A multifaceted phosphate tether: Application to the C15-C30 subunit of dolabelides A-D

Article abstract of DOI:10.1021/ol8001865

(Chemical Equation Presented) Construction of the C15-C30 subunit of dolabelide utilizing a temporary phosphate tether is described. Two routes are reported that make use of the orthogonal protecting- and leaving-group properties innate to phosphate ester

Full text of DOI:10.1021/ol8001865

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1421-1424
A Multifaceted Phosphate Tether:
Application to the C15 C30 Subunit of
Dolabelides A
−
−D
Alan Whitehead, Joshua D. Waetzig, Christopher D. Thomas, and
Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045
phanson@ku.edu
Received January 25, 2008
ABSTRACT
Construction of the C15−C30 subunit of dolabelide utilizing a temporary phosphate tether is described. Two routes are reported that make use
of the orthogonal protecting- and leaving-group properties innate to phosphate esters. One route relies on a selective terminal oxidation, while
a second utilizes a CM/selective hydrogenation sequence. Both routes depend on a highly regio- and diastereoselective cuprate addition to
set the requisite stereochemistry at C22.
Dolabelide A and B1 are 22-membered macrolides collected
and characterized from the sea hares Dolabella auricularia.
Upon further investigation of these extracts, researchers
uncovered two additional 24-membered macrolide analogs
of dolabelide A and B and termed them dolabelide C (1)
and D (Scheme 1).2 Dolabelides A-D show cytotoxicity
against human cervical cancer HeLa-S3 cells with IC50 values
of 6.3, 1.3, 1.9, and 1.5 µg/mL, respectively. Despite this
promising activity, their mechanism of action remains
unknown. The biological activity and stereochemical com-
plexity of this family present worthy and formidable synthetic
challenges and warrant continued synthetic studies directed
at this family of macrolides.
been presented, with Leighton and co-workers publishing
the only complete C15-C30 fragment bearing the requisite
stereochemistry.3d
Retrosynthetic analysis reveals a logical disconnection at
C1-C14 and C15-C30 (2, Scheme 1) for the entire family
of dolabelides. A key acid coupling between the C1
carboxylic acid and either the C23 or C21 carbinol centers
will serve to join the two major subunits. Subsequent RCM
macrocyclization, following the precedent established by
Leighton4 will deliver the C14/C15 trisubstituted olefin
moiety.
(3) (a) Grimaud, L.; Rotulo, D.; Ros-Perez, R.; Guitry-Azam, L.; Prunet,
J. Tetrahedron Lett. 2002, 43, 7477-7479. (b) Grimaud, L.; de Mesmay,
R.; Prunet, J. Org. Lett. 2002, 4, 419-421. (c) Desroy, N.; Le Roux, R.;
Phansavath, P.; Chiummiento, L.; Bonini, C.; Geneˆt, J.-P. Tetrahedron Lett.
2003, 44, 1763-1766. (d) Schmidt, D. R.; Park, P. K.; Leighton, J. L. Org.
Lett. 2003, 5, 3535-3537. (e) Le Roux, R.; Desroy, N.; Phansavath, P.;
Geneˆt, J.-P. Synlett 2005, 429-432. (e) Keck, G. E.; McLaws, M. D.
Tetrahedron Lett. 2005, 46, 4911-4914. (f) Vincent, A.; Prunet, J. Synlett
2006, 2269-2271.
Several synthetic studies3 have recently been reported for
the dolabelide family, including one total synthesis of
dolabelide D by Leighton and co-workers in 2006.4 Among
these efforts, two reports toward the C15-C30 fragment have
(1) Ojika, M.; Nagoya, T.; Yamada, K. Tetrahedron Lett. 1995, 36,
7491-7494.
(2) Suenaga, K.; Nagoya, T.; Shibata, T.; Kigoshi, H.; Yamada, K. J.
Nat. Prod. 1997, 60, 155-157.
(4) Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am.
Chem. Soc. 2006, 128, 2796-2797.
10.1021/ol8001865 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/07/2008

Scheme 1. Retrosynthetic Analysis of Dolabelide C
Scheme 2. Synthesis of Aldehyde 11
acid stability of bicyclic phosphate (S,S)-5. A regio- and
diastereoselective SN2′ cuprate addition5 to 7 followed by
methylation (TMSCHN2 and MeOH) afforded cyclic phos-
phate ester 8 in excellent overall yield (87%, ds ) >95:5).
The unique orbital alignment within bicyclic phosphate 7,
in synergy with its concave nature, dictates the high
selectivity in this SN2′ cuprate reaction.8
The remaining steps to aldehyde 11 were non-problematic
and involved an intitial reductive cleavage of the monocyclic
phosphate ester with LiAlH4 in Et2O to provide diol 9 as a
single diastereomer in excellent yield (96%). Quantitative
acetonide formation and subsequent ozonolysis afforded 11a
in good yield. Alternatively, selective mono-TIPS protection
(9, TIPSCl, imidazole, rt)9 followed by MOM protection and
ozonolysis produced 11b in good to excellent yields over
three steps.
Construction of the C24-C30 vinyl iodide fragment 13
was achieved in two steps from known 12 (Scheme 2).3d
Alkyne 12 was produced from commercially available R-
(-)-epichlorohydrin, employing the Yamaguchi protocol for
oxirane alkynylation.10 Subsequent zirconocene-promoted
carboalumination, utilizing Wipf’s water-accelerated proce-
dure11 and iodine quench, provided trisubstituted vinyl iodide
in 61% yield. Methylmethoxy (MOM) protection ultimately
afforded 13 in >95% yield.
Convergent assembly of the C15-C30 subunit via the
C23-C24 bond is envisioned to occur through vinylate
coupling of metalated 3 with aldehyde 4 (Scheme 1). The
1,3-anti diol moiety contained within subunit 2 (C19 and
C21) can be derived from phosphate triester building block
(S,S)-5,5 assembled via phosphate tether mediated de-
symmetrization of C2-symmetric anti-diol (S,S)-6. The
complimentary phosphate tether approach to the C1-C14
subunit of the dolabelide family has been recently reported
and highlights a cross-metathesis and phosphate-mediated
regioselective olefin transposition strategy emanating from
(R,R)-5.6 Herein we report ongoing progress toward the
dolabelide family of macrolides through preparation of the
C15-C30 subunit.
Initial efforts toward the construction of the C15-C30
subunit of dolabelide began with the enantiomeric bicyclic
phosphate (S,S)-5 (Scheme 2). Mild NaBO3 oxidation condi-
tions were employed following a chemoselective hydro-
boration of the exocyclic olefin of (S,S)-5. A perborate
oxidation protocol developed by Burke and co-workers was
implemented7 and optimized for bicyclic phosphate 5. Yields
in this study were highly dependent on the amount of oxidant,
equivalents of H2O, and reaction time. Subsequent PMB ether
formation using the p-methoxybenzyl trichloroacetimidate
of PMBOH produced 7 in good yields and highlights the
(8) This reaction occurs via a highly regio- and stereoselective anti-SN2′
attack at the C(22) olefinic carbon within bicyclic phosphate 7 where proper
orthogonal alignment of the CdCπ* and C-OP(O)σ* orbitals allows for
anti-SN2′ attack to proceed exclusively on the convex face of 7; see Scheme
4 in ref 5a.
(5) (a) Whitehead, A.; McReynolds, M. D.; Moore, J. D.; Hanson, P. R.
Org. Lett. 2005, 7, 3375-3378. (b) Whitehead, A.; McParland, J. P.;
Hanson, P. R. Org. Lett. 2006, 8, 5025-5028. (c) Waetzig, J. D.; Hanson,
P. R. Org. Lett. 2006, 8, 1673-1676.
(6) Waetzig, J. D.; Hanson, P. R. Org. Lett. 2008, 10, 109-112.
(7) Burke and coworkers have shown this protocol to be compatible with
multiple acetate protecting groups; see: Lucas, B. S.; Luther, L. M.; Burke,
S. D. Org. Lett. 2004, 6, 2965-2968.
(9) For selective silylation of similar 1,3-diols, see: (a) Soltani, O.; De
Brabander, J. K. Org. Lett. 2005, 7, 2791-2793.
(10) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-
394. (b) See also: Morris, J.; Wishka, D. G. Tetrahedron Lett. 1986, 27,
803-806.
(11) (a) Wipf, P.; Lim, S. Angew. Chem. 1993, 105, 1095-1097; Angew.
Chem., Int. Ed. Engl. 1993, 32, 1068-1071. (b) Rand, C. L.; Van Horn, D.
E.; Moore, M. W.; Negishi, E. J. Org. Chem. 1981, 46, 4093-4096.
1422
Org. Lett., Vol. 10, No. 7, 2008

With 11a/11b and vinyl iodide 12 in hand, methods for
the construction of both the C23-C24 C-C bond and C23
stereochemistry were investigated (Scheme 3). Reaction of
desired 1,3-syn diastereomer (14b) as a 4.3:1 mixture of
diastereomers in 90% yield.18
Scheme 4. Construction of Alcohol 14b
Scheme 3. Asymmetric Vinylate Additions into 11a/11b
With 14b in place, only the installation of the C14-C15
terminal olefin was needed to complete the C15-C30 subunit
of dolabelide. Following MOM-protection of the C23 alcohol
(15), DDQ removal of the PMB ether proceeded in good
yield to afford alcohol 16 (Scheme 5). Tosylation of the
Scheme 5. Completion of the C15-C30 Subunit of Dolabelide
acetonide-protected 11a with the lithium-halogen exchange
metalate of 13 (tBuLi, -78 °C to rt) or the vinyl Grignard
of 13 (tBuLi, -78 °C, MgBr2‚Et2O) provided Felkin C22/
C23-syn selectivity of the undesired C21-C23 1,3-anti
product 14a in modest diastereoselectivity (2-4:1 dr).
Selectivity for the undesired C23 epimer was highest when
employing Oshima protocol12 using vinyl magnesiate forma-
tion in the presence of MgBr2‚Et2O, where selectivities of
∼8:1 were observed in favor of the undesired C23 epimer,
1,3-anti-14a.13
To circumvent this selectivity issue we employed reagent
controlled asymmetric addition to 11b using Oppolzer’s zinc
vinylate-lithium alkoxy N-methylephedrine complex14 re-
cently described by Marshall15 and co-workers for vinylate
additions to R-chiral aldehydes. Under these conditions 14b
was formed in an 11:1 ratio of diastereomers favoring the
desired C21-C23-syn product in moderate yield.
Despite this success, difficulties in reaction reproducibility
(also recently noted by Marshall)16 and low product yields
prompted investigation of an alternative oxidation/hydride
reduction sequence for the formation of the requisite 1,3-
syn diol within 14. Thus, Dess-Martin periodinane oxidation
of the C23 epimers of 14b, followed by reduction of the
resulting ketone using Suzuki’s 1,3-syn selective, chelation-
controlled reduction conditions (LiAlH4, LiI)17 afforded the
primary alcohol provided 17 in 90% yield. Treatment of 17
with an allyl Grignard in the presence of stoichiometric CuI
led to the formation of allylated product 18 in 89% yield.
Overall, the sequence represents a 12-step synthesis to 18
from 5, bearing the requisite stereochemistry for the C15-
C30 subunit of dolabelide.
An alternative approach to the C15-C30 side chain was
additionally investigated employing previously established
cross metathesis (CM) methodology (Scheme 6).5c As
anticipated, 5 underwent CM with 19 in the presence of 6
mol % H-G catalyst19 in DCE (90 °C) providing E-configured
20 in 82% yield (>95:5, E:Z).5c Selective reduction of the
(12) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2001, 66, 4333-4339.
(13) These results are in accordance with literature precedence that larger
counterions effect the Felkin selectivity; see: Mengel, A.; Reiser, O. Chem.
ReV. 1999, 99, 1191-1223.
(17) (a) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron
Lett. 1988, 29, 5419-22. (b) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002,
67, 8783-8788.
(18) Additional reductions using a variety of reducing agents (DIBAL-
H, LiAlH4, Zn(BH4)2, NaBH4) failed to generate the desired C23 stereo-
chemistry. (a) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc.
1993, 115, 11446-59. (b) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17,
338-344. (c) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J.
Am. Chem. Soc. 1998, 120, 5921-5942.
(14) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777-
5780.
(15) Marshall, J. A.; Eidam, P. M. Org. Lett. 2004, 6, 445-448.
(16) Marshall and coworkers reported protonolysis products under
Oppolzer conditions with similar homoallylic protected vinyl iodides, which
we witnessed in unsuccessful reactions, along with decomposed aldehyde;
see: Marshall, J. A.; Eidam, P. M. Org. Lett. 2008, 10, 93-96.
Org. Lett., Vol. 10, No. 7, 2008
1423

cuprate addition into 21, under the aforementioned condi-
tions, followed by phosphate tether removal afforded diol
22 in good yield.
Scheme 6. CM Route to the C15-C30 Subunit of Dolabelide
Aldehyde 24 was rapidly accessed using a three-step TIPS-
MOM-ozonolysis sequence (Scheme 6). Lithiate addition into
aldehyde 24 produced 25 as a 1:1 mixture of C23 epimers
in 70% yield (Scheme 6). Subsequent employment of the
aforementioned oxidation/Suzuki reduction conditions gener-
ated the desired diastereomer of 25 in 92% yield (ds ) 5:1
at C23).17 Substrate 25 was MOM-protected and the PMB-
ether removed using DDQ to produce primary alcohol 26.
Iodination of the C14 primary alcohol occurred in 83% yield,
followed by facile E2 elimination of a primary iodide in the
presence of tBuOK (THF, 30 min, rt) afforded 18, in 92%
yield. Given the success, and convenience of the alternative
elimination approach to the C14/C15 olefin, we are currently
investigating selective vinylate addition with 24 for stereo-
controlled formation of C23 within 25.
In conclusion, we have successfully completed the syn-
thesis of the C15-C30 subunit of dolabelides A-D using
two routes relying on a temporary phosphate tether meth-
odology developed in our laboratories. Both pathways make
use of the orthogonal protecting- and leaving-group proper-
ties innate to phosphate esters. Ongoing efforts toward the
completion of dolabelide are currently in progress and will
be reported in due course.
Acknowledgment. This investigation was supported by
funds provided by NSF CHE-0503875, NIH RO1 GM077309,
and the NIH Dynamic Aspects in Chemical Biology Training
Grant (A.W., J.D.W.). The authors would also like to thank
Materia for supplying metathesis catalyst.
Supporting Information Available: Experimental details
and spectroscopic data of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8001865
(20) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7505-7507.
(21) For examples of diimide reductions in synthesis, see: (a) Haukaas,
M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771-1774. (b) Buszek, K.
R.; Brown, N. J. Org. Chem. 2007, 72, 3125-3128.
external olefin was achieved with o-nitrobenzenesulfonyl-
hydrazine,20 which provided 21 in (>95:5) regioselectivity
and 75% yield.21 Regio- and diastereoselective methyl
(19) Second generation Hoveyda-Grubbs catalyst: Garber, S. B.;
Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168-8179.
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