A multifaceted phosphate tether: Application to the C1-C14 subunit of dolabelides A-D

Article abstract of DOI:10.1021/ol7025944

A phosphate tether approach to the C1-14 subunit of dolabelide is described. The phosphate tether serves a multifaceted role mediating several processes, including (i) diastereotopic differentiation via RCM, (ii) selective CM by imparting Type III behavior to the exocyclic olefin, (iii) regioselective hydrogenation, and (iv) regioselective Pd(0)-catalyzed reductive opening of the bicyclic phosphate. Overall, this strategy uses orthogonal protecting- and leaving-group properties innate to phosphate esters to rapidly assembly the titled subunit.

Full text of DOI:10.1021/ol7025944

ORGANIC
LETTERS
2008
Vol. 10, No. 1
109-112
A Multifaceted Phosphate Tether:
Application to the C1 C14 Subunit of
Dolabelides A
−
−D
Joshua D. Waetzig and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045
phanson@ku.edu
Received October 25, 2007
ABSTRACT
A phosphate tether approach to the C1−14 subunit of dolabelide is described. The phosphate tether serves a multifaceted role mediating
several processes, including (i) diastereotopic differentiation via RCM, (ii) selective CM by imparting Type III behavior to the exocyclic olefin,
(iii) regioselective hydrogenation, and (iv) regioselective Pd(0)-catalyzed reductive opening of the bicyclic phosphate. Overall, this strategy
uses orthogonal protecting- and leaving-group properties innate to phosphate esters to rapidly assembly the titled subunit.
In 1995, isolation and structural characterization of two new
22-membered macrolides, dolabelides A (1) and B,1 from
the sea hare Dolabella auricularia were reported. Isolation
of dolabelides C and D,2 24-membered macrolides, was
achieved from the same source. Cytotoxicity studies of
dolabelides A-D revealed promising results against cervical
cancer HeLa-S3 cells with IC50 values of 6.3, 1.3, 1.9, and
1.5 µg/mL, respectively. Synthetic studies toward various
subunits of dolabelide have recently been reported.3 These
efforts include synthesis of protected intermediates of the
C1-C14 subunit, with Leighton and co-workers reporting
the properly acetylated C1-C14 fragment and completing
the only total synthesis of dolabelide D in 2006.4 Key features
common among the dolabelide family are 11 stereogenic
centers, eight of which bear oxygen, and two E-configured
trisubstituted olefins. Other attributes possessed by this family
of molecules include 1,3-anti-diol fragments found at
C7/C9 and C19/C21, along with an accompanying 1,3-syn-
diol at C9/C11 and polypropionate fragments at C1/C4 and
C22/23. The endgame strategy for ring closure was envi-
sioned to hinge on a key ring-closing metathesis (RCM) of
the C14/C15-trisubstitued olefin following a precedent set
by Leighton and co-workers.4 Preceding this macrocycliza-
tion is a simple esterification connecting the C1 carboxylic
acid and C23 alcohol, thus coupling the C1-C14 (2) and
C15-C30 (3) subunits of dolabelide. The stereochemical
complexity and known biological activity of the dolabelide
family present a worthy and formidable challenge. In this
regard, we herein report the use of a multifaceted phosphate
tether toward the synthesis of the C1-C14 subunit of
dolabelide.
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The cornerstone for the title work hinged on recent studies,
countering historical views, which have revealed a function-
(4) Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am.
Chem. Soc. 2006, 128, 2796-2797.
10.1021/ol7025944 CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/07/2007

ally active phosphate triester tether5 within the P-chiral
bicyclic phosphate 5 (Scheme 1).6 These studies also revealed
necessary aldehyde 9 (Scheme 2).7 Reaction of the formed
Scheme 2. Synthesis of CM Partner 2.3
Scheme 1. Retrosynthetic Analysis of Dolabelide
aldehyde with the Z-crotyl (-)-Ipc-borane generated enan-
tiopure homoallylic alcohol 10 in 80% yield.8 PMB-protec-
tion of alcohol 10 was achieved using p-methoxybenzyl-
bromide and sodium hydride to afford 11 in 95% yield.9
Scheme 3. CM Studies with Bicyclic Phosphate 5
selective cleavage pathways operative through displacement
reactions at carbon (SN2, SN2′) and phosphorus, ultimately
affording multipositional activation, which extends through-
out the bicyclic framework. Overall, rapid access to advanced
polyol synthons was attained, thus providing impetus for this
study.5
Retrosynthetic analysis shows that assembly of the
C1-C14 (2) portion can be achieved via a Grignard addition
into the C11 aldehyde, which is accessed by regioselective
hydride opening of the advanced phosphate intermediate 4.
Regioselective cross metathesis (CM) between bicyclic
phosphate (R,R)-5 and terminal olefin 6 generates the
C5-C6 bond and installs five of the six stereocenters found
within the C1-C14 subunit of dolabelide. Bicyclic phosphate
tether (R,R)-5 is readily constructed from the proper enan-
tiomeric, C2-symmetric 1,3-anti-diol, (R,R)-7 via a P-tether-
mediated diastereotopic differentiation using RCM. The
C15-C30 portion of dolabelide can also be accessed using
this phosphate methodology and the enantiomer of the
C2-symmetric 1,3-anti-diol (S,S)-7.
A key component of the proposed synthesis of dolabelide
was the selective CM between bicyclic phosphate (R,R)-5,5a
and the synthesized homoallylic alcohol 11. Previous studies
have shown CM of bicyclic phosphate (R,R)-510 in which
the exocyclic olefin was shown to possess Type III olefin
behavior, implying that no detrimental homodimerization
pathways are operative.10,11 Other derivatives of 11 (TBDPS
(12)12a and PMP acetal(13)12b) were synthesized to test their
ability to undergo the necessary CM reaction. Utilizing
Synthesis of CM partner 11 was achieved through initial
reduction of TBS-protected Roche ester 8, followed by
subsequent Swern oxidation of the alcohol, providing the
(5) For examples of P(III)/P(V)-based tethers in synthesis, see: (a)
Rubinstenn, G.; Esnault, J.; Mallet, J.-M.; Sinay, P. Tetrahedron: Asymmetry
1997, 8, 1327-1336. (b) Sprott, K. T.; McReynolds, M. D.; Hanson, P. R.
Org. Lett. 2001, 3, 3939-3942.
(6) For use of phosphate tethers in synthesis, see: (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.
(7) Burke, S. D.; Cobb, J. E.; Takeuchi, K. J. Org. Chem. 1990, 55,
2138-2151.
(8) (a) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem.
Soc. 1996, 118, 11054-11080. (b) Ramachandran, P. V.; Srivastava, A.;
Hazra, D. Org. Lett. 2007, 9, 157-160.
(9) M´ınguez, J. M.; Kim, S.-Y.; Giuliano, K. A.; Balachandran, R.;
Madiraju, C.; Day, B. W.; Curran, D. P. Bioorg. Med. Chem. 2003, 11,
3335-3357.
(10) Waetzig, J. D.; Hanson, P. R. Org. Lett. 2006, 8, 1673-1676.
(11) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360-11370.
(12) (a) Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68, 1319-
1333. (b) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5,
1147-1150.
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Org. Lett., Vol. 10, No. 1, 2008

TBDPS as a protecting group (12) gave low reactivity, as
well as low yields during CM (Scheme 3, entries 1-3). CM
was next attempted between (R,R)-5 and 11 under the
conditions previously reported (6 mol % Hoveyda-Grubbs
cat., DCM, 45 °C),10 but incomplete consumption of the
starting phosphate was observed after 6 h (entry 4). Optimiz-
ing the reaction conditions with various solvents revealed
that use of toluene (90 °C), with the same catalyst loading,
gave essentially the same results (entry 5). However, an
improved yield of 60% was obtained (entry 6) when 12 mol
% catalyst was added to the CM reaction. Switching to DCE
(90 °C) and adding only 6 mol % Hoveyda-Grubbs catalyst
gave the optimized results for 11, providing 72% yield of
CM product 14 after 2 h. When removing the silyl protecting
group altogether, 13 furnished results similar to those with
11. It should be noted that in all cases excess 11, 12, 13,
Type II CM partners, could be recovered in near quantitative
yield and recycled in future CM events. This differential
reactivity pattern toward CM demonstrates that both proximal
and distal steric interactions play vital roles in the success
of selective CM reactions.13
catalyst, Pd/C) it was found that an in situ generated diimide
reduction under mild conditions (o-nitrobenzenesulfonyl-
hydrazine,14 Et3N, DCM) provided the necessary regiose-
lective hydrogenated phosphate 15 with near complete
selectivity for the exocyclic olefin. Other diimide conditions
(tosylhydrazine, NaOAc, H2O, DCE, 90 °C) gave drastically
lower yields, likely due to bicyclic phosphate instability under
basic medium.
With phosphate 15 in hand, efforts were directed to an
additional use of the tether in a potential regioselective olefin
transposition to the desired terminal olefin. Initial attempts
focused on the use of allylic hydride addition employing
various reagents (Stryker’s reagent, CuCN‚LiCl/PhSiH3,
CeCl3‚7H2O/NaBH4). To our dismay, however, all conditions
probed provided only unreacted starting material or total
decomposition of the reaction mixture. Pd-catalyzed formate
reductions were next investigated for generation of the
requisite terminal olefin.15 Employment of 1.5 equiv of
formic acid and 5 mol % palladium acetate at 40 °C in DCE
selectively opened phosphate 15 to provide the desired
terminal olefin. Methylation of phosphate acid intermediate
showed that a highly regioselective process was operative
(37:1 ratio of regioisomers as evident by 31P NMR analysis).
Purification provided phosphate 17 in 87% yield. The
remarkable regioselectivity reveals another feature of the
phosphate tether, whereby orthogonal orbital alignment5
within 15 allows for selective Pd(0)-catalyzed allylic phos-
phate ionization at C12 over C9.
With optimal CM conditions, 11 was chosen over 13,
owing to the facile removal of the silyl protecting group in
the late stages of the synthesis. The CM between (R,R)-5
and 11 provided phosphate 14 in 72% yield on multigram
scale (Scheme 4). Regioselective hydrogenation of exocyclic
Scheme 4. Selective Phosphate Cleavage in the Synthesis of
Phosphate 17
Scheme 5. Synthesis of the C1-C15 Subunit of Dolabelide
Installation of the C11-C14 fragment began with cleavage
of the phosphate 17 using LiAlH4, which generated a diol
C5-C6 olefin in the presence of the C10-C11 internal olefin
was paramount to allow for subsequent regioselective open-
ing of the bicyclic system. Upon investigating several
hydrogenation conditions, (Wilkinson’s catalyst, Crabtree’s
(14) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507.
(15) For a related study on using Pd-formate reductions to form terminal
olefins see: (a) Hughes, G.; Lautens, M.; Wen, C. Org. Lett. 2000, 2, 107-
110. (b) Chau, A.; Paquin, J.-F.; Lautens, M. J. Org. Chem. 2006, 71, 1924-
1933.
(13) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210-10211.
Org. Lett., Vol. 10, No. 1, 2008
111

that was subsequently protected as the acetonide (PPTS, 2,2-
methoxypropane, DCM) to yield 18 in 96% yield (Scheme
5). Ozonolysis (O3, pyridine, DCM:MeOH 1:1, Me2S) of the
terminal olefin produced the intended aldehyde, which was
subjected to the Grignard generated from 1-iodo-3-methyl-
3-butene16 affording 19 in a 95% yield. Dess-Martin
periodinane (DMP, NaHCO3, DCM) oxidation of the free
alcohol in 19 generated the requisite ketone in 90% yield.
Attempts to selectively reduce the acetonide protected ketone,
using an assortment of reducing agents, resulted in no
diastereoselectivity at C11.17 This problem seemed likely to
be circumvented by deprotection of the acetonide and
subsequent syn reduction utilizing the C9 free alcohol.
Removal of the acetonide was achieved by the addition of
CeCl3‚7H2O and water,18 which efficiently cleaved the
acetonide protecting group without loss of the primary TBS
group and provided diol 20 in 86% yield. Final chelation-
controlled reduction of ketone 20 using Et2BOMe and NaBH4
afforded triol 21 in 60% (95% based on recovered starting
material) with excellent diastereoselectivity (ds g 20:1).
In conclusion, successful completion of the synthesis of
the C1-C14 subunit of dolabelides A-D using phosphate
tether methodology has been achieved. Overall, the phosphate
tether serves a multifaceted role by (i) mediating the initial
desymmetrization event leading to (R,R)-5, (ii) a selective
Type III CM to couple two major complex fragments in the
C1-C14 subunit of dolabelides, (iii) differentiating the two
olefins within the bicyclic system 14, allowing for a selective
hydrogenation, and finally (iv) serving as an excellent leaving
group in a regioselective Pd(0)-mediated formate reduction.
The route outlined above makes use of orthogonal protecting-
and leaving group properties innate to phosphate esters. This
work provides evidence that counters historical and tradi-
tional applications associated with the utilization of phos-
phates in synthesis. Efforts to complete the total synthesis
are ongoing in our laboratories 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 (J.D.W.). We also thank Materia for supplying
metathesis catalyst as well as Danielle Coverdell (University
of Kansas) and John Nguyen (University of Kansas) for their
synthetic contributions.
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.
(16) Helmboldt, H.; Koehler, D.; Hiersemann, M. Org. Lett. 2006, 8,
1573-1576.
(17) See Supporting Information for further details.
(18) Umezawa, T.; Hayashi, T.; Sakai, H.; Teramoto, H.; Yoshikawa,
T.; Izumida, M.; Tamatani, Y.; Hirose, T.; Ohfune, Y.; Shinada, T. Org.
Lett. 2006, 8, 4971-4974.
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