred vigorously at room temperature for 1 h. After
addition of saturated NaHCO3 solution, the reaction mixture was
extracted with ethyl acetate. Combined organic layers were washed
with water and saturated NaCl solution, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by passing through a silica gel short column (ethyl
acetate-hexane ) 1:2) to give 51 (183 mg, 79%) as a colorless
oil: [R]23D +6.99 (c 0.41, CHCl3); IR νmax (KBr) 3070, 2854, 1612,
1513 cm-1; 1H NMR (270 MHz, CDCl3) δ 0.08 (3H, s), 0.09 (3H
s), 0.81 (3H, t, J ) 7 Hz), 0.88 (9H, s), 1.04 (9H, s), 1.04-1.14
(1H, m), 1.29 (6H, s), 1.40-1.50 (1H, m), 1.53-1.74 (3H, m),
1.90-2.00 (1H, m), 2.05 (1H, br s), 2.45-2.57 (1H, m), 3.51 (1H,
d, J ) 12 Hz), 3.63-3.84 (4H, m), 3.86-3.99 (3H, m), 4.14 (1H,
dd, J ) 9, 12 Hz), 5.09 (1H, t, J ) 11 Hz), 5.46 (1H, d, J ) 15
Hz), 5.69 (1H, dd, J ) 7, 15 Hz), 5.82 (1H, td, J ) 7, 11 Hz),
7.33-7.44 (6H, m), 7.63-7.67 (4H, m); 13C NMR (67.8 MHz,
CDCl3) δC -4.6, -4.2, 12.0, 18.1, 19.2, 24.7, 25.9 (3C), 26.7, 26.9
(3C), 28.3, 33.3, 36.6, 45.2, 57.9, 60.3, 67.2, 70.3, 74.3, 80.0, 82.9,
107.9, 127.5 (2C), 127.5 (2C), 129.5, 129.5, 130.1, 131.7, 132.6,
133.1, 133.7, 133.9, 135.4 (4C); mass (FAB) m/z 749 (M + Na+);
HRMS calcd for C41H66O7Si2Na 749.4245, found 749.4251.
(2R,4R,5R)-2-tert-Butyldimethylsiloxy-7-tert-butyldiphenylsi-
loxy-5-[(E)-2-iodovinyl]-4,5-isopropylidenedioxy-1-(4-methoxy-
benzyloxy)heptane (52). To a stirred solution of 48 (740 mg, 1.02
mmol) in CH2Cl2 (10 mL) were added powdered MS4A (1.6 g),
N-methylmorpholine N-oxide (155 mg, 1.33 mmol), and tetrabu-
tylammonium perruthenate (29 mg, 8 mol%), and the reaction was
stirred at room temperature for 1 h. After filtration, the solvent was
evaporated off under reduced pressure, and the resulting residue
was passed through a silica gel short column (ethyl acetate-hexane
) 1:8) to give aldehyde (733 mg), which was immediately
employed for the next reaction. To a stirred suspension of CrCl2
(753 mg, 6.12 mmol) in THF (7.0 mL) was added dropwise a THF
(7.0 mL) solution of the aldehyde (733 mg) and iodoform (801
mg, 2.03 mmol). After being stirred at room temperature for 2 h,
the reaction mixture was diluted with ether, washed with water and
saturated NaCl solution, dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (ethyl acetate-hexane ) 1:20) to afford
52 (562 mg, 65% from 48) as a colorless oil: [R]25D +6.51 (c 3.40,
CHCl3); IR νmax (KBr) 3070, 2930, 2856, 1611, 1588, 1513 cm-1
;
1H NMR (270 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 1.06
(9H, s), 1.26 (3H, s), 1.29 (3H, s), 1.44-1.89 (4H, m), 3.37 (2H,
ddd, J ) 5, 10, 13 Hz), 3.68-3.81 (2H, m), 3.81 (3H, s), 3.89-3.98
(2H, m), 4.47 (1H, d, J ) 12 Hz), 4.49 (1H, d, J ) 12 Hz), 6.30
(1H, d, J ) 15 Hz), 6.38 (1H, d, J ) 15 Hz), 6.90 (1H, d, J ) 9
Hz), 7.26 (1H, d, J ) 9 Hz), 7.33-7.47 (6H, m), 7.61-7.68 (4H,
m); 13C NMR (67.8 MHz, CDCl3) δC -4.8, -3.9, 18.2, 19.2, 26.0
(3C), 26.6, 27.0 (3C), 28.3, 33.9, 36.5, 55.3, 59.9, 68.7, 72.9, 74.6,
76.8, 79.3, 85.4, 108.1, 113.6 (2C), 127.5 (2C), 127.6 (2C), 129.2
(2C), 129.5 (2C), 130.2, 133.7, 133.7, 135.4 (2C), 135.5 (2C), 146.3,
159.0; mass (FAB) m/z 867 (M + Na+); HRMS calcd for
C42H61O6Si2NaI 867.2949, found 867.2979.
(2Z,4S,5S,6E,8R,9R,11R)-11-tert-Butyldimethylsiloxy-8-(2-tert-
butyldiphenylsiloxyethyl)-4-ethyl-8,9-isopropylidenedioxy-1,12-
bis(4-methoxybenzyloxy)-2,6-dodecadien-5-ol (53a). To a stirred
solution of segment A2 (5) (30 mg, 0.121 mmol) and 52 (133 mg,
0.157 mmol) in degassed DMSO (0.6 mL) were added NiCl2 (0.6
mg, 4 mol%) and CrCl2 (60 mg, 0.484 mmol), and the reaction
was stirred at room temperature for 2 h. After being diluted with
ether, the reaction mixture was washed with water and saturated
NaCl solution, dried over MgSO4, and concentrated under reduced
pressure. The resulting residue was purified by flash silica gel
column chromatography (ethyl acetate-hexane ) 1:6) to give 53a
(22 mg, 19%, 53a:53b ) >20:1) and 53b (66 mg, 56%, 53a:53b
) 1:14) as a colorless oil, respectively. Compound 53a: [R]25
D
+18.5 (c 0.78, CHCl3); IR νmax (KBr) 3471, 3070, 2931, 2856,
1612, 1587, 1513. cm-1; 1H NMR (500 MHz, CDCl3) δ 0.03 (6H,
s), 0.78 (3H, t, J ) 7 Hz), 0.84 (9H, s), 1.03 (9H, s), 1.08 (1H, m),
1.25 (3H, s), 1.27 (3H, s), 1.38-1.48 (2H, m), 1.61 (1H, m), 1.70
(1H, m), 1.92-1.98 (2H, m), 2.41 (1H, m), 3.36 (2H, ddd, J ) 3,
5, 9 Hz), 3.68 (1H, m), 3.76-3.84 (2H, m), 3.80 (3H, s), 3.80 (3H,
s), 3.88-4.01 (4H, m), 4.42 (1H, d, J ) 12 Hz), 4.43 (1H, d, J )
12 Hz), 4.46 (1H, d, J ) 12 Hz), 4.48 (1H, d, J ) 12 Hz), 5.16
(1H, t, J ) 11 Hz), 5.42 (1H, d, J ) 16 Hz), 5.64 (1H, dd, J ) 7,
16 Hz), 5.71 (1H, td, J ) 7, 11 Hz), 6.87 (2H, d, J ) 9 Hz), 6.89
(2H, d, J ) 9 Hz), 7.26 (2H, d, J ) 9 Hz), 7.27 (2H, d, J ) 9 Hz),
7.33-7.40 (6H, m), 7.64-7.65 (4H, m); 13C NMR (67.8 MHz,
CDCl3) δC -4.7, -4.0, 12.1, 18.2, 19.2, 24.3, 26.0 (3C), 26.7, 27.0
(3C), 28.4, 33.8, 36.8, 45.8, 55.3 (2C), 60.5, 65.5, 68.7, 72.1, 72.9,
74.5, 74.9, 79.6, 82.8, 107.6, 113.6 (2C), 113.7 (2C), 127.5 (4C),
129.2 (2C), 129.3, 129.4 (2C), 129.4 (2C), 129.7, 130.1, 130.3,
132.2, 133.7, 133.8, 133.9, 135.4 (4C), 159.0, 159.0; mass (FAB)
m/z 990 (M + Na+); HRMS calcd for C57H82O9Si2Na 989.5395,
found 989.5408. Compound 53b: [R]25 +12.1 (c 1.08, CHCl3);
D
J. Org. Chem. Vol. 73, No. 14, 2008 5367

Miyashita et al.
IR νmax (KBr) 3480, 3070, 2931, 2856, 1613, 1587, 1514. cm-1
;
were added diacetoxyiodobenzene (404 mg, 1.25 mmol) and 2,2,6,6-
tetramethylpiperidine 1-oxyl (11 mg, 0.072 mmol), and the reaction
was stirred at room temperature for 1.5 h. After addition of saturated
Na2S2O3 solution, the reaction mixture was extracted with ether.
Combined ethereal layers were washed with saturated NaHCO3
solution, water, and saturated NaCl solution, dried over MgSO4,
and concentrated under reduced pressure. The resulting residue was
passed through a silica gel short column (ethyl acetate-hexane )
1:6) to give 55 (236 mg), which was immediately employed for
the next reaction. To a stirred solution of (iodomethyl)triph-
enylphosphonium iodide (208 mg, 0.393 mmol) in THF (1.9 mL)
was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 350
µL, 0.35 mmol) at room temperature. The reaction mixture was
stirred at room temeperature for 3 min and then cooled to -60 °C.
After addition of HMPA (285 µL, 1.64 mmol) at the same
temperature, the reaction mixture was cooled to -100 °C, to which
a solution of 55 (236 mg) in THF (1.5 mL) was added slowly. The
reaction mixture was stirred at -100 °C for 10 min, then warmed
to 0 °C and stirred at the same temperature for 20 min. After
addition of saturated NH4Cl solution, the reaction mixture was
extracted with ether. Combined ethereal layers were washed with
water and saturated NaCl solution, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (chloroform-hexane
) 7:2) to give a geometric mixture of 56 (Z:E ) 4.3:1, 179 mg,
1H NMR (500 MHz, CDCl3) δ 0.03 (6H, s), 0.71 (3H, t, J ) 7
Hz), 0.85 (9H, s), 0.96 (1H, m), 1.03 (9H, s), 1.08 (1H, m), 1.27
(3H, s), 1.28 (3H, s), 1.36 (1H, m), 1.47 (1H, m), 1.58-1.77 (2H,
m), 1.95 (1H, m), 2.19 (1H, m), 3.37 (2H, ddd, J ) 5, 10, 15 Hz),
3.68-3.73 (2H, m), 3.78-3.88 (2H, m), 3.79 (3H, s), 3.80 (3H,
s), 3.93-4.03 (3H, m), 4.40 (1H, d, J ) 12 Hz), 4.41 (1H, d, J )
12 Hz), 4.46 (1H, d, J ) 12 Hz), 4.49 (1H, d, J ) 12 Hz), 5.28
(1H, t, J ) 11 Hz), 5.46 (1H, d, J ) 16 Hz), 5.65 (1H, dd, J ) 7,
16 Hz), 5.82 (1H, td, J ) 7, 11 Hz), 6.86 (2H, d, J ) 9 Hz), 6.89
(2H, d, J ) 9 Hz), 7.24 (2H, d, J ) 9 Hz), 7.28 (2H, d, J ) 9 Hz),
7.33-7.40 (6H, m), 7.63-7.65 (4H, m); 13C NMR (67.8 MHz,
CDCl3) δC -4.7, -4.0, 11.8, 18.2, 19.2, 23.8, 26.0 (3C), 26.8, 27.0
(3C), 28.4, 33.9, 36.9, 46.3, 55.3, 55.3, 60.5, 65.8, 68.8, 72.0, 72.9,
74.8 (2C), 79.7, 82.7, 107.7, 113.6 (2C), 113.7 (2C), 127.5 (2C),
127.5 (2C), 129.2 (2C), 129.3, 129.4 (2C), 129.7 (2C), 130.2, 130.3,
130.7, 133.0, 133.8, 133.9, 134.2, 135.4 (4C), 159.0, 159.0; HRMS
calcd for C57H82O9Si2Na 989.5395, found 989.5408.
Deprotection of MPM Groups of 53a. To a stirred solution of
53a (73 mg, 0.075 mmol) in CH2Cl2 (1.0 mL) containing water
(0.1 mL) was added DDQ (43 mg, 0.189 mmol), and the reaction
was stirred at room temperature for 1 h. After addition of saturated
NaHCO3 solution, the reaction mixture was extracted with ethyl
acetate. The organic solution was washed with water and saturated
NaCl solution, dried over Na2SO4, and concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (ethyl acetate-hexane ) 1:2) to give 51 (50 mg,
92%).
1
59% from 51) as a colorless oil: H NMR (500 MHz, CDCl3) δ
0.05 (3H, s), 0.07 (3H s), 0.76 (3H, t, J ) 7 Hz), 0.85 (9H, s),
1.03, (9H, s), 1.11-1.42 (3H, m), 1.29 (3H, s), 1.34 (3H, s),
1.48-1.67 (2H, m), 1.98 (1H, m), 2.25 (1H, m), 3.66 (1H, dt, J )
5, 11 Hz), 3.79 (1H, m), 3.87 (1H, dd, J ) 2, 10 Hz), 4.52 (1H,
ddd, J ) 3, 6, 10 Hz), 4.90 (1H, m), 5.64 (2H, m), 6.01 (1H, d, J
) 10 Hz), 6.19-6.24 (2H, m), 6.90 (1H, dd, J ) 6, 10 Hz),
7.32-7.42 (6H, m), 7.62-7.66 (4H, m); mass (FAB) m/z 867 (M
+ Na+); HRMS calcd for C42H61O6Si2NaI 867.2949, found
867.2919.
Oxidation and Reduction with L-Selectride. To a stirred
solution of 53 (18 mg, 0.018 mmol, 53a:53b ) ca. 1:2.3) in CH2Cl2
(0.4 mL) was added Dess-Martin periodinane (7.9 mg, 0.024
mmol), and the reaction was stirred at room temperature for 30
min. A mixture of saturated NaHCO3 solution and saturated
Na2S2O3 solution (1:2, one drop) was added to the reaction mixture,
which was then stirred for 10 min. After extraction with ether, the
ethereal layer was washed with saturated NaHCO3 solution, water,
and saturated NaCl solution, dried over MgSO4, and concentrated
under reduced pressure to give crude ketone 54 (17 mg). To a stirred
solution of the ketone 54 (17 mg) in THF (0.4 mL) was added
lithium tributylborohydride (1.0 M in THF, 30 µL, 0.030 mmol) at
-78 °C, and the reaction was stirred at the same temperature for
1 h. After addition of saturated NH4Cl solution, the reaction mixture
was stirred vigorously for 30 min and extracted with ethyl acetate.
The organic solution was washed with saturated NaHCO3 solution,
water, and saturated NaCl solution, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (ethyl acetate-hexane
) 1:6) to give 53b (14 mg, 78% from 53, 53a:53b ) 1:>20).
Transformation of 53b into 53a via Mitsunobu Reaction. To
a solution of 53b (66 mg, 0.068 mmol) in toluene (0.6 mL) were
added triphenylphosphine (36 mg, 0.137 mmol), p-nitrobenzoic acid
(18 mg, 0.109 mmol), and diethyl azodicarboxylate (2.2 M in
toluene, 62 µL, 0.137 mmol), and the reaction was stirred at room
temperature for 3 h. After being diluted with ether, the reaction
mixture was washed with saturated NaHCO3 solution, water, and
saturated NaCl solution, dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (ethyl acetate-hexane ) 1:6) to give
p-nitrobenzoate (81 mg), which was treated with K2CO3 (19 mg,
0.137 mmol) in methanol (1.0 mL) at room temperature for 1 h.
After being diluted with ether, the reaction mixture was washed
with saturated NaCl solution, dried over MgSO4, and concentrated
under reduced pressure. The resulting residue was purified by flash
silica gel column chromatography (ethyl acetate-hexane ) 1:6)
to give 53a (51 mg, 78%, 53a:53b ) >20:1)
(5S,6S)-6-[(1E,3R,4R,6R,7Z)-6-Hydroxy-3-(2-hydroxyethyl)-
8-iodo-3,4-isopropylidenedioxy-1,7-octadienyl]-5-ethyl-5,6-dihy-
dro-2H-pyran-2-one (57). To a stirred solution of 56 (74 mg, 0.088
mmol) in THF (1.1 mL) were added acetic acid (30 µL, 0.53 mmol)
and then tetrabutylammonium fluoride (1.0 M in THF, 263 µL,
0.263 mmol) at room temperature, and the reaction was stirred at
room temperature for 6 h. Again, acetic acid (30 µL, 0.53 mmol)
and then tetrabutylammonium fluoride (1.0 M in THF, 263 µL,
0.263 mmol) were added to the reaction mixture, which was stirred
at room temperature overnight. After addition of saturated NaHCO3
solution at 0 °C, the reaction mixture was extracted with ethyl
acetate. Combined organic layers were washed with saturated NaCl
solution, dried over Na2SO4, and concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (ethyl acetate-hexane ) 2:1) to give geometrically
pure Z-isomer 57 (27 mg, 63%) as a colorless oil: [R]23 +114.0
D
(c 4.80, CHCl3); IR νmax (KBr) 3390, 2968, 2881, 1716, 1378 cm-1
;
1H NMR (270 MHz, CDCl3) δ 0.97 (3H, t, J ) 8 Hz), 1.25 (3H,
s), 1.40-1.68 (3H, m), 1.53 (3H, s), 1.73s1.93 (2H, m), 2.05 (1H,
m), 2.34 (1H, d, J ) 5 Hz), 2.44 (1H, m), 2.60 (1H, dd, J ) 2, 8
Hz), 3.69 (1H, m), 3.83 (1H, m), 4.04 (1H, dd, J ) 3, 10 Hz), 4.60
(1H, m), 5.06 (1H, dd, J ) 2, 4 Hz), 5.89 (1H, d, J ) 15 Hz), 5.93
(1H, dd, J ) 2, 15 Hz), 6.07 (1H, d, J ) 10 Hz), 6.34 (1H, t, J )
8 Hz), 6.38 (1H, d, J ) 8 Hz), 7.00 (1H, dd, J ) 5, 10 Hz); 13C
NMR (67.8 MHz, CDCl3) δC 11.1, 21.7, 26.4, 28.2, 33.8, 35.4,
39.2, 59.6, 72.1, 79.3, 79.6, 82.5, 85.4, 108.6, 120.8, 125.2, 132.6,
142.6, 149.9, 163.7; mass (FAB) m/z 515 (M + Na+); HRMS calcd
for C20H29O6NaI 515.0906, found 515.0903.
(5S,6S)-6-[(1E,3R,4R,6R,7Z)-6-tert-Butyldimethylsiloxy-3-(2-
hydroxyethyl)-8-iodo-3,4-isopropylidenedioxy-1,7-octadienyl]-
5-ethyl-5,6-dihydro-2H-pyran-2-one (58). To a stirred solution
of 57 (25 mg, 0.051 mmol) and 2,6-lutidine (35 µL, 0.31 mmol) in
CH2Cl2 (0.5 mL) was added tert-butyldimethylsilyl triflate (35 mL,
0.15 mmol) at -78 °C, and the reaction was stirred at the same
(5S,6S)-6-[(1E,3R,4R,6R,7Z)-6-tert-Butyldimethylsiloxy-3-(2-
tert-butyldiphenylsiloxyethyl)-8-iodo-3,4-isopropylidenedioxy-
1,7-octadienyl]-5-ethyl-5,6-dihydro-2H-pyran-2-one (56). To a
stirred solution of 51 (230 mg, 0.358 mmol) in CH2Cl2 (4 mL)
5368 J. Org. Chem. Vol. 73, No. 14, 2008

Total Synthesis of Leustroducsin B
temperature for 1 h. After addition of saturated NaHCO3 solution,
the reaction mixture was warmed to room temperature and extracted
with ethyl acetate. Combined organic layers were washed succes-
sively with water, 0.5 M KHSO4 solution, water, saturated NaHCO3
solution, water, and saturated NaCl solution, dried over Na2SO4,
and concentrated under reduced pressure. The resulting bis-TBDMS
ether was dissolved in THF (0.2 mL), to which p-toluenesulfonic
acid monohydrate (0.3 mg, 3 mol%) was added at 0 °C. After being
stirred for 1 h at 0 °C, the reaction mixture was neutralized with
saturated NaHCO3 solution and extracted with ethyl acetate.
Combined organic layers were washed with saturated NaCl solution,
dried over Na2SO4, and concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(ethyl acetate-hexane ) 1:2) to give 58 (26 mg, 81%) as a colorless
oil: [R]22D +68.6 (c 1.60, CHCl3); IR νmax (KBr) 3451, 2938, 2889,
1725, 1612, 1464, 1376 cm-1; 1H NMR (270 MHz, CDCl3) δ 0.04
(3H, s), 0.08 (3H, s), 0.85 (9H, s), 0.95 (3H, t, J ) 7 Hz), 1.25
(3H, s), 1.37-1.71 (5H, m), 1.52 (3H, s), 2.03 (1H, m), 2.41 (1H,
m), 2.69 (1H, d, J ) 8 Hz), 3.68 (1H, m), 3.81 (1H, dt, J ) 4, 11
Hz), 3.99 (1H, dd, J ) 2, 11 Hz), 4.53 (1H, m), 5.04 (1H, t, J )
4 Hz), 5.86 (1H, d, J ) 15 Hz), 5.94 (1H, dd, J ) 4, 15 Hz), 6.06
(1H, dd, J ) 10 Hz), 6.20 (1H, t, J ) 8 Hz), 6.22 (1H, d, J ) 8
Hz), 6.98 (1H, dd, J ) 6, 10 Hz); 13C NMR (67.8 MHz, CDCl3)
δC -4.8, -4.1, 11.1, 18.1, 21.6, 25.8 (3C), 26.5, 28.3, 35.3, 35.4,
39.3, 59.7, 72.6, 78.8, 79.5, 80.1, 85.0, 108.3, 120.8, 124.8, 133.1,
144.1, 149.8, 163.7; mass (FAB) m/z 629 (M + Na+); HRMS calcd
for C26H23O6SiNaI 629.1772, found 629.1755.
(5S,6S)-6-[(1E,3R,4R,6R,7Z)-3-[2-(Allyloxylcarbonylamino)-
ethyl]-6-tert-butyldimethylsiloxy-8-iodo-3,4-isopropylidenedioxy-
1,7-octadienyl]-5-ethyl-5,6-dihydro-2H-pyran-2-one (60). To a
stirred solution of 58 (26 mg, 0.043 mmol), triphenylphosphine
(22 mg, 0.086 mmol), and diphenylphosphoryl azide (18 µL, 0.086
mmol) in THF (0.6 mL) was added diethyl azodicarboxylate (2.2
M in toluene, 39 µL, 0.086 mmol), and the reaction was stirred at
room temperature for 1 h. After being diluted with ether, the reaction
mixture was washed with saturated NaHCO3 solution, water, and
saturated NaCl solution, dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was passed through a silica
gel short column (ethyl acetate-hexane ) 1:2) to give azide 59
(30 mg), which was immediately employed for the next reaction.
To a stirred solution of 59 (30 mg) in THF (0.6 mL) were added
triphenylphosphine (22 mg, 0.086 mmol) and water (8 µL, 0.428
mmol) at room temperature. After stirring at room temperature for
12 h, pyridine (21 µL, 0.26 mmol) and allyl chloroformate (14 µL,
0.13 mmol) were added to the reaction mixture, which was stirred
at room temperature for 20 min and then diluted with ethyl acetate.
The organic solution was washed with saturated NaHCO3 solution
and saturated NaCl solution, dried over Na2SO4, and concentrated
under reduced pressure. The resulting residue was purified by silica
gel column chromatography (ethyl acetate-hexane ) 1:2) to give
60 (20 mg, 74% from 58) as a colorless oil: [R]23D +81.2 (c 2.20,
CHCl3); IR νmax (KBr) 3348, 3071, 2955, 2931, 2884, 2857, 1724,
1519, 1463, 1380 cm-1; 1H NMR (270 MHz, CDCl3) δ 0.04 (3H,
s), 0.07 (3H, s), 0.85 (9H, s), 0.95 (3H, t, J ) 8 Hz), 1.36 (3H, s),
1.39-1.67 (5H, m), 1.51 (3H, s), 1.85 (1H, m), 2.41 (1H, m),
3.12-3.37 (2H, m), 3.96 (1H, d, J ) 9 Hz), 4.48-4.54 (3H, m),
5.02 (1H, t, J ) 4 Hz), 5.18 (1H, d, J ) 11 Hz), 5.27 (1H, d, J )
17 Hz), 5.79-5.97 (3H, m), 6.06 (1H, d, J ) 10 Hz), 6.19 (1H, t,
J ) 8 Hz), 6.22 (1H, d, J ) 8 Hz), 6.97 (1H, dd, J ) 5, 10 Hz);
13C NMR (67.8 MHz, CDCl3) δC -4.8, -4.1, 11.1, 18.1, 21.6,
25.8 (3C), 26.6, 28.4, 33.4, 35.3, 36.9, 39.3, 65.3, 72.6, 78.8, 79.6,
80.0, 83.9, 108.2, 117.3, 120.8, 125.0, 133.0, 133.3, 144.2, 149.8,
155.9, 163.7; mass (FAB) m/z 690 (M + H+); HRMS calcd for
C30H49O7NSiI 690.2379, found 690.2351.
temperature for 15 h. Evaporation of the solution under reduced
pressure gave crude triol 61 (36 mg). To a solution of 61 (36 mg)
and segment C (7) (111 mg, 0.202 mmol) in degassed DMF (0.6
mL) was added bis(acetonitrile)dichloropalladium (3.3 mg, 10
mol%), and the reaction was stirred at room temperature for 1 h.
After concentration under reduced pressure, the resulting residue
was passed through a silica gel short column (chloroform-hexane
) 1:1) to give 62 (85 mg), which was dissolved in CH2Cl2 (0.8
mL) containing 2,6-lutidine (23 µL, 0.20 mmol). To the solution
was added tert-butyldimethylsilyl triflate (23 µL, 0.10 mmol) at
-78 °C, and the reaction was stirred at the same temperature for
30 min. After addition of saturated NaHCO3 solution, the reaction
mixture was warmed to room temperature and extracted with ethyl
acetate. Combined organic layers were washed successively with
water, 0.5 M KHSO4 solution, water, saturated NaHCO3 solution,
water, and saturated NaCl solution, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (ethyl acetate-hexane
) 1:1) to give 63 (28 mg, 60% from 60) as a colorless oil: [R]26
D
+89.9 (c 0.99, CHCl3); IR νmax (KBr) 3401, 2932, 2858, 1727,
1
1521, 1463 cm-1; H NMR (500 MHz, CDCl3) δ 0.03 (3H, s),
0.06 (3H, s), 0.83 (3H, d, J ) 6 Hz), 0.84 (3H, t, J ) 7 Hz), 0.87
(9H, s), 0.95 (3H, t, J ) 8 Hz), 1.01-1.67 (19H, m), 1.78-1.84
(2H, m), 1.90-1.98 (2H, m), 2.26 (2H, t, J ) 8 Hz), 2.43 (1H, m),
2.57 (1H, m), 3.06 (1H, br s), 3.16 (1H, m), 3.34 (1H, m),
3.77-3.80 (2H, m), 4.54 (2H, d, J ) 5 Hz), 4.74 (1H, m), 4.96
(1H, m), 5.06 (1H, t, J ) 4 Hz), 5.19 (1H, dd, J ) 1, 11 Hz), 5.29
(1H, dd, J ) 1, 17 Hz), 5.34 (1H, t, J ) 11 Hz), 5.52 (1H, t, J )
11 Hz), 5.81-5.95 (3H, m), 6.05 (1H, d, J ) 10 Hz), 6.05 (1H, t,
J ) 11 Hz), 6.21 (1H, t, J ) 11 Hz), 6.95 (1H, dd, J ) 6, 10 Hz);
13C NMR (125.65 MHz, CDCl3) δC -5.2, -4.4, 11.0, 11.4, 18.0,
19.1, 21.6, 23.6, 25.4, 25.7 (3C), 26.6, 29.4, 31.3, 31.9, 34.2, 34.6,
34.7, 35.0, 36.1, 36.7, 37.4, 38.0, 39.3, 65.5, 67.8, 72.1, 73.9, 76.9,
79.9, 117.5, 120.9, 121.5, 123.1, 125.5, 133.0, 133.3, 136.0, 138.2,
149.9, 156.4, 163.9, 173.3; mass (FAB) m/z 810 (M + Na+); HRMS
calcd for C44H73O9NSiNa 810.4952, found 810.4948.
Allyl (1E,3R,4R,6R,7Z,9Z)-3-[2-(Allyloxylcarbonylamino)-
ethyl]-6-tert-butyldimethylsiloxy-3,4-dihydroxy-10-{(1R,3S)-3-
[(6S)-methyloctanoyloxy]cyclohexyl}-1-[(5S,6S)-5-ethyl-5,6-di-
hydro-2-oxo-2H-pyran-6-yl]-1,7,9-decatrien-4-yl Triethylam-
monium Phosphate (65a). To a stirred solution of 63 (8.7 mg,
0.011 mmol) in pyridine (0.2 mL) was added phosphorus oxychlo-
ride (5 µL, 0.055 mmol) at 0 °C, and the reaction was stirred at 0
°C for 1.5 h. At 0 °C, allyl alcohol (80 µL, 1.11 mmol) was added
to the reaction mixture, which was stirred for 20 min and then
diluted with ethyl acetate. The reaction mixture was washed
successively with saturated NaHCO3 solution, 0.5 M KHSO4
solution, water, saturated NaHCO3 solution, and saturated NaCl
solution, dried over Na2SO4, and concentrated under reduced
pressure to give cyclic phosphate 64, which was dissolved in a
mixture of trifluoroethanol, triethylamine, and water (20:1:1, 1 mL).
After being stirred at room temperature for 1 h, the reaction mixture
was concentrated under reduced pressure to give a mixture of 65a,
65b, and 65c as a colorless oil, which was employed for the next
reaction without separation: IR νmax (KBr) 3320, 2933, 2858, 2675,
1
1726, 1516, 1463, 1382 cm-1; H NMR (500 MHz, CD3CN) δ
0.00 (3H, s), 0.08 (3H, s), 0.84-0.87 (15H, m), 0.91 (3H, t, J ) 7
Hz), 1.02-1.62 (19H, m), 1.24 (9H, t, J ) 8 Hz), 1.70-1.95 (4H,
m), 2.23 (2H, t, J ) 8 Hz), 2.48 (1H, m), 2.62 (1H, m), 3.00-3.02
(6H, m), 3.11-3.18 (2H, m), 4.13 (1H, t, J ) 9 Hz), 4.33-4.46
(4H, m), 4.70 (1H, m), 4.89 (1H, br t, J ) 9 Hz), 5.01 (1H, m),
5.23-5.43 (4H, m), 5.76-6.02 (5H, m), 6.14-6.25 (2H, m), 7.03
(1H, dd, J ) 5, 10 Hz), 11.3 (1H, br s); 31P NMR (202.35 MHz,
CD3CN) δP 2.4; minor isomers δP -2.1, 12.2; mass (FAB) m/z
1010 (M + H+); HRMS calcd for C53H94O12N2SiP 1009.6314,
found 1009.6303.
(5S,6S)-6-[(1E,3R,4R,6R,7Z,9Z)-3-[2-(Allyloxylcarbonylamino)-
ethyl]-6-tert-butyldimethylsiloxy-3,4-dihydroxy-10-{(1R,3S)-3-
[(6S)-methyloctanoyloxy]cyclohexyl}-1,7,9-decatrienyl]-5-ethyl-
5,6-dihydro-2H-pyran-2-one (63). A solution of 60 (38 mg, 0.060
mmol) in conc. HCl-methanol (1:30. 0.7 mL) was stirred at room
Leustroducsin B (1b). A solution of 65 (5.0 mg, 0.005 mmol)
in a mixture of 48% HF, acetonitrile, and pyridine (1:19:5, 0.5 mL)
was stirred at room temperature for 10 h. After being neutralized
J. Org. Chem. Vol. 73, No. 14, 2008 5369

Miyashita et al.
with saturated NaHCO3 solution, the reaction mixture was con-
centrated under reduced pressure. The resulting residue was passed
through a reversed phase silica gel short column (water-acetonitrile
) 40:1 to 2:1) to give crude product (2.9 mg), which was dissolved
in THF (0.1 mL) and treated with triphenylphosphine (1.2 mg, 0.005
mmol), ammonium formate (6.1 mg, 0.097 mmol), and tetraki-
s(triphenylphosphine)palladium (0.9 mg, 0.001 mmol) at 50 °C for
3 h. The solvent was evaporated off under reduced pressure, and
the resulting residue was purified by preparative silica gel TLC
(methanol) and then reversed phase silica gel TLC (water-acetonitrile
) 40:1 and then 1:2) to give leustroducsin B (1b) (1.6 mg, 49%
from 65) as a white solid: [R]25D +98.8 (c 0.050, MeOH); 1H NMR
(400 MHz, CD3OD) δ 0.86 (3H, d, J ) 6 Hz), 0.88 (3H, t, J ) 7
Hz), 0.96 (3H, t, J ) 8 Hz), 1.03-1.19 (3H, m), 1.24-1.74 (15H,
m), 1.81-1.96 (4H, m), 2.18 (1H, m), 2.28 (2H, t, J ) 7 Hz),
2.54-2.67 (2H, m), 2.97-3.11 (2H, m), 4.29 (1H, dt, J ) 3, 10
Hz), 4.72 (1H, m), 4.95 (1H, br t, J ) 8 Hz), 5.10 (1H, dd, J ) 4,
6 Hz), 5.31 (1H, br t, J ) 9 Hz), 5.46 (1H, br t, J ) 8 Hz), 5.95
(1H, d, J ) 16 Hz), 6.02 (1H, dd, J ) 1, 10 Hz), 6.07 (1H, dd, J
NMR (125.65 MHz, CD3OD) δC 11.4, 11.7, 19.6, 22.7, 24.6, 26.4,
27.6, 30.5, 32.4, 33.0, 34.3, 35.4, 35.5, 36.1, 37.1, 37.3, 39.4, 40.5
(2C), 64.6, 73.9, 77.7, 78.4, 82.3, 121.0, 123.7, 124.2, 127.6, 135.2,
137.2, 138.2, 152.7, 166.4, 175.0; mass (FAB) m/z 692 (M + Na+);
HRMS calcd for C34H56O10NPNa 692.3539, found 692.3554.
Acknowledgment. We thank Dr. Kousei Shimada (Sankyo
Co. Ltd.) and Professor Tohru Fukuyama for their kind gift of
spectral data for authentic leustroducsin B. Part of this work
was supported by a Grant-in-Aid from the JSPS.
Supporting Information Available: Experimental details for
the syntheses of compounds 4-7, 12, 14, 16, 18-20, 22, 24,
1
26, 27, 29, 33, 35, 36, 38-40, 42, 44, and 46 and H and 13C
NMR spectra for compounds 1b, 4-7, 12, 14, 16, 18-20, 22,
24, 26, 27, 29, 33, 35, 36, 38-40, 42, 44, 46, 48, 50-53, 56-58,
60, 63, and 65. This material is available free of charge via the
Internet at http://pubs.acs.org.
) 6, 16 Hz), 6.24-6.33 (2H, m), 7.09 (1H, dd, J ) 5, 10 Hz); 13
C
JO8005599
5370 J. Org. Chem. Vol. 73, No. 14, 2008