Total synthesis of irciniastatin A (psymberin)

Article abstract of DOI:10.1021/ol901655e

The total synthesis of (+)-iriciniastatin A (psymberin) is reported in 19 steps and 6% overall yield. Key reactions include a highly convergent enolsilane-oxocarbenium ion union to generate the C8-C25 fragment and a late-stage coupling of a hemiaminal and

Full text of DOI:10.1021/ol901655e

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3990-3993
Total Synthesis of Irciniastatin A
(Psymberin)
Michael T. Crimmins,* Jason M. Stevens, and Gregory M. Schaaf
Kenan and Caudill Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received July 21, 2009
ABSTRACT
The total synthesis of (+)-iriciniastatin A (psymberin) is reported in 19 steps and 6% overall yield. Key reactions include a highly convergent
enolsilane-oxocarbenium ion union to generate the C8-C25 fragment and a late-stage coupling of a hemiaminal and acid chloride to complete
the synthesis.
In 2004, Pettit and Crews independently reported the isolation
of two remarkably potent and selective cancer cell growth
inhibitors from the extracts of deep water sponges. Irciniastatin
A (1) was obtained from Ircinia ramosa by Pettit,1 and
psymberin was isolated from Psammocina sp. by Crews.2 The
two secondary metabolites were shown to be structurally related
on the basis of spectroscopic studies; however, incomplete and
conflicting stereochemical analyses precluded a definitive as-
signment of absolute configuration. Each displayed incredibly
powerful and selective cancer cell growth inhibition. Irciniastatin
A was reported to exhibit a greater than 104 differential in
activity across related cell lines. The limited natural abundance
and lack of an absolute stereochemical assignment, as well as
interest in further exploration of the unique chemotherapeutic
profile and mode of action, sparked immediate interest within
the synthetic community.
Ultimately, it was the seminal total synthesis by DeBrabander5
that confirmed the absolute configuration and demonstrated that
irciniastatin A (1) and psymberin were identical. Subsequent
reports, including fragment synthesis,6 a formal synthesis,7 two
total syntheses,8,9 and two reports of analogue syntheses,10,11
all offered creative and distinct approaches toward the unique
structural elements of irciniastatin A.
Our interest in (+)-irciniastatin A (psymberin) focused on
developing a highly diastereoselective and modular synthesis
that might be suitable for analogue preparation. Our efforts
(5) Jiang, X.; Garcia-Fortanet, J.; DeBrabander, J. K. J. Am. Chem. Soc.
2005, 127, 11254.
(6) (a) Rech, J. C.; Floreancig, P. E. Org. Lett. 2005, 7, 5175. (b) Henssen,
B.; Kasparyan, E.; Marten, G.; Pietruszka, J. Heterocycles 2007, 74, 245.
(c) Pietruszka, J.; Simon, R. Eur. J. Org. Chem. 2009, 3628. (d) The following
report appeared during the preparation of this manuscript: Brown, L. E.;
Landaverry, Y. R.; Davies, J. R.; Milinkevich, K. A.; Ast, S.; Carlson, J. S.;
Oliver, A. G.; Konopelski, J. P. J. Org. Chem. 2009, 74, 5405.
(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.
Early reports shed light on the stereochemical ambiguities
through fragment synthesis3 and natural product degradation.4
Lett. 2007, 9, 2597
.
(9) Smith III, A. B.; Jurica, J. A.; Walsh, S. P. Org. Lett. 2008, 10,
(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,
1149.
5625
.
(10) (a) Huang, X.; Shao, N.; Huryk, R.; Palani, A.; Aslanian, R.; Seidel-
Dugan, C. Org. Lett. 2009, 11, 867. (b) Huang, X.; Shao, N.; Palani, A.;
Aslanian, R.; Buevich, A.; Seidel-Dugan, C.; Huryk, R. Tetrahedron Lett.
(2) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6,
1951.
2008, 49, 3592
(11) Jiang, X.; Williams, N.; De Brabander, J. K. Org. Lett. 2007, 9,
227
.
(3) Kiren, S.; Williams, L. J. Org. Lett. 2005, 7, 2905.
(4) Green, M. E.; Rech, J. C.; Floreancig, P. E. Org. Lett. 2005, 7, 4117.
.
10.1021/ol901655e CCC: $40.75
Published on Web 08/11/2009
 2009 American Chemical Society

toward (+)-1 recently culminated in a completed total synthesis
that is reported here.
congener synthesis. The synthesis of acid chloride 2 (Scheme
2) began with the known13 anti-aldol12a reaction of glycolate
Retrosynthetically (Scheme 1), (+)-irciniastatin A (1) was
envisioned to arise from two key disconnections. A late-stage
attachment of the psymberic acid chain would be accomplished
Scheme 2. Synthesis of the Psymberic Acid Side Chain
Scheme 1. Retrosynthetic Analysis of Irciniastatin A
9 and 3-methyl-but-3-enal to deliver aldol adduct 10 that
was converted to known TIPS ether 11.13 Methylation of
the alcohol was followed by removal of the allyl protecting
group under Kulinkovich conditions13,14 to give alcohol 12.
Protection of alcohol 12 as the SEM ether was followed by
selective removal of the primary TIPS ether. The resultant
primary alcohol 13 was oxidized under Smith’s conditions,
giving the corresponding acid over two steps. The acid (9
steps, 28% overall) was converted to acid chloride 2.
The synthesis of the acetate 5 (Scheme 3) began from
known p-methoxybenzylidine acetal 1415 available from
2-deoxy-D-ribose in two steps. Methylation of alcohol 14
was followed by a dihydroxylation-oxidative cleavage
by coupling of acid chloride 2 with hemiaminal 3, the product
of a Curtius rearrangement of the carboxylic acid derived from
benzyl ether 4. This tactic would allow for a highly stereocon-
trolled entry to the C8 hemiaminal and efficient incorporation
of the side chain. Tetrahydropyran 4 would arise from the
stereoselective addition of enolsilane 6 to the oxocarbenium ion
derived from acetate 5. These two key disconnections segregate
the three major subunits of irciniastatin A (1), each of similar
size and complexity and accessible in a highly stereocontrolled
fashion from standard aldol synthons.
Scheme 3. Synthesis of Acetate 5
All reported syntheses of the psymberate side chain have
relied on functionalizing commercially available chiral pools
or enzymatic resolutions. In addition, analogue studies10,11 have
shown the side chain to be required for high activity.
Therefore, an enantioselective and highly tunable synthesis
of the side chain would be ideal for further investigation of
side chain function. We reasoned that an oxazolidinethione
asymmetric glycolate aldol reaction12 would allow for
enantioselective entry to the psymberate side chain as well
as provide sufficient opportunities for derivitization and
(12) (a) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591. (b)
Crimmins, M. T.; She, J. Synlett 2004, 1371.
(13) Crimmins, M. T.; McDougall, P. J.; Emmitte, K. A. Org. Lett. 2005,
7, 4033.
(14) Lee, J.; Cha, J. K. Tetrahedron Lett. 1996, 37, 3663.
(15) (a) Fu¨rstner, A.; Schlede, M. AdV. Synth. Catal. 2002, 344, 657.
(b) Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.;
Le Brazidec, J.-Y.; Hirama, M. Tetrahedron 2002, 58, 6493.
(16) Kiyooka, S.-I.; Kira, H.; Hena, M. A. Tetrahedron Lett. 1996, 37,
2597.
(17) Juaristi, E.; Cruz-Sanchez, S. J. Org. Chem. 1988, 53, 3334.
Org. Lett., Vol. 11, No. 17, 2009
3991

sequence to reveal aldehyde 16. A catalyst-controlled Kiyoo-
ka16 aldol reaction of aldehyde 16 and enolsilane 1717
provided carbinol 18 in 84% yield and 9:1 dr. Protection of
alcohol 18 to give TBS ether 19 was followed by acid-
catalyzed cyclization to provide a 10:1 mixture of lactone
20 and the corresponding diol, which was converted to
lactone 20 by exposure to CF3CO2H. Protection of the
primary alcohol gave benzyl ether 21 and subsequent one-
pot reductive acetylation18 afforded acetate 5 in quantitative
yield (9 steps, 34% overall from 2-deoxy-D-ribose).
Scheme 5. Coupling of Acetate 5 with Enolsilane 6
The synthesis of enolsilane 6 (Scheme 4) began from
known catechol 246,19 prepared by cycloaddition of allene
Scheme 4. Synthesis of Enolsilane 6
enolsilane for the assembly of 5 and 6. Most intriguing,
however, was that addition of a solution of enolsilane 6 to
a premixed solution of 5 and BF3·OEt2 at -40 °C was
required for efficient coupling. The union proceeded with
high diastereoselectivity, giving tetrahydropyran 4 as the only
detectable diastereomer. The high diastereoselectivity can be
rationalized by well precedented23 pseudoaxial addition of
the nucleophile to the oxocarbenium conformer 29, proceed-
ing through a favorable chairlike conformation. Conformer
29 would also be expected to be favored as a result of
through-space stereoelectronic stabilization23 of the oxocar-
benium ion by the axially positioned C11 ether.
With the C8-C25 carbon framework in place, conditions
to set the C15 stereocenter were investigated (Scheme 6).
Standard achiral reducing agents proved to be nonselective
or completely selective for the undesired diastereomer;24
however, the use of the chiral (R)-CBS25 agent exclusively
provided desired diastereomer 3026 in 82% yield. After
protection of the secondary alcohol as its TBS ether and
cleavage of the benzyl ether, carbinol 31 was oxidized over
2 steps to carboxylic acid 32. Initial studies showed the one-
pot Curtius reaction with (O,O)-diphenylphosphoryl azide27
to be ineffective, providing significant quantities of insepa-
rable carbamoyl azide impurity.28 Therefore, Weinstock’s
procedure9,29 was employed to generate the intermediate
isocyanate, which under mild conditions using copper(I)
2320 and diene 22.21 Protection of catechol 24 as the bis-
TIPS ether was followed by selective ester reduction to give
aldehyde 25 in 78% yield over 2 steps. An asymmetric
propionate aldol22 reaction of aldehyde 25 and propionyl
thiazolidinethione 26 afforded the Evans-syn-aldol adduct
27 in 94% yield and >20:1 dr. Direct displacement of the
chiral auxiliary with Weinreb’s amine was followed by
protection of the secondary alcohol as a TBS ether to deliver
silyl ether 28. The methyl ketone prepared from Weinreb’s
amide 28 was then readily converted to desired enolsilane 6
(7 steps; 66% overall from catechol 24).
Having devised highly stereocontrolled routes to all three
key fragments, the union of enolsilane 6 and acetate 5 was
investigated (Scheme 5). Rigorous experimentation revealed
that BF3·OEt2 was the optimum Lewis acid and that TBS
enolsilane 6 performed better than the corresponding TMS
(21) Langer, P.; Schneider, T.; Stoll, M. Chem.sEur. J. 2000, 6, 3204.
(22) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883. (b) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2,
775. (c) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J.
Org. Chem. 2001, 65, 894. (d) Crimmins, M. T.; Shamszad, M. Org. Lett.
2007, 9, 149.
(23) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521.
(24) DIBAL in toluene at -78 °C was completely selective for the
undesired isomer.
(25) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1987.
For a review, see: Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.;
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925.
(26) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511. Also see Supporting Information.
(27) Shioiri, T.; Yamada, S.; Ninomiya, K. J. Am. Chem. Soc. 1972,
94, 6203.
(18) (a) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65,
191. (b) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,
8317.
(28) (a) Shioiri, T.; Yamada, S. I. Chem. Pharm. Bull. 1974, 22, 855.
(b) Csuk, R.; Schabel, M. J.; von Scholz, Y. V. Tetrahedron: Asymmetry
1996, 7, 3505. (c) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62,
5864.
(19) Langer, P.; Kracke, B. Tetrahedron Lett. 2000, 41, 4545.
(20) (a) Node, M.; Fujiwara, T.; Ichihashi, S.; Nishide, K. Tetrahedron
Lett. 1998, 39, 6331. (b) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64,
6984.
(29) Weinstock, J. J. Org. Chem. 1961, 26, 3511. Also see: Smith, A. B.,
III.; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002, 124, 11102
.
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Org. Lett., Vol. 11, No. 17, 2009

Scheme 6. Completion of the Synthesis of (+)-Irciniastatin A
chloride afforded Teoc-protected hemiaminal 33.30 Much to
our dismay, a screen of reported conditions31 for acylation
of stucturally related intermediates never yielded N-acyl
hemiaminal 34. A survey of the previous syntheses of
irciniastatin A finds that all feature a late stage aminal and
side chain incorporation with a preformed lactone of the
dihydroisocoumarin. Albeit unlikely that such remote func-
tionality should have any effect on the hemiaminal coupling,
the limited number of available options warranted pursuit
of this lead.32
Strategically, after the CBS reduction, the lactone was
formed concomitantly with removal of the TBS ether to give
35, adding only one synthetic step over the original plan
(bottom of Scheme 6). An analogous sequence of TBS
protection of the C15 carbinol and hydrogenolysis of the
benzyl ether gave carbinol 36, which was subjected to a two-
step oxidation to acid 37. Acid 37 was subjected to the
previously established Curtius conditions to give hemiaminal
3. With hemiaminal 3 featuring the lactonized dihydroiso-
coumarin, it was found that i-PrMgCl, a base not previously
used for this transformation, successfully effected reaction
with acid chloride 2 in a remarkable 87% yield. Finally,
global deprotection with TASF in DMF at 50 °C provided
(+)-irciniastatin A (1) in 94% yield.
In summary, the total synthesis of (+)-irciniastatin A (1)
was completed in 19 steps with a 6% overall yield from
2-deoxy-D-ribose. The successful application of this strategy
allowed for rapid assembly of the three key fragments with
high diastereocontrol. Studies directed toward analogue
synthesis and further evaluation of the antitumor activity of
irciniastatin A are underway in collaboration with the
Lineberger Comprehensive Cancer Center.
Acknowledgment. Financial support from the National
Institute of General Medical Sciences (GM60567) is grate-
fully acknowledged.
(30) (a) Duggan, M. E.; Imagire, J. S. Synthesis 1989, 131. (b) Evans,
S. D.; Houghton, R. P. J. Mol. Catal. 2000, 164, 157.
Supporting Information Available: Experimental details
and spectral data for new compounds as well as irciniastatin
A. This material is available free of charge via the Internet
at http://pubs.acs.org.
(31) (a) Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2007, 46,
6502. (b) Marron, T. G.; Roush, W. R. Tetrahedron Lett. 1995, 36, 1581.
(c) Roush, W. R.; Pfeiffer, L. A. Org. Lett. 2000, 2, 859. (d) Kagawa, N.;
Ihara, M.; Toyota, M. J. Org. Chem. 2006, 71, 6796.
(32) NOE experiments on related compounds by DeBrabander indicate
a close spatial relationship between these two regions of the molecule (see
ref 11).
OL901655E
Org. Lett., Vol. 11, No. 17, 2009
3993