Synthetic studies toward the pyran core and the amide side chain of psymberin

Article abstract of DOI:10.1016/j.tetlet.2008.07.170

A synthetic approach to the polysubstituted pyran core and amide side chain of psymberin (irciniastatin A) using stereoselective organoboron methodology is described. An advanced oxyranyl pyran intermediate was prepared using a catalytic enantioselective and diastereoselective three-component reaction involving first an inverse electron-demand hetero [4+2] cycloaddition between 3-boronoacrolein pinacolate and 1-ethoxy-2-methylpropene, followed by an allylboration of ethyl glyoxylate. The amide side chain was prepared highly efficiently using the first example of a doubly diastereoselective allylboration of a chiral α-alkoxy aldehyde under the Lewis acid-catalyzed reaction manifold.

Full text of DOI:10.1016/j.tetlet.2008.07.170

Tetrahedron Letters 49 (2008) 6061–6064
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Tetrahedron Letters
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Synthetic studies toward the pyran core and the amide side chain of psymberin
*
Hugo Lachance, Olivier Marion, Dennis G. Hall
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic approach to the polysubstituted pyran core and amide side chain of psymberin (irciniastatin
A) using stereoselective organoboron methodology is described. An advanced oxyranyl pyran intermedi-
ate was prepared using a catalytic enantioselective and diastereoselective three-component reaction
involving first an inverse electron-demand hetero [4+2] cycloaddition between 3-boronoacrolein pinaco-
late and 1-ethoxy-2-methylpropene, followed by an allylboration of ethyl glyoxylate. The amide side
chain was prepared highly efficiently using the first example of a doubly diastereoselective allylboration
Received 12 June 2008
Revised 23 July 2008
Accepted 29 July 2008
Available online 3 August 2008
Keywords:
Allylboration
Catalysis
of a chiral
a
-alkoxy aldehyde under the Lewis acid-catalyzed reaction manifold.
Ó 2008 Elsevier Ltd. All rights reserved.
Hetero-Diels–Alder cycloaddition
Psymberin
Stereocontrol
1. Introduction
occurring and highly potent polyketide recently isolated indepen-
dently by two research groups. Crews and co-workers reported in
2004 the isolation of psymberin from a sea sponge from the waters
of Papua New Guinea, Psammocinia sp.2 At about the same time, a
group led by Pettit also reported the isolation of the same com-
pound, named irciniastatin A, from the Indo-Pacific marine sponge
Ircinia ramose.3 In the same publication, Pettit and co-workers also
described the isolation of a related structure, irciniastatin B, 2 (Fig.
1). Psymberin (irciniastatin A) is a complex pyran-containing nat-
ural product that embeds nine stereogenic centers. It is related
with its central pyran core to the pederin family (e.g., 3, Fig. 1),
which includes over 35 related structures known to display a range
of anticancer activities.4 Psymberin was tested in the NIH-60
human cancer cell line screen, and displayed an unusual profile.3 It
was found to be specific toward solid tumor cell lines, with a high
level of selectivity for melanoma cells characterized by a LC50 in
the low nanomolar range. It also showed activity against some
breast and colon cancer cell lines. The promising biological proper-
ties and novel structure of psymberin have attracted the attention
of the synthetic chemistry community, and thus far two total
syntheses have been achieved by the groups of De Brabander and
Buevich,5,6 as well as one formal synthesis.7 A few other synthetic
studies toward advanced fragments have been realized.8
The isolation of natural products from marine organisms has
provided organic chemists with numerous challenges and opportu-
nities to develop new cures for diseases of great consequences,
such as cancer.1 In this regard, psymberin (1, Fig. 1) is a naturally
MeO
O
OMe
O
OH
N
H
OH
OH O
OH
O
OH
OH
1 psymberin (irciniastatin A)
MeO
O
OMe
O
O
OH
N
H
OH
OH O
O
2 irciniastatin B
MeO
O
O
OMe
O
N
OMe
H
OH
OMe
We aimed to develop a convergent route to psymberin and its
subunits that would allow a structure–activity study of its antican-
cer activity that could lead to the design of a simplified analogue.
In this preliminary Letter, we describe our results focusing on the
central pyran core and the left-hand amide side chain (Fig. 2),
which altogether comprise six of the nine stereogenic centers of
psymberin. As shown in Figure 2, we anticipated that two of our
group’s organoboron-based methodologies could be put to use.
OH
3 pederin
Figure. 1. Psymberin (irciniastatin A), irciniastatin B, and pederin.
* Corresponding author. Tel.: +1 780 492 3141; fax: +1 780 492 8231.
E-mail address: dennis.hall@ualberta.ca (D. G. Hall).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.170

6062
H. Lachance et al. / Tetrahedron Letters 49 (2008) 6061–6064
RO
OMe
MeO
O
Sc(OTf)3
(10 mol%)
O
OH
B
1 psymberin
OH
OH
N
RO
H
A
O
+
OH
RO
OH
+
O
O
CH2Cl2,
–78 ˚C, 36 h
O
O
O
B
OH
O
OH
Doubly diastereocon-
trolled Sc(OTf)3
catalyzed allylboration
H
O
11 (anti)
12 (syn)
OH
O
O
OEt
10
Ph
O
O
6
5
:
4
B
O
B
Cr(III)* catalyzed
oxa[4+2]cycloaddition /
allylboration MCR
O
O
(at rt w/o Sc(OTf)3)
O
4
+
5
:
1
13
OEt
O
O
+
+
RO
H
Ph
H
OPG'
O
O
B
OPG
Bpin
8
> 49
:
1
(75% yield)
9
5
7
O
(+)-4
Figure. 2. Retrosynthetic plan for fragments A and B of psymberin (1).
Ph
O
1
:
2
First, our scandium-catalyzed allylboration with the methallyl
camphordiol boronate 49 could be exploited in the context of a
doubly diastereoselective addition to provide fragment A from a
B
O
(–)-4
protected, chiral
a,b-dihydroxy aldehyde 5. This transformation
Figure. 3. Doubly diastereocontrolled allylboration toward fragment A.
will provide the first ever test of the stereodirecting ability of this
Lewis acid-catalyzed allylboration procedure. Then, to assemble
the polysubstituted pyran unit, our tandem three-component
oxa[4+2] cycloaddition/allylboration10 between boronoacrolein
pinacolate (7), enol ethers, and aldehydes would be employed
under catalysis with Jacobsen’s Cr(III) chiral complex.11 To access
fragment B, the hindered 2,2-disubstituted enol ether 812 will be
employed for the first time in this three-component reaction,
with reagent (+)-4 was accomplished in multigram quantities.
Homoallylic alcohol 11 was methylated with ease to afford the
desired ether 14 (Eq. 1).14 The latter could be transformed to the
requisite carboxylic acid precursor of fragment
A using the
same straightforward sequence described by De Brabander and
co-workers.5
which was foreseen as an additional element of difficulty.11c,13
A
OH
OMe
NaH, CH3I
reactive glyoxylate 9 will be used for the carbonyl allylboration
step leading to 6. It was further envisaged that a Lewis acid-cata-
lyzed reaction between allylSnBu3 and the acetal functionality in
the multicomponent reaction product, 6, would be performed in
order to extend the right-hand side chain of psymberin. Ultimately,
fragments A and B would be coupled using a known Curtius rear-
rangement/amidation sequence described in synthetic studies on
pederin.4b
O
O
ð1Þ
THF, 0 °C to rt
O
O
11
14 (85%)
The preparation of the pyran core, fragment B, required a chal-
lenging extension of our previously reported inverse electron-
demand hetero Diels–Alder cycloaddition of enal 7 catalyzed by
Jacobsen’s chiral chromium catalyst11 (15, Scheme 1).10 Whereas
vinyl ethyl ether reacts with 3-boronoacrolein pinacolate (7) in less
than 1 h at room temperature to afford the expected cycloadduct in
96% ee, the 2,2-dimethylated analogue 812 required about 24 h to
provide cycloadduct 16 (Scheme 1). The latter was obtained at best
in 90% ee, as measured on the corresponding alcohol 17 according
to Eq. 2. Enol ether 8 needs to be freshly distilled for the cyclo-
addition to proceed most efficiently. It was possible but not
beneficial to realize the allylboration in ‘one-pot’ as it led to lower
yields and the formation of unidentified decomposition products.
To avoid these problems, the Cr(III) catalyst was removed by
quickly passing the crude product through a pad of silica.
2. Results and discussion
The doubly diastereoselective methallylation of known alde-
hyde 10 was tested with both antipodes of chiral camphordiol bor-
onate reagent 4 (Fig. 3). To this end, the intrinsic diastereofacial
selectivity of this system was first tested with achiral pinacol
methallylboronate 13 under both thermal (uncatalyzed) conditions
and under Sc(OTf)3 catalysis. The uncatalyzed reaction required
room temperature to proceed with an appreciable rate, and led
to almost no selectivity in the products 11 and 12. The low-tem-
perature Sc(III)-catalyzed variant led to an improvement, but the
modest diastereoselectivity of 5-to-1 in favor of the desired
product 11 emphasized the need for a double diastereoselection
strategy that would circumvent the need for separating diastereo-
meric products. To our great satisfaction, the use of chiral boronate
(+)-4 led to the exclusive formation of allylic alcohol 11 in good
yield.14 To confirm the powerful stereodirecting power of this re-
agent, the (ꢀ) antipode was reacted with the same aldehyde (10)
under identical conditions, only to observe a 1:2 ratio of products
11 and 12, respectively. Thus, even in a mismatched case, reagent 4
was capable of inverting the intrinsic diastereofacial bias of this
allylation reaction. The high selectivity obtained in the preparation
of 11 compares favorably to the use of Brown’s chiral methallyl-
boration method.5 It is noteworthy that the methallylation of 10
O
OEt
O
OEt
NaOAc, H2O2
THF, 0 ˚C, 1 h
ð2Þ
Bpin
HO
17 (96%, 85-90% ee, 10:1 dr)
16
The second stage of this three-component reaction between 16
and the glyoxylate 18 was straightforward, and led to the desired
a
-hydroxyalkylated pyran 19 in 91% yield and 10:1 diastereoselec-
tivity (85–90% ee for the major diastereomer shown, 19).14 Having
proven the feasibility of the key step for fragment B, several
methods were envisaged to functionalize the alkene of product
19. Toward this end,
methyldioxirane proved very efficient in affording 20 in good yield
a stereoselective epoxidation with di-
(Scheme 1).14

H. Lachance et al. / Tetrahedron Letters 49 (2008) 6061–6064
6063
Me
O
OEt
R
O
R
i)
OEt
O
[O]
N
O
R = CH(OH)CO2Et
Cr
Cr(III)
Cl
Figure. 5. Rationale for the stereoselective epoxidation of 19.
OEt
O
B
O
OEt
15 (1 mol%)
+
BaO, rt, 24 h
preliminary way. To this end, the secondary hydroxyl group of
20 was easily inverted under Mitsunobu conditions to afford inter-
mediate 21 with the requisite stereochemistry for psymberin.
Initial efforts to reductively open the epoxide of 21 and to allylate
the acetal functionality are underway, and should provide an
advanced precursor of the unit B of psymberin ready for fragment
coupling.
8
pinB
O
O
7
O
H
ii)
EtO
OH
OEt
O
EtO
O
OEt
O
18
O
toluene,
60 °C, 6 h
3. Conclusion
Bpin
19 (91%, 85-90% ee, 10:1dr)
16
This preliminary Letter demonstrates the feasibility of a syn-
thetic approach to the polysubstituted pyran core and amide side
chain of psymberin (irciniastatin A) using stereoselective organo-
boron methodology. An advanced oxyranyl pyran intermediate
was prepared using a catalytic enantioselective and diastereoselec-
tive three-component reaction involving first an inverse electron-
demand hetero [4+2] cycloaddition between 3-boronoacrolein
and 1-ethoxy-2-methylpropene, followed by an allylboration of
ethyl glyoxylate. The cycloaddition step was realized highly
enantioselectively for the first time with such a hindered enol
ether as the dienophilic component. Furthermore, the amide side
chain of psymberin was prepared highly efficiently using the first
example of a doubly diastereoselective allylboration under the
Lewis acid-catalyzed reaction manifold.
1. 4-NO2-C6H4CO2H
PPh3, DEAD
THF–toluene,
OH
O
EtO
OEt
OEt
oxone, NaHCO3
0 ˚C to rt, 1 h
O
acetone–H2O
rt, 16 h
2. Cs2CO3, MeOH
rt, 2 h
O
20 (76%)
OH
MeO
O
O
21 (70%)
Scheme 1.
O
The formation of the desired stereoisomer 20 was confirmed by
X-ray crystallographic evidence on the p-iodobenzoate derivative
22 (Fig. 4).15 The facial selectivity can be explained by electrophilic
attack of the dioxirane on the least hindered alpha face of the most
favored half-chair conformation of 19 (Fig. 5). We were delighted
with this successful approach to an advanced precursor of
fragment B, and a few more transformations were explored in a
Acknowledgments
This work was funded by the Natural Sciences and Engineering
Research Council (NSERC) of Canada, the Alberta Cancer Board
(Bridge/Pilot Grant), and the University of Alberta. HL thanks
NSERC and the Alberta Ingenuity Foundation for Graduate Scholar-
ships. We thank Dr. Robert McDonald (University of Alberta) for
the X-ray crystallographic analysis of 22.
O
References and notes
(4-I-C6H4)
EtO
O
OH
4-I-C6H4CO2H
PPh3, DEAD
EtO
O
OEt
O
OEt
1. (a) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2004, 67, 1216–1238; (b) Simmons,
T. L.; Andrianasolo, E.; McPhail, K. Mol. Cancer Therap. 2005, 4, 333–342.
2. Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6, 1951–1954.
3. 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, 1149–1152.
4. (a) Review: Narquizian, R.; Kocienski, P. J.; The Pederin Family of Antitumor
Agents: Structures, Synthesis and Biological Activity. In The Role of Natural
Products in Drug Discovery, Mulzer, J.; Bohlmann, R., Eds.; Ernst Schering
Research Foundation Workshop 32; Springer: New York, 2000; Vol. 9, pp 25–
56. For a recent total synthesis: (b) Jewett, J. C.; Rawal, V. H. Angew. Chem., Int.
Ed. 2007, 46, 6502–6504.
O
O
THF, toluene
0 °C to rt, 1 h
O
O
22 (95%)
20
5. Jiang, X.; Garcia-Fontanet, J.; De Brabander, J. K. J. Am. Chem. Soc. 2005, 127,
11254–11255.
6. Huang, X.; Shao, N.; Palani, A.; Aslanian, R.; Buevich, A. Org. Lett. 2007, 9, 2597–
2600.
7. Ning, S.; Kiren, S.; Williams, L. J. Org. Lett. 2007, 9, 1093–1096.
8. (a) Rech, J. C.; Floreancig, P. E. Org. Lett. 2005, 7, 5175–5178; (b) Greene, M. E.;
Rech, J. C.; Floreancig, P. E. Org. Lett. 2005, 7, 4117–4120; (c) Kiren, S.; Williams,
L. J. Org. Lett. 2005, 7, 2905–2908; (d) Jiang, X.; Williams, N.; De Brabander, J. K.
Org. Lett. 2007, 9, 227–230; (e) Huang, X. H.; Shao, N.; Palani, A.; Aslanian, R.;
Buevich, A.; Seidel-Dugan, C.; Huryk, R. Tetrahedron Lett. 2008, 49, 3592–3595.
9. (a) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc. 2003, 125,
10160–10161; (b) Gravel, M.; Lachance, H.; Lu, X.; Hall, D. G. Synthesis 2004,
1290–1302; (c) Rauniyar, V.; Hall, D. G. J. Am. Chem. Soc. 2004, 126, 4518–4519.
10. (a) Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41,
3059–3061; (b) Chavez, D. E.; Jacobsen, E. N. Org. Synth. 2005, 82, 34.
11. (a) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 9308–9309; (b) Gao, X.; Hall,
D. G. J. Am. Chem. Soc. 2005, 127, 1628–1629; (c) Gao, X.; Hall, D. G.; Deligny,
M.; Favre, A.; Carreaux, F.; Carboni, B. Chem. Eur. J. 2006, 13, 3132–3142.
Figure. 4. Preparation and ORTEP of crystalline derivative 22.

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H. Lachance et al. / Tetrahedron Letters 49 (2008) 6061–6064
12. (a) Brannock, K. C. J. Org. Chem. 1960, 25, 258–260; (b) Gosselin, P.; Rouessac,
F.; Zamarlik, H. Bull. Soc. Chim. Fr. 1981, 192–198; (c) Gong, W.; Wang, B.; Yan,
L.; Yang, L.; Suo, J. Synth. Commun. 2004, 34, 4243–4247.
13. (a) Dauben, W. G.; Krabbenhoft, H. O. J. Org. Chem. 1977, 42, 282–287; (b)
Vandenput, D. A. L.; Scheeren, H. W. Tetrahedron 1995, 51, 8383–8388.
14. Procedures and characterization data for key synthetic intermediates:
Preparation of 11 by methallylation of 10 with reagent (+)-4:
2H), 4.15 (dd, J = 9.7, 2.7 Hz, 1H), 3.90 (dddd, J = 16.9, 9.8, 9.8, 7.1 Hz, 1H), 3.61
(d, J = 9.7 Hz, 1H), 3.50 (dddd, J = 16.9, 9.8, 7.1, 7.1 Hz, 1H), 1.31 (t, J = 7.1 Hz,
3H), 1.22 (t, J = 7.1 Hz, 3H), 1.02 (s, 3H), 1.00 (s, 3H); 13C NMR (CDCl3,
125 MHz): d 172.1, 136.9, 122.4, 104.2, 75.2, 72.8, 65.3, 61.4, 35.2, 25.7, 22.3,
14.4, 14.2; IR (neat): 3502, 2977, 1750 cmꢀ1
; HRMS (ESI, m/z) calcd for
C
13H22O5Na: 281.1359; found 281.1359 [MNaꢀH]+.
Preparation of 20 by dimethyldioxirane epoxidation of 19:
This reaction was performed as described in Ref. 9b, except for the use of
2 equiv of aldehyde 10, and reaction mixture was stirred for 36 h at ꢀ78 °C.
The resulting product 11 is known and the spectroscopic data matched the
reported values.5 Ether 14 is also known.5
In a round-bottomed flask open to air and equipped with a teflon stirbar was
added the dihydropyran 19 (1.25 g, 4.84 mmol) and sodium bicarbonate (2.2 g)
in water (5 mL) and acetone (15 mL). To the stirred mixture at room
temperature were added oxone (5.0 g, 12.9 mmol) in one portion. The
resulting mixture was stirred at room temperature for 12 h, then extracted
three times with ethyl acetate. The combined organic layers were washed once
with a saturated aqueous solution of sodium metabisulfite, once with water,
and once with brine. The resulting organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash
chromatography on Et3N-deactivated silica gel (pentane–ether 3:2) to give the
epoxide 20 in 76% yield (1.01 g, 3.7 mmol).
Preparation of 19 by oxa[4+2]cycloaddition/allylboration: In a flame-dried round-
bottomed flask equipped with a teflon stirbar was placed a mixture of 3-
boronoacrolein pinacolate 7 (1.5 g, 8.24 mmol, freshly distilled by Kugelrohr)
and 1-ethoxy-2-methylpropene (8) (2.23 g, 22.3 mmol). To this stirred solution
was added the (1R,2S) Jacobsen catalyst 15 and powdered barium oxide (2.4 g).
The reaction mixture was allowed to stir at room temperature for 48 h. The
mixture was then passed through a short pad of Et3N-deactivated silica gel (4:1
pentane–ether) to remove the catalyst. The crude product was concentrated
and used directly in the next step. This crude material was mixed with ethyl
glyoxylate (18) (1.50 g, 14.7 mmol, 50% in toluene, 3.3 mL) and stirred in a
sealed tube at 60 °C for 12 h. The vessel was allowed to cool to room
temperature and a saturated aqueous solution of NaHCO3 (10 mL) was added
with subsequent stirring for 30 min. The resulting mixture was extracted twice
with ether (2 ꢁ 60 mL) and the ethereal layers were combined, washed with
brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was
purified by a short column chromatography on Et3N-deactivated silica gel
(pentane–ether 4:1) to afford the desired product 19 (1.90 g, 7.5 mmol, 91%
yield, 10:1 dr). The ee of the major diastereomer 19 was determined to be 90%
by chiral HPLC of the phenylcarbamate derivative of alcohol 17).
Compound 20 was obtained as a white solid. Mp 56–58 °C (uncorrected);
½
a 2D3
ꢂ
ꢀ 51:81 (c 2.8, CHCl3) check; 1H NMR (CDCl3, 500 MHz): d 4.39 (dd, J = 8.8,
2.2 Hz, 1H), 4.35–4.22 (m, 3H), 4.21 (s, 1H), 3.68 (dddd, J = 14.2, 9.2, 7.1, 7.1 Hz,
1H), 3.38 (dddd, J = 14.2, 9.8, 7.1, 7.1 Hz, 1H), 3.36 (d, J = 7.0 Hz, 1H), 3.14 (d,
J = 8.8 Hz, 1H), 3.02 (dd, J = 4.1, 0.6 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.14 (t,
J = 7.1 Hz, 3H), 1.10 (s, 3H), 1.04 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 171.4,
101.6, 75.4, 72.1, 65.1, 62.1, 61.8, 54.0, 34.8, 21.1, 16.5, 14.9, 14.1; IR (neat):
3477, 2977, 2933, 2874, 1748 cmꢀ1; HRMS (ESI, m/z) calcd for C13H22O6Na:
297.1307; found 297.1309 [MNaꢀH]+.
15. Crystallographic data (excluding structure factors) for the structure of
compound 22 in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC-
690426. Copies of the data can be obtained free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk or via www.ccdc.cam.ac.uk/data_request/cif).
Compound 19 was obtained as a colorless oil: ½a D23
ꢀ 33:70 (c 2.5, CHCl3)
ꢂ
check; 1H NMR (CDCl3, 300 MHz): d 5.69 (dd, J = 10.2, 2.4 Hz, 1H), 5.54 (dd,
J = 10.2, 1.8, 1H), 4.68 (dd, J = 2.3, 2.0 Hz, 1H), 4.34 (s, 1H), 4.27 (q, J = 7.1 Hz,