Asymmetric total synthesis of (+)-phoslactomycin B

Article abstract of DOI:10.1021/ol8004672

(Chemical Equation Presented) (+)-Phoslactomycin B was synthesized by a highly enantio- and stereoselective approach involving asymmetric pentenylation, Suzuki-Miyaura coupling, ring-closing metathesis, asymmetric dihydroxylation, and Stille coupling. The synthetic method developed enables us to synthesize three other isomers concerning the C11-OH and Δ¹²-double bond.

Full text of DOI:10.1021/ol8004672

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2139-2142
Asymmetric Total Synthesis of
(+)-Phoslactomycin B
Setsuya Shibahara, Masataka Fujino, Yasumasa Tashiro, Keisuke Takahashi,
Jun Ishihara, and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki UniVersity,
Nagasaki 852-8521, Japan
susumi@nagasaki-u.ac.jp
Received March 1, 2008
ABSTRACT
(+)-Phoslactomycin B was synthesized by a highly enantio- and stereoselective approach involving asymmetric pentenylation, Suzuki-Miyaura
coupling, ring-closing metathesis, asymmetric dihydroxylation, and Stille coupling. The synthetic method developed enables us to synthesize
three other isomers concerning the C11-OH and ∆12-double bond.
The soil bacteria species Streptomyces produce a series
of structurally novel antifungal and antitumor antibiotics that
include phoslactomycins A-F and I,1 phosphazomycins C1
and C2,2 leustroducsins A-C and H,1e,3 and fostriecin (Fig-
ure 1).4
(1) (a) Fushimi, S.; Nishikawa, S.; Shimizu, 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) Shibata, T.; Kurihara, S.; Yoda, K.; Haruyama,
H. Tetrahedron 1995, 51, 11999–12012. (f) Sekiyama, Y.; Palaniappan,
N.; Reynolds, K. A.; Osada, H. Tetrahedron 2003, 59, 7465–7471. (g)
Choudhuri, S. D.; Ayers, S.; Soine, W. H.; Reynolds, K. V. J. Antibiot.
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(3) (a) Kohma, 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) Kohma, T.; Nakamura, T.;
Figure 1. Related phosphate esters produced by Streptomyces.
These compounds are highly potent and selective inhibitors
of protein serine/threonine phosphatase 2A (PP2A), which
is proposed to be responsible for their antitumor activity.4–6
Due to their intriguing molecular architectures and the
potential as a lead compound for anticancer drugs as well
as the importance as a biological tool, this class of com-
pounds has attracted much attention in the chemical and
biological communities.7 Thus, there have been a number
Kinoshita, T.; Kaneko, I.; Shiraishi, A. J. Antibiot. 1993, 46, 1512–1519
.
(4) (a) Lewy, D. S.; Gauss, C.-M.; Soenen, D. R.; Boger, D. L. Curr.
Med. Chem. 2002, 9, 2005–2032. (b) Buck, S. B.; Hardouin, C.; Ichikawa,
S.; Soenen, D. R.; Gauss, C.-M.; Hwang, I.; Swingle, M. R.; Bonness, K. M.;
Honkanen, R. E.; Boger, D. L. J. Am. Chem. Soc. 2003, 125, 15694–15695.
10.1021/ol8004672 CCC: $40.75
Published on Web 05/08/2008
2008 American Chemical Society

of synthetic studies including formal and total syntheses of
fostriecin,8,9 leustroducsin B,10,11 and phoslactomycin B.12
However, apart from fostriecin, additional C4-ethyl, quater-
nary C8-aminoethyl, and cyclohexyl substituents in their
structures hampers the development of an effective route to
these natural products. Herein, we describe an efficient
asymmetric synthesis of (+)-phoslactomycin B (1), which
enables us to prepare various analogues required for biologi-
cal testing as well.
phoslactomycin B (1) to make our approach flexible. We
expected that advanced intermediate 3 as well as its stere-
oisomers 4, 5, and 6 would each be available from 7 by the
combination of stereoselective formation of the E- or
Z-iodoenone and 9-OH directed anti- or syn-selective reduc-
tion. To access 7, we envisaged the approach from alcohol
8 involving Suzuki-Miyaura coupling,13 ring-closing me-
tathesis,14 and Sharpless asymmetric dihydroxylation15 as
major transformations. In this synthetic plan, the first key
issue to be addressed is, therefore, the enantio- and stereo-
controlled construction of alcohol 8. We envisaged that
reaction of aldehyde 10 with chiral (Z)-2-pentenylborane or
boronate 9 would proceed in the same fashion as Brown’s
or Roush’s asymmetric crotylation16,17 to produce 8 in
desired diastereo- and enantioselectivity, although such
asymmetric pentenylation was unprecedented.
Scheme 1. Retrosynthetic Analysis of Phoslactomycin B
Our synthesis of 1 thus began with the enantio- and
stereoselective preparation of alcohol 15 (Scheme 2). 1,3-
Scheme 2. Synthesis of Alcohol 15
Our synthetic plan is illustrated in Scheme 1. Based on
the methodology we have demonstrated in the total synthesis
of fostriecin,9f we envisaged ynone 7 as a precursor of
(5) (a) Walsh, A. H.; Cheng, A.; Honkanen, R. E. FEBS Lett. 1997,
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179–188. (d) Teruya, T.; Shimizu, S.; Kanoh, N.; Osada, H. FEBS Lett.
Propanediol was first converted to iodoalkene 11 as a 4:1
Z/E-mixture by a three-step sequence involving p-methoxy-
benzylation, Swern oxidation, and Horner-Emmons reaction
using in situ generated triethyl iodophosphonoacetate.18 Upon
DIBAH reduction followed by TEMPO oxidation, 11 af-
forded Z-aldehyde 12 in high geometrical purity (20:1), so
that the moderate Z/E-selectivity of the iodolalkenylation step
did not become a serious problem. It is important to note
2005, 579, 2463–2468
.
(6) (a) An acyloxy moiety on the cyclohexane ring, the only structural
variation seen in these phosphate esters, does not affect the PP2A-specific
inhibitory activity. Usui, T.; Marriott, G.; Inagaki, M.; Swarup, G.; Osada,
H. J. Biochem. 1999, 125, 960–965
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Imanishi, T. Chem. Commun. 2002, 742–743. (f) Esumi, T.; Okamoto, N.;
Hatakeyama, S. Chem. Commun. 2002, 3042–3043. (g) Wang, Y.-G.;
Kobayashi, Y. Org. Lett. 2002, 4, 4615–4618. (h) Miyashita, K.; Ikejiri,
M.; Kawasaki, H.; Maemura, S.; Imanishi, T. J. Am. Chem. Soc. 2003,
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Lett. 2003, 5, 733–736. (j) Maki, K.; Motoki, R.; Fujii, K.; Kanai, M.;
Kobayashi, T.; Tamura, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
17111–17117. (k) Trost, B. M.; Frederiksen, M. U.; Papillon, J. P. N.;
Harrington, P. E.; Shin, S.; Shireman, B. T. J. Am. Chem. Soc. 2005, 127,
3666–3667. (l) Hayashi, Y.; Yamaguchi, H.; Toyoshima, M.; Okado, K.;
Toyo, T.; Shoji, M. Org. Lett. 2008, 10, 1405–1408. (m) Yadav, J. S.;
(11) Miyashita, K.; Tsunemi, T.; Hosokawa, T.; Ikejiri, M.; Imanishi,
T. Tetrahedron Lett. 2007, 48, 3829–33833. The convergent synthesis
required 33 total steps exclusive of the manipulation on the cyclohexane
ring. The overall yield of the longest linear sequence was 0.32% in 24 steps
.
(12) Wang, Y.-G.; Takeyama, T.; Kobayashi, Y. Angew. Chem., Int.
Ed. 2006, 45, 3320–3323. The first synthesis was achieved in 0.61% overall
yield in 40 steps exclusive of the manipulation on the cyclohexane ring
(13) For reviews, see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457–2483. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168
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.
(10) Shimada, K.; Kabburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003,
125, 4048–4049. The first synthesis was achieved in 0.07% overall yield
(18) (a) Braun, N. A.; Klein, I.; Spitzner, D.; Vogler, B.; Braun, S.;
Borrmann, H.; Simon, A. Liebigs Ann. 1995, 2165–2169. (b) Moreau, X.;
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in 47 steps exclusive of the manipulation on the cyclohexane ring
.
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Org. Lett., Vol. 10, No. 11, 2008

that Dess-Martin and Swern oxidation conditions did not
promote the above-mentioned isomerization effectively.
Wittig reaction of 12 with Ph3PdCHCO2Et produced ester
13 stereoselectively, which was then subjected to DIBAH
reduction and Swern oxidation to afford 14 in good yield.
The key asymmetric pentenylation of 14 was first exam-
ined following the procedures for asymmetric crotylation
developed by Brown et al.16 (Table 1). When the reaction
Scheme 3. Synthesis of Ynone 21
Table 1. Asymmetric Pentenylation of 14
entry
methoda
yieldb (%)
syn/antic,d
ee (%) (config)e
1
2
3
A
B
C
98
82
79
25/75
100/0
100/0
not determined
93 (S,S)
46 (S,S)
a Method A: (Z)-2-pentenyl bromide, Mg, Et2O, -20 °C, then (+)-
(Ipc)2BOMe, -78 °C to rt, then 14, toluene, -78 °C. Method B: (Z)-2-
pentene, t-BuOK, n-BuLi, THF, -78 °C, then (+)-(Ipc)2BOMe, BF3·Et2O,
14, THF, -78 to -50 °C. Method C: (Z)-2-pentene, t-BuOK, n-BuLi, THF,
-78 °C, then B(O-i-Pr)3, then 1 M HCl, D-DIPT, then 14, toluene, -78
°C. b Isolated yield. c Determined by 1H NMR analysis of the product.
d Determined by NOE analysis of 17 and its C4-epimer. e Determined by
1H NMR analysis of the corresponding (R)- and (S)-MTPA esters as well
as HPLC analysis of 17 using a chiral column.
suggesting the concomitant kinetic resolution23 of 17 during
the dihydroxylation reaction. Successive acidic hydrolysis
followed by allyloxycarbonylation in the same flask con-
verted 18 to the triol which was silylated to give tri-TES
ether 19 in good yield. Exposure of 19 to Swern oxidation
conditions24 allowed the direct production of aldehyde 20
via selective cleavage of the primary triethylsilyl ether group.
Aldehyde 20 thus obtained was then converted to ynone 21
by ethynylation followed by Dess-Martin oxidation.
According to the procedure we have previously estab-
lished,9f 21 was converted to advanced intermediate 25 and
three other isomers 26, 27, and 28 (Scheme 4).
was conducted using the pentenylborane reagent prepared
from 2-pentenylmagnesium bromide and (+)-(Ipc)2BOMe,
a 1:3 syn/anti-mixture was unexpectedly obtained although
the yield was almost quantitative (entry 1). This result
suggests that a partial isomerization would take place during
the preparation of the Grignard reagent from (Z)-2-pentenyl
bromide. However, to our delight, the use of the reagent
prepared from 2-pentenylpotassium and (+)-(Ipc)2BOMe
allowed highly diastereo- and enantioselective pentenylation
to give (S,S)-syn-isomer 15 in 100% de and 93% ee in 82%
yield (entry 2). In the reaction employing the (Z)-2-
pentenylboronate following Roush’s protocol,17 the enanti-
oselectivity was unsatisfactorily low, although the diastere-
oselectivity was perfect (entry 3).
Assembly of ynone 21, a pivotal intermediate, was
achieved from 15 in completely stereoselective fashion as
illustrated in Scheme 3. Suzuki-Miyaura coupling19 of 15
with 9-(N-Boc-aminoethyl)-9-BBN prepared from tert-butyl
vinylcarbamate effectively introduced the C8-aminoethyl
appendage to give amino alcohol 16. After acryloylation of
16, the resulting acrylate was subjected to ring-closing
metathesis20 using the second generation Grubbs’ catalyst
in boiling CH2Cl2 to afford unsaturated lactone 17 cleanly.
Upon reaction of 17 with Super-AD-mix21,22 using (DHQD)2-
PHAL as a chiral ligand in aqueous t-BuOH at 0 °C, highly
diastereoselective dihydroxylation occurred preferentially at
the ∆8-double bond to give diol 18 and its 6,7-dihydroxy
isomer in a ratio of 87:13. However, very high regioselec-
tivity was not observed in this case unlike the similar
dihydroxylation in our previous synthesis of fostriecin.9f
Interestingly, diol 18 was found to be enantiomerically pure
despite the use of 17 (93% ee) as a starting material,
Thus, treatment25 of 21 with 2 equiv of NaI and 1.1 equiv
of acetic acid in acetone at room temperature produced a
chromatographically easily separable 92:8 Z/E-mixture of 22
and 23 in nearly quantitative yield. When this reaction was
conducted using NaI (2 equiv) in acetic acid, thermodynami-
cally more stable E-isomer 23 was obtained exclusively.
After selective desilylation of 22, reduction of aldol 24 with
Me4NB(OAc)3H proceeded with excellent anti-selectivity26
to afford 11R-diol 25 almost quantitatively. On the other
hand, NaBH4 reduction of 24 in the presence of Et3B27 gave
(19) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743–8744.
(20) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
(21) Nicolaou, K. C.; Yue, E. W.; Naniwa, Y.; Riccardis, F. D.; Nadin,
A.; Leresche, J. E.; Greca, S. L.; Yang, Z. Angew. Chem., Int. Ed. 1994,
33, 2187–2190.
(22) Dihydroxylation employing AD-mix-ꢀ turned out to be unsatisfac-
tory in terms of reproducibility.
(23) This phenomenon was also proved by the enantiomeric purity of
the recovered 17 (59% ee).
(24) Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron
Lett. 1999, 40, 5161–5164.
(25) Taniguchi, M.; Kobayashi, S.; Nakagawa, M.; Hino, T.; Kishi, Y.
Tetrahedron Lett. 1986, 27, 4763–4766.
(26) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560–3578.
Org. Lett., Vol. 10, No. 11, 2008
2141

Scheme 4. Synthesis of Phoslactomycin B
11S-diol 26 exclusively. Similarly, from E-isomer 23, the
corresponding 11R-diol 27 and 11S-diol 28 were obtained
with very high selectivity, respectively.
of 32 in the presence of n-Bu3SnH and H2O furnished (+)-
phoslactomycin B (1), [R]23 +83.0 (c 0.20, MeOH) [lit.1c
D
[R]21 +81 (c 1.0, MeOH)]. The spectral data (1H and 13C
D
Having secured reliable routes to attain 25 and all of its
isomers including the C11 stereocenter and ∆12-double bond,
we then moved on to the final stage toward the total synthesis
of phoslactomycin B (1). In this particular case, Stille
coupling28 of 25 with stannane 229 was low yielding under
various conditions. However, we eventually found a reliable
method which gave 29 with good reproducibility. Namely,
when 25 was reacted with 2 in the presence of 0.3 equiv of
Pd(MeCN)2Cl2 in MeCN-THF (4:1) at room temperature
for 1 h, 29 was obtained in 46% yield along with the clean
recovery of 25 (43%). After separation, the recovered 25
was again subjected to the above-mentioned coupling condi-
tions. As a result of this sequence, 29 was obtained in >60%
yield. Upon selective silylation of the C11-OH and phos-
phorylation of the C9-OH, 29 afforded phosphate 30 in good
yield. Finally, desilylation of 30 using HF-pyridine-
H2O-MeCN30 followed by Pd(0)-catalyzed deallylation12
NMR, IR, and FAB-Mass) exhibited good agreement with
those1c reported for the natural specimen.
In conclusion, we have accomplished a total synthesis of
(+)-phoslactomycin B from 1,3-propanediol in 26 steps in
1.3% overall yield. The synthetic method developed is
flexible and of potential value for the preparation of various
analogues. The synthesis of stereoisomers of 1 from 26, 27,
and 28 is currently under investigation.
Acknowledgment. This work was partly supported by
Grant-in-Aid for Scientific Research of Japan Society for
the Promotion of Science (JSPS) and The Ministry of
Education, Culture, Sports, Science and Technology (MEXT).
We thank Professor Yuichi Kobayashi (Tokyo Institue of
1
Technology) for the H and 13C NMR spectra of phoslac-
tomycin B.
(27) Chen, K.-M.; Hardtmann, E.; Prasad, K.; Repic, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155–158.
Supporting Information Available: Experimental details
for all new compounds and 1H and 13C NMR spectra for 1,
2, and 11-32. This material is available free of charge via
the Internet at http://pubs.acs.org.
(28) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813–817.
(29) Prepared from ethynylcyclohexane in 69% yield: (i) n-BuLi,
n-Bu3SnCl, THF, -78 °C; (ii) CpZrHCl, THF.
(30) Exposure of 30 to the desilylation conditions over 3 h caused
appreciable decomposition of 32. The optimal procedure to obtain 32
involves a 2 h reaction of 30 and another 2 h reaction of 31 formed together
with 32 in the first desilylation (see the Supporting Information).
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