Total synthesis of (-)-irciniastatin B and structural confirmation via chemical conversion to (+)-irciniastatin A (psymberin)

Article abstract of DOI:10.1021/ol301783p

The total synthesis and structural confirmation of the marine sponge cytotoxin (-)-irciniastatin B has been achieved via a unified strategy employing a late-stage, selective deprotection/oxidation sequence that provides access to both (+)-irciniastatin A (psymberin) and (-)-irciniastatin B.

Full text of DOI:10.1021/ol301783p

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4350–4353
Total Synthesis of (ꢀ)-Irciniastatin B and
Structural Confirmation via Chemical
Conversion to (þ)-Irciniastatin A
(Psymberin)
Chihui An, Adam T. Hoye, and Amos B. Smith III*
Department of Chemistry, Laboratory for Research on the Structure of Matter
and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, United States
smithab@sas.upenn.edu
Received June 28, 2012
ABSTRACT
The total synthesis and structural confirmation of the marine sponge cytotoxin (ꢀ)-irciniastatin B has been achieved via a unified strategy
employing a late-stage, selective deprotection/oxidation sequence that provides access to both (þ)-irciniastatin A (psymberin) and
(ꢀ)-irciniastatin B.
In 2004, Pettit and co-workers reported the isolation of
(þ)-irciniastatin A (1) and (ꢀ)-irciniastatin B (2) from the
Indo-Pacific marine sponge Ircinia ramosa (Figure 1).1
Months later, Crews et al. independently reported the isola-
tion of (þ)-psymberin from the marine sponge Psammocinia.2
Initial reports suggested that all three metabolites possessed
structures with notable architectural features including a
substituted trans-2,6-tetrahydropyran core, a dihydroisocou-
marin, and an N,O-hemiaminal moiety. (þ)-Irciniastatin A
(1) and (ꢀ)-irciniastatin B (2) differed only in the oxidation
state at C(11), while (þ)-irciniastatin A (1) and(þ)-psymberin
appeared to be possible diastereomers. The C(4) stereo-
genicity, however, remained undefined with opposite stereo-
chemical assignments reported for C(8). In 2005, De
Brabander and colleagues reported the first total synthesis
of (þ)-irciniastatin A (1) that established the complete struc-
ture including the absolute configuration and confirmed
that both (þ)-irciniastatin A (1) and (þ)-psymberin were
identical.3
From a biomedical perspective, both (þ)-irciniastatin A
(1) and (ꢀ)-irciniastatin B (2) possess selective tumor cell
growth inhibition (0.004ꢀ0.0005 μg/mL).1 Interestingly,
although structurally almost identical, (ꢀ)-irciniastatin B
(2) was reported to be almost 10-fold more potent than
(þ)-irciniastatin A (1) against human pancreas (BXPC-3),
breast (MCF-7), and central nervous system (SF268) cell
lines. Recent studies by Usui and co-workers determined
that the cytotoxicity of (þ)-irciniastatin A (1) derives from
activation of stress-activated protein kinases such as JNK
and p38.4 In addition, analogue studies by the Schering-
Plough group revealed that the C(11) hydroxyl group
was not necessary for biological activity; in particular, the
(þ)-C(11)-deoxy analogue possesses a 3ꢀ10 fold increase
(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.
(2) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6,
1951.
(3) Jiang, X.; Garcıa-Fortanet, J.; DeBrabander, J. K. J. Am. Chem.
Soc. 2005, 127, 11254.
(4) Chinen, T.; Nagumo, Y.; Watanabe, T.; Imaizumi, T.; Shibuya,
M.; Kataoka, T.; Kanoh, N.; Iwabuchi, Y.; Usui, T. Toxicol. Lett. 2010,
199, 341.
r
10.1021/ol301783p
Published on Web 08/14/2012
2012 American Chemical Society

in activity against all cancer cell lines tested compared to
(þ)-irciniastatin A (1).5
further exploration of the irciniastatin chemotype as a
potent therapeutic lead.
Scheme 1
Figure 1
Given the biological profile and limited abundance of
both 1 and 2, significant interest has arisen within the
synthetic community. To date, seven total syntheses have
been reported for (þ)-irciniastatin A,3,6 including one
report from our laboratory.6b To the best of our knowl-
edge, the total synthesis of (ꢀ)-irciniastatin B has yet to be
reported. Due to the greatly enhanced cytotoxic activity of
(ꢀ)-irciniastatin B (2) compared to (þ)-irciniastatin A (1)
in several cancer cell lines, we set out to develop a unified
syntheticstrategytoaccess bothnatural products aswell as
analogues varying in substitution at C(11). Herein, we
report the first total synthesis of (ꢀ)-irciniastatin B (2)
that includes structural confirmation via chemical conver-
sion to (þ)-irciniastatin A (1).
Our synthetic strategy for the synthesis of (ꢀ)-ircinias-
tatin B (2) is based on our previous route to (þ)-ircinias-
tatin A (1) (Scheme 1).6b In order to introduce the requisite
oxidation at C(11), we selected advanced intermediate
(þ)-36b for the orthogonal protection at C(15) (Scheme 1).
However, careful attention to the selection of a suitable
protecting group at C(15) would clearly be required.
Initially, the SEM group (cf. 5) was selected with the
expectation of selective removal of the sterically hindered
TBS protecting group at the C(11) position. Oxidation of
the resultant alcohol and global deprotection was then
envisioned to provide (ꢀ)-irciniastatin B (2). The advan-
tage of this approach compared to our orginal strategy for
(þ)-irciniastatin A (1) would be ready access to a late-stage
intermediate [i.e., (þ)-3] en route to both (þ)-irciniastatin
A (1) and (ꢀ)-irciniastatin B (2). Additionally, chemical
modification of both the C(11) alcohol or ketone in late
stage intermediates would permit access to analogues
varying at the C(11) stereogenic center, thus permitting
Having accessed advanced Teoc carbamate (þ)-3 via
our published route,6b we were surprised that all attempts
to protect (þ)-3 as the SEM ether at C(15) resulted in the
unforeseen loss of the phenolic SEM ethers during workup
and purification steps.7 Moreover, reprotection to intro-
duce the phenolic SEM ethers proved to be ineffective even
at elevated temperatures. After considerable experimenta-
tion, we discovered that the phenolic 3,4-dimethoxybenzyl
group (DMB) could be easily removed under standard
oxidative conditions in model studies while at the same
time be suitable for the orthogonal TBS ether removal.
The synthesis of (ꢀ)-irciniastatin B (2) began with bis-
DMB aryl fragment 7, which was obtained by protection
of known bis-phenol 68 followed by chemoselective reduc-
tion to aldehyde 7 (Scheme 2). From here, the synthetic
route employed a similar sequence as applied in our earlier
synthesis of (þ)-irciniastatin A (1).6b Pleasingly, union
between aldehyde 7 and known ketone (þ)-86b was
(5) Huang, X.; Shao, N.; Huryk, R.; Palani, A.; Aslanian, R.;
Seidel-Dugan, C. Org. Lett. 2009, 11, 867.
€
achieved by employing dichlorophenylborane and Hunig’s
(6) (a) Huang, X.; Shao, N.; Palani, A.; Aslanian, R.; Buevich, A.
Org. Lett. 2007, 9, 2597. (b) Smith, A. B., III; Jurica, J. A.; Walsh, S. P.
Org. Lett. 2008, 10, 5625. (c) Crimmins, M. T.; Stevens, J. M.; Schaaf,
G. M. Org. Lett. 2009, 11, 3994. (d) Watanabe, T.; Imaizumi, T.; Chinen,
T.; Nagumo, Y.; Shibuya, M.; Usui, T.; Kanoh, N.; Iwabuchi, Y. Org.
Lett. 2010, 12, 1040. (e) Wan, S.; Wu, F.; Rech, J. C.; Green, M. E.;
Balachandran, R.; Horne, W. S.; Day, B. W.; Floreancig, P. E. J. Am.
Chem. Soc. 2011, 133, 16668. (f) Byeon, S. R.; Park, H.; Kim, H.; Hong,
J. Org. Lett. 2011, 13, 5816.
(7) While particularly deleterious at this point in the synthesis, the
loss of phenloic SEM ethers had plagued the route at various stages and
contributed to our decision to identfiy an alternative protecting group
strategy.
(8) Langer, P.; Kracke, B. Tetrahedron Lett. 2000, 41, 4545.
(9) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984, 13,
1729.
Org. Lett., Vol. 14, No. 17, 2012
4351

A
6b to install the N,O-aminal moiety with complete stereo-
selectively. To this end, thermal rearrangement of the acyl
azide derived from (þ)-12, followed by treatment with
2-trimethylsilylethanol to intercept the isocyanate, led to
the Teoc-protected N,O-aminal in 67% yield, again with
complete retention of stereochemical configuration. Protec-
tion of the C(15) alcohol was then achieved in 82% yield
upon treatment with SEMCl, TBAI, and i-Pr2NEt. Gratify-
ingly, the resulting SEM ether (þ)-13 proved to be much
more stable than other congeners such as the tris-SEM ether
and thus could be isolated without decomposition following
workup and purification.
Scheme 2
Initial attempts to append the side chain to provide (þ)-
14 proved difficult (Scheme 3). The original optimized
conditions employed in our (þ)-irciniastatin A synthesis,
which called for treatment with LiHMDS and the mixed
pivalate anhydride 15,6b proved to be ineffective, furnish-
ing the desired (þ)-14 in only a poor yield (ca. 15%). After
considerable screening, the conditions established by
Crimmins and co-workers,6c specifically acid chloride 16
in conjuction with i-PrMgCl, furnished amide (þ)-14 in
72% yield. It is interesting to note that slight differences in
molecular structure, even in regions distal to the reactive
site, seem to play a significant role in the successful construc-
tion of this challenging amide bond.
With the full carbon skeleton of (ꢀ)-irciniastatin B (2)
intact, we next explored the selective removal of the hindered
neopentyl C(11) TBS group. Treatment of (þ)-14 with TBAF
at room temperature initially removed the Teoc carbamate
group. The reaction mixture was then warmed to 50 °C, and
over the course of 42 h, the C(11) TBS ether underwent clean
hydrolysis in good yield (79%). Oxidation of the resulting
secondary alcohol to ketone (ꢀ)-17 was then achieved by
treatment with DessꢀMartin periodinane12 in 87% yield.
We next discovered, after considerable experimentation,
a two-stage deprotection sequence was required to remove
the two sets of orthogonal protecting groups in (ꢀ)-17.
Interestingly, introduction of the C(11)-ketone moiety
greatly increases the sensitivity of the molecule: according
to the literature on similar systems, basic conditions lead to
a retro-Michael/Michael sequence epimerizing13 the C(9)
stereogeniccenter of the tetrahydropyrancore, while acidic
conditions lead to hydrolysis of the N,O-aminal.14 Pleasingly,
treatment of ketone (ꢀ)-17 with DDQ provided the desired
bis-phenol without visible decomposition (Scheme 3). For
removal of the remaining protecting groups, the use of TASF
or TBAF in the second step proved unworkable, leading only
to a complex mixture of products. Eventually, we discovered
that a premixed solution of MgBr2, n-butanethiol, and
nitromethane15 in Et2O removed the SEM ethers to furnish
(ꢀ)-irciniastatin B (2) in 78% yield over two steps. The
spectral data of synthetic (ꢀ)-irciniastatin B (2) were identical
base to furnish the desired syn-aldol product (þ)-9,
achieved in 70% yield with excellent selectivity (>20:1).9
A chelation-controlled reduction protocol10 nextfurnished
a mixture of the desired syn-diol 10 and lactone 11 (ca. 8:1),
which upon treatment with LiOH followed by an acid
workup led to the desired acid (þ)-12 in 69% yield for the
two steps (Scheme 3). The acidic workup was required
after saponification to achieve lactonization of the unde-
sired bis-acid byproduct.
We next turned to the required installation of the
N,O-aminal functionality via a stereoretentive Curtius re-
arrangement (Scheme 2), a tactic successfully utilized earlier
in our synthesis of (þ)-zampanolide11 and (þ)-irciniastatin
(12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(13) Allevi, P.; Anastasia, M.; Ciuffreda, P.; Fiecchi, A.; Scala, A.
J. Chem. Soc., Perkins Trans. 1 1989, 7, 1275.
(14) Mori, M.; Uozumi, Y.; Ban, Y. J. Chem. Soc., Chem. Commun.
1986, 11, 841.
(10) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
(11) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem.
(15) Denmark, S. E.; Kobayashi, T.; Regens, C. S. Tetrahedron 2010,
66, 4745.
Soc. 2002, 124, 11102.
4352
Org. Lett., Vol. 14, No. 17, 2012

Scheme 3
Scheme 4
In summary, the first total synthesis of (ꢀ)-irciniastatin
B (2) has been achieved. The central features of this
synthetic venture entailed a modified protecting group
strategy that is amenable to scalable synthesis and a late-
stage selective deprotection and oxidation sequence. Im-
portantly, the availability of ketone (ꢀ)-17 now permits
access to both (þ)-irciniastatin A (1) and (ꢀ)-ircinaistatin
B (2) as well as to epi-C(11)-irciniastatin A (18) and
potential future analogues. Development of a more effi-
cient strategy toward (ꢀ)-17, in conjunction with the
synthesis of analogues for biological evaluation, con-
tinue in our laboratory.
Acknowledgment. Financial support was provided by
the National Institutes of Health (National Cancer Institute)
through Grant No. CA-19033. We thank Drs. George Furst
and Rakesh Kohli (University of Pennsylvania) for their
help in obtaining the high-resolution NMR and mass
spectral data, respectively. We thank Professor G. R. Pettit
(Arizona State University) for his generous help in providing
the 1H and 13C NMR spectra of (ꢀ)-irciniastatin B.
in all respects with the spectral data kindly provided to us by
Pettit and co-workers.1
To confirm the structure of (ꢀ)-irciniastatin B (2), the
chemical conversion of (ꢀ)-irciniastatin B (2) to (þ)-irci-
niastatin A (1) was carried out (Scheme 4). To this end,
treatment of synthetic (ꢀ)-irciniastatin B (2) with NaBH4
provided a 1:1 mixture of (þ)-irciniastatin A (1) and
epi-C(11)-irciniastatin A (18). After separation of the two
diastereomers by preparatory TLC, the spectral data of the
more rapidly moving congener on TLC proved identical to
(þ)-irciniastatin A (i.e., 1H and 13C NMR and HRMS), thus
confirming that the structure of the (þ)-irciniastatin A (1)
and (ꢀ)-irciniastatin B (2) are identical except for the oxida-
tion state at C(11).
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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