Total synthesis of phoslactomycin A

Article abstract of DOI:10.1021/ol900757k

A convergent total synthesis of the PP2A-inhibitor phoslactomycin A was achieved using a CuTC-mediated coupling of an alkenyl iodide C1-C13 fragment with an C14-C21 alkenyl stannane in the presence of a protected phosphate. Key features for the assembly of the C1-C13 fragment were an asymmetric dihydroxylation, an Evans-Aldol reaction, and a well-balanced protective group strategy. An asymmetric 1,4addition to cyclohexenone was the key step in the preparation of the C14-C21 fragment.

Full text of DOI:10.1021/ol900757k

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2728-2731
Total Synthesis of Phoslactomycin A
Christian M. Ko¨nig, Bjo¨rn Gebhardt, Cornelia Schleth, Mario Dauber, and
Ulrich Koert*
Fachbereich Chemie, Philipps-UniVersity Marburg, Hans-Meerwein-Strasse,
D-35032 Marburg, Germany
koert@chemie.uni-marburg.de
Received April 8, 2009
ABSTRACT
A convergent total synthesis of the PP2A-inhibitor phoslactomycin A was achieved using a CuTC-mediated coupling of an alkenyl iodide
C1-C13 fragment with an C14-C21 alkenyl stannane in the presence of a protected phosphate. Key features for the assembly of the C1-C13
fragment were an asymmetric dihydroxylation, an Evans-Aldol reaction, and a well-balanced protective group strategy. An asymmetric 1,4-
addition to cyclohexenone was the key step in the preparation of the C14-C21 fragment.
Phoslactomycin A, phoslactomycin B, and phoslactomycin
F (leustroducsin B) are representative members of the
phoslactomycins1 from Streptomyces nigrescens and the
leustroducsins2 from Streptomyces platensis (Figure 1). Their
Synthetic efforts in the phoslactomycin field led to total
syntheses of phoslactomycin F4 and phoslactomycin B5 as
well as formal total syntheses of both6 and a synthesis of
the C7-C13 part.7 Here, we present the first total synthesis
of phoslactomycin A.
Our synthetic strategy relied on a very late cross-coupling
of an already phosphorylated C1-C13 alkenyl iodide 1 with
a C14-C21 stananne 2 (Scheme 1). An Evans-Aldol
reaction was chosen for the introduction of the C4,C5
stereocenters and an asymmetric dihydroxylation of a trisub-
stituted alkene 3 for the formation of the C8,C9 dioxygen
functionality. The cis-disubstituted cyclohexane fragment 2
should be prepared via an asymmetric 1,4-addition to
cyclohexenone 4.
The synthesis of the C1-C13 fragment started with a
Cu-mediated opening of the epoxide 58 by vinyl-MgBr
(Scheme 2). After TIPS protection of the resulting alcohol,
oxidative clevage of the alkene gave an aldehyde 6 which
was subjected to a Wittig reaction with the phosphorane
Figure 1. Representative phoslactomycins.
(1) (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.
(2) (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.
various biological activities (induction of colony-stimulating
factors, anti-infective, and antitumor) were connected with
serine/threonine protein phosphatase 2A inhibition.3
10.1021/ol900757k CCC: $40.75
Published on Web 06/01/2009
 2009 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis of Phoslactomycin A
Scheme 2. Synthesis of the C1-C13 Fragment Part I
79 to yield the alkene 8. The asymmetric dihydroxyla-
tion10 of the trisubstituted double bond in 7 gave with
various ligands (DHQD)2PHAL, (DHQD)2PYR, and
(DHQD)2AQN a low diastereoselectivity of maximum 3:1
only. After lactone opening to the ethyl ester 3, the
dihydroxylation using (DHQD)2PYR delivered the desired
diol with 9:1 selectivity. The major stereoisomer was
chromatographically purified and transformed into the
DMP-acetal 9. Conversion of the ester into an unsaturated
aldehyde 10 and a subsequent Evans-aldol reaction11 (dr
95:5) with the oxazolidone 11 gave alcohol 12. TES
protection and removal of the chiral auxilary led to the
thiol ester 13.
(3) (a) Usui, T.; Marriott, G.; Inagaki, M.; Swarup, G.; Osada, H.
J. Biochem. 1999, 125, 960–965. (b) Truya, T.; Simizu, S.; Kanoh, N.;
Osada, H. FEBS Lett. 2005, 579, 2463–2468. For the role of the unsaturated
lactone in PP2A inhibition, see: (c) Buck, S. B.; Hardoin, 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.
(4) (a) Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc.
2003, 125, 4048–4049. (b) Miyashita, K.; Tsunemi, T.; Hosokawa, T.;
Ikejiri, M.; Imanishi, T. Tetrahedron Lett. 2007, 48, 3829–3833. (c)
Miyashita, K.; Tsunemi, T.; Hosokawa, T.; Ikejiri, M.; Imanishi, T. J. Org.
Chem. 2008, 73, 5360–5370.
The synthesis of the C1-C13 fragment continued with
the construction of the unsaturated lactone. First, the thiol
ester 13 was reduced to the corresponding aldehyde. An
Ando olefination12 of this aldehyde gave the unsaturated
ester 14. Selective deprotection of the TES and TBS silyl
ethers led to a diol which cyclized to the six-membered
lactone 15 upon treatment with catalytic amounts of
Ti(OiPr)4 in refluxing benzene (Scheme 3).
(5) (a) Wang, Y. G.; Takeyama, R.; Kobayashi, Y. Angew. Chem., Int.
Ed. 2006, 45, 3320–3323. (b) Shibahara, S.; Fujino, M.; Tashiro, Y.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2008, 10, 2139–
2142.
Our protection and functionalization strategy made use
of experiences from earlier syntheses4,5 but differed in the
timing for the introduction of the phosphate and the amine.
So far the phosphate was introduced at the very end of the
synthesis after completion of the carbon skeleton.4,5 We set
out to cross-couple fragments 1 and 2 with the protected
phosphate already attached to C9.
(6) (a) Druais, V.; Hall, M. J.; Corsi, C.; Wendeborn, S. V.; Meyer, C.;
Cossy, J. Org. Lett. 2009, 11, 935–938. (b) Moise, J.; Sonawane, R. P.;
Corsi, C.; Wendeborn, S. V.; Arseniyadis, S.; Cossy, J. Synlett 2008, 2617–
2620.
(7) Nonaka, H.; Maeda, N.; Kobayashi, Y. Tetrahedron Lett. 2007, 48,
5601–5604.
(8) Gaunt, M. J.; Hook, D. F.; Tanner, H. R.; Ley, S. V. Org. Lett.
2003, 5, 4815–4818.
(9) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. Tetrahedron 1992,
48, 9373–9384.
A zinc azide mediated Mitsunobu reaction13 was used
to convert the primary alcohol 15 into the corresponding
(10) Kolb, H. C.; VanNieuwenzhe, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483–2547.
(11) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099–3111.
(12) Ando, K. J. Org. Chem. 1997, 62, 1934–1939.
Org. Lett., Vol. 11, No. 13, 2009
2729

Scheme 3. Synthesis of the C1-C13 Fragment Part II
azide. The following cleavage of the DMP acetal to the
diol 16 required a careful optimization which finally led
to TFA in methanol as the best conditions. Next, the diol
was differentiated via formation of the bis TMS ether and
subsequent selective cleavage of the secondary TMS ether.
The resulting secondary alcohol at C9 was phosphorylated
by use of diallyl phosphoroamidite followed by oxidation
with tert-butyl hydroperoxide.14
aqueous H2SiF6 in CH3CN17 at -30 f 0 °C, which led
to simultaneous removal of the TMS ether at C8 and the
formation of compound 1.
A stereocontrolled 1,4-addition of an alkenyl moiety
was chosen for the introduction of the C16 stereocenter
(scheme 4). Among the various methods for asymmetric
With the protected C9-phosphate and a C25 azide as
latent amine in place, the deprotection of the PMB ether
at C12 was addressed next. Treatment of 17 with DDQ
delivered the free alcohol, which was oxidized using
Dess-Martin conditions15 to the aldehyde 18. The latter
was converted into the alkenyl iodide 19 according to the
Stork-Zhao protocol.16 The stereoselectivity for this
olefination step was >20:1 in favor of the Z isomer. The
Staudinger reduction of 19 with in situ Alloc-protection
gave the carbamate 20. Compound 20 is a completely
functionalized C1-C13 fragment and should be suitable
for cross-coupling reactions with the C14-C21 stananne
2. However, all attempts to use compound 20 in a cross-
coupling reaction with a Z-alkenylstannanes were unsuc-
cessful. A possible explanation could be the steric
shielding of the alkenyl iodide by the bulky TIPS group.
Therefore, the TIPS group was removed using 25%
Scheme 4. Synthesis of the C14-C21 Fragment
(13) Viaud, M. C.; Rollin, P. Synthesis 1990, 130–132.
(14) Hayakawa, Y.; Wakabayashi, S.; Nobori, T.; Noyori, R. Tetrahedron
Lett. 1987, 28, 2259–2262.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156–4158.
(16) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173–2174.
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Org. Lett., Vol. 11, No. 13, 2009

1,4-addition, the Rh-mediated addition of alkenylboronic
acids developed by Hayashi stands out in terms of catalyst
loading and enantioselectivity.18 The addition of the
E-styrylboronic acid to cyclohexenone 4 gave the ketone
21 with very good yield and enantioselectivity. The
subsequent NaBH4 reduction followed by TBS protection
delivered the alkene 22. A 7:1 diastereoselectivity in favor
of the cis-disubstituted cyclohexane was observed for the
reduction step. After ozonolysis of the double bond, the
resultingaldehydewassubjectedtoaZ-selectiveStork-Zhao
olefination. The resulting Z-alkenyl iodide was transformed
via iodine-lithium exchange into the desired Z-alkenyl-
stannane. Removal of the TBS group led to the alcohol
23, which was esterified to the desired building block 2.
Scheme 5. Final Coupling and Deprotection
With both fragments in hand, we turned our attention to
the final coupling (Scheme 5). A priori, a Pd-catalyzed Stille
reaction19 or a Cu-mediated Liebeskind coupling20 are
suitable to link an alkenyl iodide with an alkenylstannane.
In order to prevent side reactions of the Pd(0) catalyst with
the allyl phosphate, we chose Cu(I) thiophene carboxylate
CuTC as reagent of choice. The reaction of the C1-C13
alkenyl iodide 1 with the C13-C21 alkenylstannane 2
delivered the desired Z,Z-diene 24 in 61% yield. After
simultaneous removal of the phosphate and amine protective
groups with Pd(PPh3)4/HCOOH4a and subsequent RP-HPLC
purification, phoslactomycin A was obtained. The spectra
and analytical data of the synthetic sample corresponded to
those reported for the natural material.1
In conclusion, we have reported the first total synthesis
of phoslactomycin A. The convergent approach used a CuTC
coupling of a C1-C13 fragment alkenyl iodide with a
C14-C21 alkenylstannane. The C8,C9 stereocenters were
established by an asymmetric dihydroxylation, the C4,C5
centers were formed in an Evans-aldol reaction, and the
C16 center was formed by an asymmetric 1,4-addition. The
present and the previous4-6 phoslactomycin syntheses ap-
plied protective-group tactics to a synthetic problem with a
very high density of different functional groups.
Acknowledgment. The Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie are gratefully
acknowledged for financial support.
(17) Wehlan, H.; Dauber, M.; Mujica-Fernaud, M. T.; Schuppan, J;
Mahrwald, R.; Ziemer, B; Juarez-Garcia, M. E.; Koert, U. Angew. Chem.,
Int. Ed. 2004, 43, 4597–4601.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) (a) Hayashi, T. Synlett 2001, 879–887. (b) Hayashi, T.; Yamasaki,
K Chem. ReV. 2003, 103, 2829–2844.
(19) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508–523.
(20) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748–
2749.
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