Total synthesis of (+)-psymberin (irciniastatin A): Catalytic reagent control as the strategic cornerstone

Article abstract of DOI:10.1021/ol802466t

(Chemical Equation Presented) An effective total synthesis of the marine sponge cytotoxin (+)-psymberin [irciniastatin A (1)] has been achieved. Highlights of the strategy include a Diels-Alder reaction between a bis-siloxy diene and an allene to construct the aromatic ring, a boron-mediated aldol reaction to elaborate the C(15-17) all syn stereotriad, catalytic reagent control to set the C(8, 9,11 and 13) stereogenic centers of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the sensitive N,0-aminal moiety. The synthesis proceeds with a longest linear sequence of 21 steps from commercially available 2,2-dimethyl-1,3-propanediol.

Full text of DOI:10.1021/ol802466t

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5625-5628
Total Synthesis of (+)-Psymberin
(Irciniastatin A): Catalytic Reagent
Control as the Strategic Cornerstone
Amos B. Smith III,* Jon A. Jurica, and Shawn P. Walsh
Department of Chemistry, Laboratory for Research on the Structure of Matter,
and Monell Chemical Senses Center, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received October 25, 2008
ABSTRACT
An effective total synthesis of the marine sponge cytotoxin (+)-psymberin [irciniastatin A (1)] has been achieved. Highlights of the strategy
include a Diels-Alder reaction between a bis-siloxy diene and an allene to construct the aromatic ring, a boron-mediated aldol reaction to
elaborate the C(15-17) all syn stereotriad, catalytic reagent control to set the C(8, 9, 11 and 13) stereogenic centers of the tetrahydropyran
core, and a late-stage Curtius rearrangement to install the sensitive N,O-aminal moiety. The synthesis proceeds with a longest linear sequence
of 21 steps from commercially available 2,2-dimethyl-1,3-propanediol.
In 2004, the laboratories of Pettit and Crews independently
disclosed the isolation of ircinistatin A1 and psymberin (1),2
respectively, from the marine sponges Ircinia ramosa and
Psammocinia sp. A closely related compound, irciniastatin
B, possessing a carbonyl moiety at C(11) was also reported
by the Pettit group. From the outset, irciniastatin A and
psymberin appeared to be constitutionally equivalent based
on high resolution mass spectrometry, in conjunction with
the 1D and 2D NMR data. The absolute configuration of
psymberin was assigned by the Crews group based on a
combination of CD studies along with the assumed analogy
to the structure of pederin.3 Neither group however assigned
the relative stereogenecity at C(4); also recorded were
conflicting stereochemical assignments for the C(8) N,O-
aminal. Importantly, both isolates displayed significant cancer
cell growth inhibitory activity against a wide variety of
human cancer cell lines. The potent cytotoxicity data, in
conjuction with the conflicting and incomplete stereochemical
assignments, quickly drew the attention of the synthetic
community. In 2005, Williams and Kiren4 assigned the
C(4,5) stereorelationship as anti based on a model compound
synthesis, in conjuction with detailed NMR comparisons.2
Shortly thereafter, the DeBrabander group announced the first
total synthesis of (+)-psymberin, complete with construction
of the four possible C(4)-C(8) epimers, which not only
established the structural assignment, including absolute
(1) Pettit, G. R.; Xu, J. P.; Chapuis, J. C.; Pettit, R. K.; Tackett, L. P.;
Doubek, D. L.; Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47,
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(3) Furusaki, A.; Watanabe, T.; Matsumoto, T.; Yanagiya, M. Tetra-
hedron Lett. 1968, 9, 6301.
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(4) Williams, L. J.; Kiren, S. Org. Lett. 2005, 7, 2905.
10.1021/ol802466t CCC: $40.75
Published on Web 12/11/2008
2008 American Chemical Society

configuration, but also confirmed that (+)-irciniastatin A and
(+)-psymberin (1) were in fact one and the same.5 Related
synthetic work followed quickly,6 with a formal synthesis
in 20077 and a second total synthesis reported by the
Schering-Plough group,8 the latter exploiting a novel
(diacetoxyiodo)benzene-mediated cyclization to construct the
central tetrahydropyran core.
We also were intrigued with (+)-psymberin (1) as a
potential new cancer therapeutic lead. Herein we report our
efforts recently culminating in an effective total synthesis
of (+)-1. Central to our synthetic plan was the use of catalytic
reagent control to set the stage for an eventual structure-
activity study to define the structural elements required for
biological activity.9
C(16,17) stereogenic centers. In the forward sense, access
to aldehyde 4 would entail a Diels-Alder reaction between
bis-siloxydiene 611 and allene 7.12 The requisite 2,6-trans-
tetrahydropyran (5) in turn would derive via cyclization of
a linear epoxy alcohol precursor (cf. 8). From the strategic
perspective, installation of the four stereogenetic centers at
C(8, 9, 11 and 13) would take advantage of catalytic reagent
control, beginning with an asymmetric vinylogous Mu-
kaiyama aldol reaction13 to furnish 9. The clear advantage
of this tactic, if successful, would be rapid access to a wide
variety of stereochemically diverse congeners, simply by
changing the enantiomer of the catalyst, thereby avoiding
significant strategy redesign to access analogues for the
prospective structure-activity relationship study.9
With this overview in mind, disconnection of the amide
bond in (+)-1 (Scheme 1), as with the earlier reported
We began with the synthesis of side chain acid 2 employing
known methyl ether (+)-10,5 which was constructed in two
steps with an overall yield of 57% yield (dr > 20:1) from
commercially available (+)-isopropylidene glyceraldyde (Scheme
2). The acetonide was then removed with aqueous hydrochloric
Scheme 1
Scheme 2
acid, followed by masking of the primary alcohol as the pivalate
ester (+)-11; the yield for the two steps was 85%. Subsequent
protection of the secondary alcohol as the SEM ether, followed
by DIBAL-H reduction of the pivalate ester, furnished primary
alcohol (+)-12, which upon a two-step Parikh-Doering14/
Pinnick15 oxidation provided the C(1-6) side chain acid (-)-2
in 89% yield.
Construction of the C(17-25) aryl aldehyde 4 began with
the proposed Diels-Alder reaction between 1,3-bis(trimeth-
ylsiloxy)-1,3-diene 611 and dimethyl-1,3-allene-dicarboxlate
7,12 followed by treatment with HF•NEt3 to effect aroma-
tization leading to known homophthalate 1316 (Scheme 3).
The two phenolic hydroxyls were then protected as SEM
ethers; selective reduction of the alkyl ester in the presence
of the benzylic ester completed construction of aldehyde 4.
The overall yield for the three-step sequence was 55%.
With the side chain and aryl fragments in hand, we turned
attention to the central fragment, tetrahydropyran 5. Beginning
with commercially available 2,2-dimethyl-1,3-propanediol (14),
monoprotection as the TBS ether, followed by Parikh-Doering
syntheses,5,7,8 leads to a side chain acid (2) and amide
coupling precursor (3), the latter bearing a Teoc-protected
N,O-aminal. We envisioned that elaboration of the N,O-
aminal could be achieved in a highly stereoselective fashion
exploiting a late-stage Curtius rearrangement similar to that
developed and employed in our total syntheses of (+)-
dactylolide and (+)-zampanolide.10 Further disconnection at
the C(16,17) bond leads to aldehyde 4 and 2,6-trans-
tetrahydropyran 5, which would be joined via a 1,4-substrate
controlled boron-mediated aldol reaction to install the
(5) Jiang, X.; Garcia-Fortanet, J.; DeBrabander, J. K. J. Am. Chem. Soc.
2005, 127, 11254.
(6) Rech, J. C.; Floreancig, P. E. Org. Lett. 2005, 7, 5175.
(7) Shangguan, N.; Kiren, S.; Williams, L. J. Org. Lett. 2007, 9, 1093.
(8) Huang, X.; Shao, N.; Palani, A.; Aslanian, R.; Buevich, A. Org.
Lett. 2007, 9, 2597.
(11) Yamamoto, K.; Suzuki, S.; Tsuji, J. Chem. Lett. 1978, 649.
(12) Bryson, T. A.; Dolak, T. M. Org. Synth. 1977, 57, 62.
(13) Simsek, S.; Horzella, M.; Kalesse, M. Org. Lett. 2007, 9, 5637.
(14) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(15) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
(9) Smith, A. B., III.; Walsh, S. P.; Frohn, M.; Duffey, M. O. Org. Lett.
2005, 7, 139.
(10) Smith, A. B., III.; Safonov, I. G.; Corbett, R. M. J. Am. Chem.
Soc. 2002, 124, 11102.
(16) Langer, P.; Kracke, B. Tetrahedron Lett. 2000, 41, 4545.
5626
Org. Lett., Vol. 10, No. 24, 2008

chromatography now proved straightforward. Parikh-Doering
oxidation of the neopentyl alcohol then completed construction
of aldehyde (+)-20 in 95% yield.
Scheme 3
Final elaboration of 8, the requisite cyclization precursor,
entailed treatment of 2-butanone (21) with (-)-DIPCl and
Et3N according to conditions developed by Paterson,21,22
followed by addition of aldehyde (+)-20; cyclization precur-
sor 8 was obtained as an inseparable mixture of diastereomers
(5:1) in 86% yield (Scheme 5). Treatment with camphor-
Scheme 5
oxidation of the free hydroxyl, provided aldehyde 15 in 85%
yield (Scheme 4). A vinylogous Mukaiyama aldol reaction
Scheme 4
sulfonic acid then led to the desired 2,6-trans-tetrahydropyran
(+)-22 in 74%, in conjunction with 14% of the cis-congener
(-)-23, the latter resulting from cyclization of the undesired
C(13) R-hydroxyl epimer formed during the Paterson aldol
reaction. Separation of (+)-22 and (-)-23 was now possible
by flash chromatography on silica gel. Of special note, the
cyclization proceeded exclusively via the 6-exo-tet pathway,
without intervention of 7-endo-tet manifold, as determined
1
by H NMR analysis. Since both processes are viewed as
“allowed” vis-a`-vis Baldwin rules,23 the six-membered ring
transition state, in conjunction with the electron-withdrawing
nature of the methyl ester that destabilizes cationic character
at the R-position, conspire to favor reaction at the ꢀ-position
to generate the required tetrahydropyran ring system. Me-
thylation of the resultant secondary alcohol utilizing trim-
ethyloxonium tetrafluoroborate with Proton Sponge as base
then furnished (+)-5, the 2,6-trans-tetrahydropyran fragment,
in 92% yield.
Turning to the union of ketone (+)-5 with aldehyde 4,
the Z-boron enolate of (+)-5 was generated exploiting the
rarely used dichlorophenylborane.24 Addition of aldehyde 4
at -78 °C provided the desired syn-aldol product (+)-24 in
90% yield (dr > 20:1), taking advantage of 1,4 substrate
stereoinduction25 (Scheme 6). Treatment of the latter with
diethylmethoxyborane and sodium borohydride resulted in
promoted by oxazaborilidinone employing silyl ketene acetal
1613 and aldehyde 15 then set the C(11) configuration, the first
of the catalytic reagent controlled reactions. The yield of (+)-9
was 66%. More importantly, a single (R) isomer resulted as
determined by Mosher’s ester analysis.17,18
Alcohol (+)-9 was next protected as the TBS ether and then
subjected to DIBAL-H reduction to provide the corresponding
allylic alcohol. Sharpless asymmetric epoxidation19 furnished
ꢀ-epoxide (+)-17 in 88% yield (ꢀ:R ) 13:1). Without separa-
tion, a one-step TEMPO oxidation20 to furnish the carboxylic
acid, followed by methylation with TMSCHN2, led to epoxy
ester (+)-18, as a mixture of epoxides. Selective removal of
the primary TBS group in the presence of the secondary TBS
group utilizing buffered HF•pyridine provided alcohol (+)-19;
removal of the minor epoxide diastereomer (dr > 20:1) by flash
(17) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
(21) Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997
.
Soc. 1991, 113, 4092
.
(22) Paterson, I.; Goodman, J. M.; Anne Lister, M.; Schumann, R. C.;
(18) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451
.
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663.
(19) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(20) Zhao, M. M.; Li, J.; Mano, E.; Song, Z. J.; Tschaen, D. M. Org.
Synth. 2005, 81.
(23) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(24) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984, 10,
1729.
Org. Lett., Vol. 10, No. 24, 2008
5627

Scheme 6
Scheme 7
chelation-controlled reduction26 of the ketone to provide the
1,3-syn diol in 95% yield (dr > 20:1), which upon exposure
to lithium hydroxide in wet methanol effected hydrolysis of
the methyl ester, with concomitant lactonization to provide
dihydroisocoumarin (+)-25; the yield was 87%.
psymberin were in complete agreement with the correspond-
ing published data for natural (+)-psymberin (1) reported
by Pettit, as well as the spectral data from the DeBrabander
laboratory.
We next called upon the Curtius rearrangement tactic
developed during the total syntheses of (+)-zampanolide and
(+)-dactylolide to set the configuration of the C(8) stereogenic
center.10 Pleasingly, this protocol, employing 2-trimethylsilyle-
thanol to capture the intermediate isocyanate, provided the Teoc-
protected N,O-aminal in 74% yield. Final protection of the free
C(15) secondary alcohol as the TBS ether completed construc-
tion of the amide coupling precursor (+)-3.
Union of (+)-3 with the side chain acid (-)-2 was not
without considerable difficulty (Scheme 7). However, after
extensive experimentation, we discovered that deprotonation
of the Teoc-protected amine (+)-3, employing LiHMDS,
followed by addition of the side chain acid activated as the
pivalate mixed anhydride (26), provided amide (+)-27
comprising the full carbon skeleton of (+)-psymberin; the
yield was 79%. Next, treatment with TASF in DMF at 50
°C, employing conditions developed during an advanced
model study used to devise the optimized conditions for the
amide coupling, as well as to address the stability of the
N,O-aminal moiety, resulted in two major products. The first
proved to be (+)-psymberin (1), with the second still bearing
a SEM group on one of the phenolic oxygens. Treatment of
the latter with magnesium bromide cleanly provided (+)-
psymberin (1) in a combined 74% yield for the two steps.
The spectral data (1H and 13C NMR) for synthetic (+)-
In summary, an enantioselective total synthesis of (+)-
psymberin has been achieved in 21 steps (longest linear
sequence). The central goal of this synthetic venture was to
construct the 2,6-trans-tetrahydropyran utilizing catalytic
reagent control to install the requisite stereogenicity within
the tetrahydropyran core, thereby permitting potential future
access to a series of stereochemically defined congeners
without major changes to the synthetic sequence. Work
focusing on the synthesis of analogues using this catalytic
reagent control approach is currently ongoing in our labora-
tory. Finally, application of the Curtius rearrangement
protocol developed in our laboratory for the synthesis of
R-methoxy acids permitted late-stage introduction of the
labile N,O-aminal in a highly diastereoselective fashion.
Acknowledgment. Financial support was provided by the
National Institute of Health (National Cancer Institute)
through Grant No. CA-19033, and to JAJ by Merck & Co.,
Inc. through the MMD-Ph.D. program. In addition, we thank
Professor Cheon-Gyu Cho (Hanyang University, Seoul,
Korea) and Won-Suk Kim (University of Pennsylvania) for
their early exploratory studies on (+)-psymberin.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds, as well as experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871.
(26) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
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