Total synthesis of 7′,8′-dihydroaigialospirol

Article abstract of DOI:10.1021/ol302498v

A highly convergent total synthesis of 7′,8′- dihydroaigialospirol is described. Key steps of the synthesis include a Nozaki-Hiyama-Kishi (NHK) coupling of an iodoalkyne with an advanced phthalide-aldehyde and a remarkable one-pot acid-mediated global deprotection/spiroacetalization.

Full text of DOI:10.1021/ol302498v

ORGANIC
LETTERS
Total Synthesis of 70,80-Dihydroaigialospirol
2012
Vol. 14, No. 19
5154–5157
Tsz-Ying Yuen and Margaret A. Brimble*
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland,
New Zealand
m.brimble@auckland.ac.nz
Received September 11, 2012
ABSTRACT
A highly convergent total synthesis of 70,80-dihydroaigialospirol is described. Key steps of the synthesis include a NozakiꢀHiyamaꢀKishi (NHK)
coupling of an iodoalkyne with an advanced phthalide-aldehyde and a remarkable one-pot acid-mediated global deprotection/spiroacetalization.
The aigialomycins AꢀE (1ꢀ5; Figure 1) belong to the
resorcylic acid lactone family of natural products that were
isolated from the mangrove fungus Aigialus parvus BCC
5311.1 These 14-membered resorcylic macrolides differ
only in the oxidation pattern around the macrocyclic ring
and/or the configuration of the olefin at C10ꢀC20. The
most potent member of the family, aigialomycin D (4),
exhibits antimalarial1 (IC50: 6.6 μg/mL against P. falci-
parum), antitumor1 (IC50: 3.0 μg/mL for KB cells and 1.8
μg/mL for Vero cells), and kinase inhibitory activity2,3
(IC50: 6 μM for CDK1/5, 21 μM for CDK2, and 14 μM for
GSK). Consequently, 4 has attracted considerable interest
from the synthetic community, resulting in eight total
syntheses.2,4 Additional aigialomycin derivatives (6ꢀ10),
obtained by extended fermentation of Aigialus parvus,
have since been reported.5 Associated bioactivity of these
novel metabolites has not been reported.
As part of our ongoing synthetic program to probe the
pharmacological properties of spiroacetal-containing nat-
ural products (especially aromatic spiroacetals),6,7 our
attention focused on the total synthesis of the spiroacetal-
containing members of the post-PKS modified aigialomy-
cin derivatives (8ꢀ10). To date, only one total synthesis of
these phthalide-spiroacetals has been reported by the
Hsung group,8 wherein aigialospirol (8) was furnished
using a cyclic acetal-tethered ring-closing metathesis with
a late stage epimerization of the spiroacetal center under
acidic conditions. Based onthisobservation, wepostulated
that an acid-catalyzed spirocyclization would be an effec-
tive strategy to achieve the direct formation of these
(1) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongasaeree,
P.; Thebtaranonth, Y. J. Org. Chem. 2002, 5, 1561.
(2) Barluenga, S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.; Winssinger,
N. Angew. Chem., Int. Ed. 2006, 45, 3951.
(3) Xu, J.; Chen, A.; Go., M.-L.; Nacro, K.; Liu, B.; Chai., C. L. L.
ACS Med. Chem. Lett. 2011, 2, 662.
(6) For selected reports on the synthesis of aromatic spiroacetals, see:
(a) Rathwell, D. C. K.; Yang, S.-H.; Tsang, K. Y.; Brimble, M. A.
Angew. Chem., Int. Ed. 2009, 48, 7996. (b) Yuen, T.-Y.; Yang, S.-H.;
Brimble, M. A. Angew. Chem., Int. Ed. 2011, 50, 8350–8353. (c) McLeod,
M. C.; Wilson, Z. E.; Brimble, M. A. Org. Lett. 2011, 13, 5382. (d)
McLeod, M. C.; Wilson, Z. E.; Brimble, M. A. J. Org. Chem. 2012, 77,
400.
(7) For reports on the synthesis and associated anti-Helicobacter
pylori activity of the phthalide-spiroacetal spirolaxine methyl ether
derivatives, see: (a) Radcliff, F. J.; Fraser, J. D.; Wilson, Z. E.; Heapy,
A. M.; Robinson, J. E.; Bryant, C. J.; Flowers, C. L.; Brimble, M. A.
Bioorg. Med. Chem. 2008, 16, 6179. (b) Dimitrov, I.; Furkert, D. P.;
Fraser, J. D.; Radcliff, F. J.; Finch, O.; Brimble, M. A. Med. Chem.
Commun. 2012, 3, 938.
(4) (a) Geng., X. D.; Danishefsky, S. J. Org. Lett. 2004, 6, 413. (b)
Yang, Z.-Q.; Geng, X. D.; Solit, D.; Pratilas, C. A.; Rosen, N.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 7881. (c) Lu, J.; Ma,
J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron: Asymmetry 2006, 17,
1066. (d) Vu, N. Q.; Chai, C. L. L.; Lim, K. P.; Chia, S. C.; Anqi, C.
Tetrahedron 2007, 63, 7053. (e) Chrovian, C. C.; Knapp-Reed, B.;
Montgomery, J. Org. Lett. 2008, 10, 811. (f) Baird, L. J.; Timmer,
M. S. M.; Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem. 2009, 74,
2271. (g) Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett. 2009, 11,
4910.
(5) (a) Vongvilai, P.; Isaka, M.; Kittakoop, P.; Srikitikulchai, P.;
Kongasaeree, P.; Thebtaranonth, Y. J. Nat. Prod. 2004, 67, 457. (b)
Isaka, M.; Yangchum, A.; Intamas, S.; Kocharin, K.; Jones, E. B. G.;
Kongsaeree, P.; Prabpai, S. Tetrahedron 2009, 65, 4396.
(8) (a) Figueroa, R.; Hsung, R. P.; Guevarra, C. C. Org. Lett. 2007, 9,
4857. (b) Figueroa, R.; Feltenberger, J. B.; Guevarra, C. C.; Hsung, R. P.
Sci. China, Ser. B: Chem. 2011, 54, 31.
r
10.1021/ol302498v
Published on Web 09/27/2012
2012 American Chemical Society

Figure 1. Structure of aigialomycins AꢀG (1ꢀ7) and the aigialospirol derivatives (8ꢀ10).
spiroacetals. We therefore report our total synthesis of
70,80-dihydroaigialospirol (9) based on the union of a
functionalized alkyne to a preformed phthalide-aldehyde
to construct the key spirocyclization precursor.
Sonogashira cross-coupling of triflate 15 with alkyne 16,
followed by semihydrogenation of the resultant disubsti-
tuted alkyne.
Our synthesis thus began with the preparation of the
Sonogashira coupling partners 15 and 16 as illustrated in
Scheme 2. Alkyne 16 was assembled from known aceto-
nide-protected D-2-deoxyribose10 17 whereby the inherent
syn-diol functionality is converted to C40 and C50 of 70,80-
dihydroaigialospirol (9). Thus, subjection of lactol 17 to
Colvin rearrangement11 followed by silyl protection of
the homologated alkyne afforded 16 in 78% over two
steps. Triflate 15 on the other hand was readily prepared
from commercially available 2,4,6-trihydroxybenzoic
acid (18) by sequential methylation, EOM protection,
and triflation.
Retrosynthetically, ketone 11 constitutes a suitable spiro-
cyclization precursor for the synthesis of 70,80-dihydroaigia-
lospirol 9 (Scheme 1). This key intermediate was envisioned
to be accessible by the addition of a suitable organometallic
reagent (12) to phthalide-aldehyde 13 followed by reduction
of the alkyne moiety. The stereocenters at C10 and C20 can be
installed via a Sharpless asymmetric dihydroxylation (SAD)
of olefin 14. While cis-disubstituted alkenes are generally
poor substrates for the SAD model, moderate to good
diastereocontrol has been observed for acyclic, benzylic
substrates using O-indolinylcarbamoyl (IND) based chiral
ligands.9 Alkene 14, in turn, could be constructed by
Scheme 2. Synthesis of Alkyne 16 and Triflate 15
Scheme 1. Retrosynthesis of 70,80-Dihydroaigialospirol (9)
Sonogashira reaction of15with16and subsequent semi-
hydrogenation of the internal triple bond over Lindlar’s
catalyst proceeded smoothly to afford alkene 14. Sharpless
(9) Wang, L.; Sharpless, B. J. Am. Chem. Soc. 1992, 114, 7568.
(10) Barbat, J.; Gelas, J.; Horton, D. Carbohydr. Res. 1983, 116, 312.
(11) (a) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun.
1973, 151. (b) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1
1977, 869. (c) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107.
Org. Lett., Vol. 14, No. 19, 2012
5155

asymmetric dihydroxylation of cis-alkene 14 using DHQ-
IND (entry 1, Table 1) proceeded with concomitant lactoni-
zation to give a separable mixture of diastereomeric phtha-
lides 20 and 21 (76% yield, dr 20:21 1:2.3). Using the
Sharpless mnemonic,9 the major phthalide was predicted to
possess the desired 10S,20Rstereochemistry (20). Surprisingly,
assignment of the C20 stereocenter by Mosher ester analysis12
established that the SAD resulted in the formation of the
undesired isomer 21. Similarly, use of DHQD-IND (entry 2)
unexpectedly provided the desired phthalide diastereoisomer
(20) but with lower stereoselectivity (dr 20:21 1.3:1). To
ensure the samples and ligands were not inadvertently mixed
up, these experiments were repeated several times, but similar
findings were obtained.
Scheme 3. Synthesis of Aldehyde 23
or anthraquinone- (AQN) based DHQ ligands (entries
3ꢀ5). Investigation of the inherent diastereoselectivity of
the chiral cis-olefin (14) using stoichiometric OsO4 and
NMO (entry 6) or TMEDA13 (entry 7) was also unreward-
ing. The origin of the unexpected reversal of the SAD selec-
tivity remains unclear.14 However, the presence of the chiral
acetonide group may have been a contributing factor. While
the level of stereocontrol was disappointing, formation of
the diastereomeric phthalide (21) does enable access to
analogues for a future medicinal chemistry program.
Moving forward, the desired alcohol 20 was protected as
the silyl ether (Scheme 3). Chemoselective cleavage of the
primary TBS ether and IBX oxidation15 delivered alde-
hyde 23. No purification of the product was required
beyond simple filtration.
Table 1. Dihydroxylation of cis-Olefin 14
Scheme 4. Synthesis of Alkynes 25 and 26
yield
The required organometallic reagent 12 for the key
alkynylation of aldehyde 23 was envisioned to be derived
from alkyne 25 or 26, both of which are available from (S)-
propylene oxide 24 (Scheme 4). Thus, ring opening of 24
with the lithium acetylideꢀethylenediamine complex pro-
ceeded cleanly to afford the corresponding homopropargylic
alcohol which was immediately converted to silyl ether 25.
Iodoalkyne 26, in turn, was synthesized by subjecting 25 to
standard iodination conditions (NIS, AgNO3).
entry
1
reaction conditions
(%)a 20:21
OsO4, DHQ-IND, K3FeCN6, K2CO3,
CH3SO2NH2, tBuOH/H2O, 0 °C to rt, 30 h
OsO4, DHQD-IND, K3FeCN6, K2CO3,
CH3SO2NH2, tBuOH/H2O, 0 °C to rt, 30 h
OsO4, (DHQ)2PHAL, K3FeCN6, K2CO3,
CH3SO2NH2, tBuOH/H2O, 0 °C to rt, 30 h
OsO4, (DHQ)2PYR, K3FeCN6, K2CO3,
CH3SO2NH2, tBuOH/H2O, 0 °C to rt, 30 h
OsO4, (DHQ)2AQN, K3FeCN6, K2CO3,
CH3SO2NH2, tBuOH/H2O, 0 °C to rt, 30 h
OsO4, NMO, acetone/H2O, 18 h
76
78
80
72
70
1:2.3
1.3:1
1:1
2
3
4
5
1:1
1.1:1
(13) (a) Donohoe, T. J.; Moore, P. R.; Waring, M. J. Tetrahedron
Lett. 1997, 38, 5027. (b) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org.
Lett. 2005, 7, 5509.
6
7
67
62
1:1
1:1
OsO4, TMEDA, CH2Cl2, ꢀ78 °C, 2 h
(14) Exceptions to the Sharpless mnemonic have been noted pre-
viously. See: (a) Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T.
J. Am. Chem. Soc. 1997, 119, 311. (b) Shao, H.; Rueter, J. K.; Goodman,
M. J. Org. Chem. 1998, 63, 5240. (c) Allen, P. A.; Brimble, M. A.;
Prabaharan, H. Synlett 1999, 295. (d) Moitessier, N.; Maigret, B.;
Chretien, F.; Chapleur, Y. Eur. J. Org. Chem. 2000, 995.
a Combined yield (over two steps, from 19) of chromatographically
separable phthalides 20 and 21.
To our disappointment, no improvement was ob-
served with phthalazine- (PHAL), pyrimidine- (PYR),
(15) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
€
(16) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806. (b) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett.
2002, 4, 2605. (c) Wilson, E. E.; Oliver, A. G.; Hughes, R. P.; Ashfeld,
B. L. Organometallics 2011, 30, 5214.
(12) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
5156
Org. Lett., Vol. 14, No. 19, 2012

of the alkyne moiety provided 29 uneventfully. At this
point, the one-pot deprotection/spiroacetalization sequence
was investigated. This process required the cleavage of three
orthogonal protecting groups to reveal five hydroxyl groups
that would selectively undergo spiroacetalization without
accompanying elimination processes. Gratifyingly, exposure
of 29 to methanolic HCl effected the desired transformation to
furnish 70,80-dihydroaigialospirol (9) as a single stereoisomer
(68% yield over two steps). The spectroscopic data for
synthetic 9 {mp 75ꢀ78 °C, [R]D þ17.3 (c 0.13, CHCl3)}
was in excellent agreement with those reported for the natural
product {mp 80ꢀ83 °C, [R]D þ14.0 (c 0.10, CHCl3)}.5b
Table 2. Union of Aldehyde 23 with Alkyne 25 or Iodoalkyne 26
entry substrate
reaction conditions
nBuLi, THF,
yield (%)a
1
2
25
25
complex mixture
ꢀ78 °C to rt, 18 h
Scheme 5. Synthesis of 70,80-Dihydroaigialospirol (9)
(þ)-N-methylephedrine
Zn(OTf)2, Et3N, toluene, 2 h
Et2Zn, PPh3, CH2Cl2, 24 h
In, CH2Cl2, 50 o C, 5 h
CrCl2, NiCl2, DMF, 18 h
CrCl2, NiCl2, THF, 18 h
complex mixture
3
4
5
6
7
8
26
26
26
26
26
26
recovered 23
decomposition
13
recovered 23
CrCl2, NiCl2, DMF, 50 °C, 18 h 36
CrCl2, NiCl2, DMSO/THF,
33
49
50 °C, 18 h
9
26
CrCl2, NiCl2, DMF/THF,
50 °C, 18 h
a Isolated yield over two steps, from 22.
Initial attempts to use the lithium or zinc16 acetylide deri-
vative of 25 and 26 to effect coupling with aldehyde 23
(entries 1ꢀ3, Table 2) to produce alcohol 27 only afforded
complex mixtures or unreacted aldehyde 23. Indium-
mediated17 coupling (entry 4) resulted predominantly
in decomposition. These complications were thought to
arise from the presence of the phthalide moiety, and the
possibility of nucleophilic addition to the phthalide car-
bonyl group could not be ruled out. Successful coupl-
ing of iodoalkyne 26 with aldehyde 23 was finally accom-
plished using NozakiꢀHiyamaꢀKishi (NHK)18 conditions
in DMF (entry 5), affording 27 as a single diastereoisomer.19
After extensive experimentation, it was found that the yield
of the NHK reaction was extremely sensitive to the sequence
of addition of the reagents, the activity of the metal salts,20
and the reaction temperature and medium. Use of THF as
solvent (entry 6) resulted in no reaction, while conducting
the NHK reaction in DMF at 50 o C (entry 7) afforded a
higher yield of 27 (36%). Pleasingly, a significant improve-
ment in yield (49%) was observed when the reaction was
carried out in a mixture of DMFꢀTHF at 50 o C (entry 9).
With alcohol 27 in hand, the endgame of the synthesis of
70,80-dihydroaigialospirol 9 commenced with IBX oxidation
of 27 to ketone 28 (Scheme 5). Subsequent hydrogenation
In summary, the synthesis of 70,80-dihydroaigialospirol 9
has been achieved in 13 steps from D-2-deoxyribose. Initial
attempts to install the stereochemistry at the C10 and C20
positions via SAD using the recommended DHQ-IND
ligand unexpectedly led to the wrong diastereoisomer in a
mismatched reaction. Use of DHQD-IND, on the other
hand, reversed the substrate bias to favor the desired 10S,20R-
isomer, albeit with reduced diastereoselectivity. Other fea-
tures of the synthesis include the use of a late stage NHK
protocol to forge a CꢀC bond between phthalide-aldehyde
23 and iodoalkyne 26 and the use of an acid-catalyzed con-
comitant global deprotection/spiroacetalization to construct
the heterocyclic core. Studies toward the total synthesis of
aigialospirol (8) and 40-deoxy-70,80-dihydroaigialospirol (10)
and analogues thereof continue in our laboratory.
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.
ꢀ
(17) Auge, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett.
2002, 43, 5255.
(18) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281. (b) Jin, H.; Uenishi, J.; Christ, W. J.;
Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.
(20) CrCl2 and NiCl2 were activated by heating to 200 °C for 4 h
under high vacuum prior to use.
(19) The stereochemistry of the secondary alcohol is inconsequential
as the stereocenter is oxidized in the next step.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5157