A reductive cyclization approach to attenol A

Article abstract of DOI:10.1021/jo0626459

A reductive cyclization strategy was applied to the synthesis of attenol A. This nontraditional approach to the spiroacetal structure illustrated several advantages of the reductive cyclization methodology. The attenol A core was formed in a carbon-carbon bond coupling that gave rise to a previously inaccessible spiroacetal epimer, a new method to synthesize thioketene acetals from a phenyl sulfone was realized, and the configurational stability of a nonanomeric spiroacetal was evaluated. A minor byproduct in the reductive cyclization reaction was identified that for the first time allowed direct evaluation of the stereoselectivity in a reductive cyclization of a dialkyloxy alkyllithium reagent.

Full text of DOI:10.1021/jo0626459

A Reductive Cyclization Approach to Attenol A
Thomas E. La Cruz and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California;IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
ReceiVed December 22, 2006
A reductive cyclization strategy was applied to the synthesis of attenol A. This nontraditional approach
to the spiroacetal structure illustrated several advantages of the reductive cyclization methodology. The
attenol A core was formed in a carbon-carbon bond coupling that gave rise to a previously inaccessible
spiroacetal epimer, a new method to synthesize thioketene acetals from a phenyl sulfone was realized,
and the configurational stability of a nonanomeric spiroacetal was evaluated. A minor byproduct in the
reductive cyclization reaction was identified that for the first time allowed direct evaluation of the
stereoselectivity in a reductive cyclization of a dialkyloxy alkyllithium reagent.
Introduction
Attenol A (1) (Figure 1) was isolated from the extract of the
Chinese bivalve Pinna attenuata by Uemura and co-workers.1
The molecular architecture of attenol A features three contiguous
stereogenic centers, two homoallylic alcohols, both terminal and
Z-disubstituted olefins, and an anomeric stabilized [5.4]-
spiroacetal core. Attenol B (2) was isolated from the same
extract as attenol A (1), and its structure was determined by
Uemura to be an isomeric form of attenol A (1).1 Both attenol
A and attenol B show moderate cytotoxic activity against P388
cells.1 Its biological activity and scarcity have made attenol A
an interesting synthetic target, and it has been prepared by three
independent research groups: D. Uemura’s,2a,b J. Eustache’s,3
and D. Enders’.4 We describe a new synthesis of attenol A using
a reductive cyclization strategy.
FIGURE 1. Structures of attenol A and B.
The reductive cyclization strategy was developed in our group
to facilitate the stereoselective assembly of nonanomeric
spiroacetals.5 An example of this cyclization reaction is il-
lustrated in Scheme 1. In contrast to traditional spiroacetal
syntheses, this strategy is convergent and gives rise to a
nonanomeric stabilized [5.4]-spiroacetal as a single stereoisomer.
The resulting nonanomeric spiroacetal equilibrates under acidic
(1) Takada, N.; Suenaga, K.; Yamada, K.; Zheng, S.-Z.; Chen, H.-S.;
Uemura, D. Chem. Lett. 1999, 1025-1026.
(2) (a) Suenaga, K.; Araki, K.; Sengoku, T.; Uemura, D. Org. Lett. 2001,
3, 527-529. (b) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D.
Tetrahedron 2002, 58, 1983-1995.
(3) Aoun, D.; Boiteau, J. G.; Eustache, J.; Van de Weghe, P. Org. Lett.
2002, 4, 4105-4108.
(5) Takaoka, L. R.; Buckmelter, A. J.; La Cruz, T. E.; Rychnovsky, S.
D. J. Am. Chem. Soc. 2005, 127, 528-529.
(4) Enders, D.; Lenzen, A. Synlett 2003, 2185-2187.
10.1021/jo0626459 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/09/2007
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J. Org. Chem. 2007, 72, 2602-2611

A ReductiVe Cyclization Approach to Attenol A
IPh12 gave unsatisfactory yields (16-63%) of â-hydroxy ketone
14. Efficient deprotection of 13 finally was achieved with MeI
in aqueous acetonitrile, which gave the desired ketone 14 in
94% yield (Scheme 2).13 Ketone 14 was reduced to alcohol 15
(structure not shown) by using Schneider’s variation of the
Tishchenko reduction catalyzed by Zr(Ot-Bu)4.14 Schneider’s
conditions led to the reduction of â-hydroxy ketone 14 with
ca. 10:1 selectivity. The reduction of ketone 14 was best carried
out at -78 °C to obtain the desired anti ester 15 with improved
stereoselectivity (98:2 anti:syn)15 and in acceptable yield (83%).
Alcohol 15 was converted to tert-butyldimethylsilyl (TBS) ether
16 in 99% yield. The acyl and benzyl protecting groups of silyl
ether 16 were simultaneously removed by treatment with Li/
NH3 to give diol 9 in 50% to 65% yields. Analysis of the crude
reaction mixture revealed a side reaction in which the oxygen
atom of the ester had been reductively removed. Similar ester
deoxygenations under dissolving metal conditions have been
reported previously.16 We hypothesized that a mild reduction
or prior acyl hydrolysis would avoid this side reaction. Reduc-
tion with sodium and ethanol at -78 °C led to slow cleavage
of the benzyl ether; upon warming to 0 °C only trace amounts
of the desired diol 9 were detected due to competing migration
of the TBS group. Prior acyl cleavage was achieved in situ by
adding MeLi to a solution of TBS ether 16 in THF/NH3 to
generate LiNH2. Subsequent addition of Li° led to removal of
the benzyl ether and gave diol 9 in excellent yield. With the
successful synthesis of diol 9 our efforts turned toward the
synthesis of its coupling partner.
SCHEME 1. Stereoselective Preparation of Nonanomeric
Spiroacetal
conditions to the more stable anomeric epimer.5 Thus both
spiroacetal epimers can be accessed from a common intermedi-
ate. The synthesis of attenol A illustrates the versatility of a
reductive cyclization strategy to efficiently prepare both ano-
meric and nonanomeric spiroacetals.6
Many biologically active natural products contain anomeric
spiroacetals, and these spiroacetals are presumably more stable
than their nonanomeric epimer. On treatment with mild acid,
one would expect that the nonanomeric spiroacetal epimer would
cleanly isomerize to the natural epimer with a significant change
in overall geometry. With such a rearrangement in mind, we
considered that nonanomeric spiroacetals might act as pro-drugs
for their natural epimers. Solid tumors are known to have
unusually low extracellular pH,7 and we considered that
spiroacetal epimerization could be triggered by this low pH
media and liberate the biologically active anomeric spiroacetal
in the presence of the tumor. There are many difficulties with
such a scheme, but one prerequisite that could be evaluated was
the expected rate of isomerization of a nonanomeric spiroacetal
to an anomeric spiroacetal in a low pH aqueous medium. We
identified attenol A and its nonanomeric spiroacetal as a
convenient test case to evaluate the lability of the spiroacetal
linkages, and discuss the results below.
Our initial strategy called for the introduction of the complete
Z-alkene side chain prior to thioketene acetal formation. This
route is illustrated in Scheme 3. Known homoallylic alcohol
1717 was reacted with allyl bromide to give allyl ether 18. Allyl
ether 18 was then subjected to a three-step reaction sequence.
First, a RCM reaction using Grubbs’ first generation catalyst
gave the dihydropyran 19 (95% yield).18 Hydrolysis of the
acetonide protection group followed by cyclization of the
resulting diol 20 gave epoxide 21 in good yield.39 Vinyl cuprate
21, prepared from vinyl iodide 25 (Scheme 3),19 reacted
with epoxide 26 to give the desired homoallylic alcohol 22
Results
The retrosynthetic analysis of attenol A is illustrated in Figure
2. The epoxide motif in 5, where the planned addition of a vinyl
cuprate reagent will install the Z-alkene side chain, lends
flexibility to the synthetic route. Acid induced epimerization
of the nonanomeric spiro intermediate 6 will give the appropriate
configuration of the spiroacetal segment of attenol A (1).
Spiroacetal 6 will be synthesized by reductive lithiation of
cyanoacetal 7, which itself is derived from spiro orthoester 8.
Spiro orthoester 8 will arise from the acid-catalyzed coupling
of diol 9 and thiophenyl ketene acetal 10, both of which can be
derived from readily available chiral materials.
The preparation of diol 9 is summarized in Scheme 2.
Optically pure epoxide 12, prepared by Jacobsen resolution,8
was treated with 2 equiv of the organolithium derived from the
known dithiane 11 to give alcohol 13 in 97% yield.9 Hydrolysis
of the dithiane with CuCl2/CuO,10 Hg(ClO4)2,11 or (CF3CO2)2-
(9) For an account of natural product synthesis based on a dithiane
strategy see: Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37,
365-377 and references cited therein.
(10) (a) Chikashita, H.; Kittaka, E.; Kimura, Y.; Itoh, K. Bull. Chem.
Soc. Jpn. 1989, 62, 833-837. (b) Also see Uemura, ref 2b.
(11) Furuta, H.; Hase, M.; Noyori, R.; Mori, Y. Org. Lett. 2005, 7, 4061-
4064.
(12) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.
(13) Petri, A. F.; Ku¨hnert, S. M.; Scheufler, F.; Maier, M. E. Synthesis
2003, 940-955.
(14) (a) Schneider, C.; Klapa, K.; Hansch, M. Synlett 2005, 91-94. (b)
Schneider, C.; Hansch, M.; Weide, T. Chem. Eur. J. 2005, 11, 3010-3021.
(15) The anti relationship of the two stereocenters of product 14 was
confirmed by 13C analysis of acetonide 14a, where the appropriate 13C
resonance signals of both the acetal and methyl carbon atoms were
observed: refer to the supporting information section. (a) Rychnovsky, S.
D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945-948. (b) Rychnovsky,
S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511-3515.
(16) Barrett, A. G. M.; Godfrey, C. R. A.; Hollinshead, D. M.; Prokopiou,
P. A.; Barton, D. H. R.; Boar, R. B.; Joukhadar, L.; McGhie, J. F.; Misra,
S. C. J. Chem. Soc., Perkin Trans. 1 1981, 1501-509.
(6) Recent reviews on spiroacetal synthesis: (a) Mead, K. T.; Brewer,
B. N. Curr. Org. Chem. 2003, 7, 227-256. (b) Aho, J. E.; Pihko, P. M.;
Rissa, T. K. Chem. ReV. 2005, 105, 4406-4440. See also: (c) Jacobs, M.
F.; Kitching, W. Curr. Org. Chem. 1998, 2, 395-436. (d) Perron, F.;
Albizati, K. F. Chem. ReV. 1989, 89, 1617-1661. (e) Boivin, T. L. B.
Tetrahedron 1987, 43, 3309-3362.
(7) (a) Montcourrier, P.; Silver, I.; Farnoud, R.; Bird, I.; Rochefort, H.
Clin. Exp. Metastasis 1997, 15, 382-392. (b) Stubbs, M.; McSheehy, P.
M. J.; Griffiths, J. R.; Bashford, C. L. Mol. Med. Today 2000, 6, 15-19.
(c) Han, S. K.; Na, K.; Bae, Y. H. Colloids Surf., A 2003, 214, 49-59. (d)
Reddy, L. H. J. Pharm. Pharmacol. 2005, 57, 1231-1242.
(8) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1315.
(17) (a) Ronald, R. L.; Roush, W. R. J. Am. Chem. Soc. 1986, 108, 294-
296. (b) Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54, 915-930. (c)
Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R.
L. J. Am. Chem. Soc. 1990, 112, 6339-6348.
(18) Schmidt, B. J. Org. Chem. 2004, 69, 7672-7687.
(19) (a) Takami, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2002, 4, 2993-
2995. (b) Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima,
K. J. Org. Chem. 2003, 68, 6627-6631.
J. Org. Chem, Vol. 72, No. 7, 2007 2603

La Cruz et al.
FIGURE 2. Disconnection plan.
SCHEME 2. Synthesis of Diol
in 85% yield.20 The alcohol 22 was converted to triisopropylsilyl
(TIPS) ether 23 in quantitative yield under standard reaction
conditions. Silyl ether 23 represents half of the attenol A carbon
skeleton. Although the route was satisfactory, the sequence
placed the ring unsaturation at C3 rather than C2. Isomerization
to the C2 enol ether was possible with similar compounds, but
the exocyclic alkene complicated the process.21,22 Selective
alkene isomerization was not observed with Wilkinson’s
catalyst.22 However, both Brimble and Nicolaou have reported
base-induced alkene isomerizations of dihydropyran systems to
form cyclic enol ethers.23 When dihydropyran 23 was treated
with LDA or t-BuOK under various conditions, only decom-
position was observed. Failure of the base-induced alkene
isomerization reactions forced us to examine a different ap-
proach to the enol ether 29.
A new route to the desired enol ether 29 was investigated,
and the outcome is illustrated in Scheme 4. The alkene
isomerization of epoxide 21, mediated by Wilkinson’s catalyst,22
gave volatile epoxide 27 in 70% yield. Addition of cuprate 26
to oxirane 27 followed by protection of the resulting homoallylic
alcohol 28 completed the synthesis of enol ether 29. All attempts
to lithiate enol ether 29 under Boeckman or Myer’s conditions
led to the decomposition of starting enol ether 29.24 Loss of
the homoallylic silyl ethers, presumably through E1cb elimina-
tion, was evident in the 1H NMR spectrum of the crude reaction
mixtures. The unsuccessful kinetic lithiation reaction forced us
to develop an alternative method to generate thioketene acetal
30 from enol ether 29.
Crich explored generating thioketene acetals directly from
arylsulfones, but his endeavor was unsuccessful.25 He showed
that lithiation of sulfone 31 and subsequent treatment with
diphenyl disulfide gave only dithioorthoester 34, and not the
expected thioketene acetal 33 (Scheme 5, part A). We repeated
the experiment in our laboratories (Scheme 5, part B) and found
that the reaction gave primarily two products. The major
(20) (a) Lipshutz, B. H. Synthesis 1987, 325-341. (b) Solladie´, G.;
Hamdouchi, C.; Ziani-Che´rif, C. Tetrahedron: Asymmetry 1991, 2, 457-
469.
(21) (a) Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.;
van Boom, J. H. Synlett 1997, 1263-1264. (b) Clark, J. S.; Kettle, J. G.
Tetrahedron Lett. 1997, 38, 127-130.
(22) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1973, 38, 3224.
(23) (a) Nicolaou, K. C.; Veale, C. A.; Hwang, C.-K.; Hutchinson, J.;
Prasad, C. V. C.; Ogilvie, W. W. Angew. Chem., Int. Ed. Engl. 1991, 30,
299-303. (b) Furkert, D. P.; Brimble, M. A. Org. Lett. 2002, 4, 3655-3658.
(24) For a review on the metalation of vinyl ethers see: Friesen, R. W.
J. Chem. Soc., Perkin Trans. 1 2001, 1969-2001.
(25) Crich, D.; Ritchie, T. J. Tetrahedron 1988, 44, 2319-2328.
2604 J. Org. Chem., Vol. 72, No. 7, 2007

A ReductiVe Cyclization Approach to Attenol A
SCHEME 3. Synthesis of DHP and Organocuprate
SCHEME 4. Attempted Lithiation
spectroscopic analysis of the crude reaction mixture. All attempts
to improve the outcome by using a milder proton source, higher
dilution, or rigorously anhydrous solvent were fruitless. The
proximity of the bulk secondary TIPS ether apparently disfavors
cyclization to the orthoester. With the outcome of these
experiments in mind we revaluated the synthetic plan for attenol
A.
A new route was designed that would delay introduction of
the side chain until the end of the synthesis. As shown in Scheme
7, enol ether 37 was readily accessed from cyclic allyl ether 19
through an alkene isomerization reaction catalyzed by (PPh3)3-
RhCl in 90% yield.22 The acetonide protecting group of enol
ether 37 was not compatible with t-BuLi treatment, so an
alternative thioketene acetal synthesis was required. Applying
the phenylsulfone protocol, sulfone 38 was prepared from enol
ether 37 and subjected to the same sequence as sulfone 35
(Scheme 5) to produce thiophenylketene acetal 10 in 72% yield.
This promising result could be applied to the synthesis of attenol
A, but an even more efficient route was identified.
Kocienski recently reported a very effective route to thioketene
acetals,28 and application of Kocienski’s strategy might stream-
line our synthesis of thioketene acetal 10. The new synthetic
sequence is shown in Scheme 8. Homoallylic alcohol 17 was
converted to vinyl ester 39 in 87% yield.29 Lactone 41 was
accessed by a sequential RCM/hydrogen reaction with both steps
mediated by Grubbs’ second generation catalyst.30 Kocienski’s
Ni0 catalyzed protocol was applied to lactone 41, and gave the
desired thioketene acetal 10 in 75% yield. Clearly, this three-
pot sequence to thioketene acetal 10 was superior to the
previously explored routes. With thioketene acetal 10 in hand,
the time came to test the orthoester formation.
constituent was dithioorthoester 34. Surprisingly, the minor
component was thioketene acetal 33. Optimization of this
reaction led to efficient formation of the desired thioketene
acetal. The optimized procedure was applied to the synthesis
of attenol A. Enol ether 29 reacted with benzenesulfinic acid
to give sulfone 35 in 74-81% yield (Scheme 5, part C). Sulfone
35 was treated with n-BuLi at -100 °C to generate the unstable
lithiated sulfone. The lithiated sulfone was quenched with
PhSSO2Ph,26 and Et3N was introduced into the reaction vessel
to scavenge the benzenesulfinic acid generated in the elimina-
tion reaction. These conditions gave the desired thioketene acetal
30 in 65% yield with none of the corresponding dithioacetal
detected. With thioketene acetal 30 in hand, the time came to
test the spiro orthoester formation.
Thioketene acetal 10 was coupled to diol 9 with use of
catalytic CSA.27 The desired spiro orthoester 8 was isolated in
86% yield as a single diastereomer (Scheme 9).31 The [5.5]-
spiro orthoester 8 was opened with BF3‚OEt2 and TMSCN with
Thioketene acetal 30 was reacted with diol 9 under standard
reaction conditions (0.1 M in DCM, 1-3 mol % camphorsul-
fonic acid (CSA), rt, 0.5 h),27 and the desired spiro orthoester
36 was isolated in a disappointing 35% yield (Scheme 6).
Several decomposition products were observed by TLC and by
(28) Milne, J. E.; Kocienski, P. J. Synthesis 2003, 584-592.
(29) Statsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc. 2004,
126, 9546-9547.
(30) (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 11312-11313. (b) Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron
2002, 58, 5909-5922.
(26) The sulfinating reagent PhSSO2Ph was crucial to the success of the
reaction: Billard, T.; Langlois, B. R.; Large, S.; Anker, D.; Roidot, N.;
Roure, P. J. Org. Chem. 1996, 61, 7545-7550.
(27) La Cruz, T. E.; Rychnovsky, S. D. Synlett 2004, 2013-2015.
J. Org. Chem, Vol. 72, No. 7, 2007 2605

La Cruz et al.
SCHEME 5. Sulfone Mediated Thioketene Acetal Synthesis
that the cyanoacetal motif is incompatible with Ph3P/CCl4.32
An alternative alcohol to alkyl chloride conversion, mesylate
formation followed by treatment with LiCl in DMF, has been
used successfully.5 However, LiCl/DMF is known to cleave TBS
ethers.33 Phosphate esters can also serve as leaving groups in
reductive cyclization reactions,34 and primary alcohol can be
converted to phosphate ester under mild reaction conditions.
Thus, alcohol 44 was treated with (EtO)2P(O)Cl and N-
methylimidazole to give the cyclization precursor, phosphate
ester 45, in 97% yield as a single stereoisomer (Scheme 9).35
The reductive cyclization of phosphate 45 produced the
nonanomeric spiroacetal 6 as the major product in a remarkable
94% yield (Scheme 10). Both cyanoacetal 48, a product of the
competitive reduction of the phosphate motif by lithium di-
tert-butylbiphenylide (LiDBB),36 and anomeric spiroacetal 47
were identified as minor products. Analysis of the crude reaction
mixture by GC returned a 78:1 ratio of nonanomeric spiroacetal
6 and anomeric spiroacetal 47. NOESY correlation confirmed
the nonanomeric configuration of spiroacetal 6 (Scheme 10).
The key reductive cyclization was a very efficient process, and
spiroacetal 6 was amendable to preparative scale synthesis.
Nonanomeric spiroacetal 6 was subjected to equilibrating
conditions (PPTS/MeOH). The reaction was complicated by
cleavage of the TBS ether and equilibration of spiroacetals 49
and 50, the attenol B core.37 Attempts to suppress the equilibra-
tion were unsuccessful, and therefore the mixture was used in
the next reaction. The traditional technique of selective sul-
fonation and subsequent cyclization gave poor yields of epoxide
5. Poor regioselectivity in the sulfonation of triol 49 by both
SCHEME 6. Disappointing Orthoester Synthesis
SCHEME 7. Truncated Thioketene Acetal
excellent regio- and chemoselectivity to give alcohol 44 (Scheme
9) in 71% yield as a single diastereomer.5 The reaction
proceeded to completion faster than the analogous reaction of
a [5.4]-spiro orthoester. In our previous synthetic endeavors the
electrophile, a primary alkyl chloride, was installed prior to
cyanoacetal synthesis.5 Unfortunately, the attenol A architecture
does not lend itself to this approach, and the electrophile had
to be installed after the cyanoacetal. Previous studies have shown
(32) Buckmelter, A. J. Ph.D. Thesis, University of California, Irvine,
2000.
(33) Farras, J.; Serra, C.; Vilarrasa, J. Tetrahedron Lett. 1998, 39, 327-
330.
(34) (a) Zeller, E.; Sajus, H.; Grierson, D. S. Synlett 1991, 44-46. (b)
Zeller, E.; Grierson, D. S. Synlett 1991, 878-880. (c) Wolckenhauer, S.
A.; Rychnovsky, S. D. Tetrahedron 2005, 61, 3371-3381.
(35) Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett. 2003, 5, 1059-
1061.
(36) Guijarro, D.; Manchen˜o, B.; Yus, M. Tetrahedron 1994, 50, 8551-
(31) The configuration of orthoester 8 was determined by 2D NMR
analysis. The minor orthoester arising from the reaction of thioketene acetal
10 and syn stereoisomer of diol 9 was removed at this stage by column
chromatography.
8558.
(37) (a) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849-3852. (b)
Bender, T.; Schuhmann, T.; Magull, J.; Grond, S.; von Zezschwitz, P. J.
Org. Chem. 2006, 71, 7125-7132.
2606 J. Org. Chem., Vol. 72, No. 7, 2007

A ReductiVe Cyclization Approach to Attenol A
SCHEME 8. Revised Strategy to Thioketene Acetal
SCHEME 9. Spiro Orthoester and Cyclization Precursor Synthesis
SCHEME 10. Reductive Cyclization
MsCl and 2,4,6-triisopropylsulfonylchloride was responsible for
the inefficient epoxidation reaction.38 An alternative epoxidation
technique was required, and the Sharpless-Moffatt cyclization
was investigated.39 The desired epoxide 5 was generated in a
satisfactory 67% yield over two steps (Scheme 11). The C16
alcohol did not interfere with the cyclization. Epoxide 5 reacted
with an excess of vinyl cuprate 26 to yield alcohol 51 in 85%
yield. Finally, removal of the TIPS silyl ether completed the
total synthesis of attenol A.
Equilibration. Solid tumors have low extracellular pH (ca.
6.8), and exploiting this property to selectively target tumor cells
has been proposed.7 Acidic media could trigger the isomerization
of nonanomeric spiroacetals to their anomeric isomers, in which
case the nonanomeric spiroacetal would act as a pro-drug for
its epimer. We selected nonanomeric spiroacetal 53 (Table 1)
(38) (a) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203. (b) Cink, R.
D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122-8123.
(39) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-10530.
J. Org. Chem, Vol. 72, No. 7, 2007 2607

La Cruz et al.
SCHEME 11. Completion of the Synthetic Sequence
SCHEME 12. Mechanism of Cyclization
as a test case. The effect of pH on the rate of isomerization of
spiroacetal 53 with its more stable epimer in aqueous buffer
solutions was evalauted.37 Spiroacetal 53 was prepared by
removal of the TBS group from spiroacetal 6 to improve the
solubility properties. The epimerization of the spiroacetal is
summarized in Table 1. Spiroacetal 53 was dissolved in a
NaOAc/HOAc buffer system, using THF as a cosolvent. After
3 days at pH 5.8, epimerization of spiroacetal 53 was not evident
by TLC or GC analysis of the reaction mixture. Epimerization
was not observed in a pH 5.0 environment over a 48 h time
span. Partial epimerization of spiroacetal 53 took place in a pH
4.0 buffer, leading to a 10:1 ratio of nonanomeric to anomeric
isomers. The half-life for the epimerization event could not be
accurately deduced from these data due to concurrent acetonide
cleavage, but it would be at least several days.40 Under normal
physiological conditions the nonanomeric spiroacetal 53 would
be stable indefinitely. Thus the use of this class of nonanomeric
spiroacetals as pro-drugs for solid tumors is impractical because
the epimerization would be too slow at an extracellular pH of
ca. 6.8.7
Discussion
The key reductive cyclization reaction proved to be a very
efficient process, but we were interested in the origin of the
minor anomeric spiroacetal 47. The experiments summarized
in Table 1 demonstrate that the nonanomeric spiroacetal 53,
and presumably 6, is not susceptible to epimerization in a neutral
aqueous solution. Detailed analysis of the radical lithiation
reaction revealed that more than one pathway could be
responsible for the genesis of anomeric spiroacetal 47. These
competing pathways are depicted in Scheme 12. Initial SET
and subsequent C-CN bond fission reveals equilibrating radical
species 55 and 59.41 Preference for the radical to occupy the
axial position has been calculated to be ∼1.86 kcal/mol in a
TABLE 1. Acetal Equilibration Studies
pH
T (°C)
time (h)
ratio (nonanomeric:anomeric)
(40) Acetonide cleavage is accompanied by formation of the attenol B
core, structure 50.
(41) (a) Rychnovsky, S. D.; Powers, J. P.; Lepage, T. J. J. Am. Chem.
Soc. 1992, 114, 8375-8384.(b) Rychnovsky, S. D.; Hata, T.; Kim, A. I.;
Buckmelter, A. J. Org. Lett. 2001, 3, 807-810.
5.8
5
4
23
23
23
72
48
22
no epimerization
no epimerization
10:1
2608 J. Org. Chem., Vol. 72, No. 7, 2007

A ReductiVe Cyclization Approach to Attenol A
SCHEME 13. Summary of the Synthesis
closely related model system (R1, R2 ) Me).42 If we take this
enthalpy as an estimate for the ∆G between the two radical
epimers, it would predict a 122:1 ratio favoring the axial radical
at -78 °C. This value is in good agreement with the 78:1 ratio
observed between the spiroacetals 6 and 47.
precisely reflect the ratio of 55:59. This outcome would be
expected in a more general Curtin-Hammett situation where
the rates of ET differ for the two radicals.43 The minor isomer
47 then would arise from a larger proportion of alkyllithium
60 formed in the reduction. We know from previous studies
that the calculated ratio of anomeric radicals is a good predictor
of the product ratios,41a so the change in ratio that might be
attributed to differential reduction rates is modest. The minor
anomeric spiroacetal 47 may reflect the true equilibrium ratio
between radicals 55 and 59, or there may be a minor loss of
selectivity attributable to either of the pathways discussed above.
The formation of spiroacetal 47 is the first characterized
anomeric spiroacetal formed directly in a reductive cyclization
reaction.
The observed selectivity for nonanomeric spiroacetal 6 is a
bit lower than that predicted by the DFT modeling, but it falls
within the uncertainty of the calculations. The difference may
indicate a modest erosion of selectivity from the thermodynamic
ratio between radicals 55 and 59. If simplified Winstein-
Holness kinetics apply,43 the ratio of alkyllithium reagents 56:
60 would reflect that of the corresponding radicals 55 and 59.
Any change in selectivity would result from differential ef-
ficiency in the reactions of 56 and 60, or from cyclization with
partial inversion of configuration.44 Examples have been
reported where stereogenic, sp3-hybridized, R-hetero alkyl-
lithium species undergo invertive electrophilic substitution
reactions,45 but the process has not been documented with R,R-
dialkyloxy alkyllithium reagents. A second possibility is that
the alkyllithium product ratio in the second SET does not
Conclusion
The synthesis of attenol A is summarized in Scheme 13. The
target molecule 1 was synthesized in 13 steps (longest linear
sequence), starting from enantiomerically pure epoxide 12, in
21.4% overall yield.46 The key intermediates, thioketene acetal
10, spiro orthoester 8, and spiroacetal 6, were efficiently
accessed on preparative scales. The attenol A core was formed
by a carbon-carbon bond reductive cyclization event that gave
rise to a previously inaccessible spiroacetal epimer.
This nontraditional approach to an anomeric spiroacetal target
illustrates several features of the reductive cyclization methodol-
ogy. The synthesis is more efficient than previous approaches
to attenol A, and demonstrates the potential of using reductive
cyclization reactions to afford anomeric spiroacetals. A thioketene
acetal and [5.5]-spiro orthoester, two uncommon chemical
entities, were efficiently synthesized en route to the synthesis
of attenol A. A new method to synthesize thioketene acetals
from a phenyl sulfone was developed. The key reductive
cyclization reaction once again proved to be an efficient process.
The configurational stability of the nonanomeric spiroacetal
moiety was also evaluated, and it was found to be unsuitable
as a pH trigger in a pro-drug. For the first time an anomeric
(42) The relative energy difference between equatorial and axial radical
isomers of 2-methoxyl-5,6-dimethyltetrahydropyran-2-yl were calculated
(6-31G(d)/UB3LYP//6-31G(d)/UB3LYP) and found to favor the axial
radical by 1.86 kcal/mol (with zero point correction; without ZPE correction
the difference was 2.03 kcal/mol). Geometries and energies of the structures
are included in the Supporting Information
.
(43) Seeman, J. I. Chem. ReV. 1983, 83, 83.
(44) Reviews on chiral organolithiums: (a) Basu, A.; Thayumanavan,
S. Angew. Chem., Int. Ed. 2002, 41, 716-738. (b) Hoppe, D.; Marr, F.;
Brueggemann, M. Top. Organomet. Chem. 2003, 5, 61-137.
(45) Inversion of configuration at the lithium bearing carbon of R-oxy
alkyllithiums has been observed in [1,2]- and [2,3]-Wittig rearrangements:
(a) Verner, E. J.; Cohen, T. J. Am. Chem. Soc. 1992, 114, 375-377. (b)
Hoffmann, R.; Bru¨ckner, R. Angew. Chem., Int. Ed. Engl. 1992, 31, 647-
649. (c) Hoffmann, R.; Ru¨ckert, T.; Bru¨ckner, R. Tetrahedron Lett. 1993,
34, 297-300. (d) For a computational study of this phenomenon see: Capo´,
M.; Saa´, J. M. J. Am. Chem. Soc. 2004, 126, 16738-16739.
(46) The longest linear sequence proceeds from commercial 3-butene-
1-ol, a precursor of epoxide 12, in 16 steps and 7.3% overall yield, which
includes a 44% yield on the resolution step.
J. Org. Chem, Vol. 72, No. 7, 2007 2609

La Cruz et al.
1063, 985 cm-1; HRMS (ESI) calcd for C27H51O6Si [M + H]+
499.3455, found 499.3471.
spiroacetal was isolated from the reductive cyclization reaction,
providing insight into the inherent selectivity of the cyclization.
Spiroacetal 6. A solution of phosphate 45 (0.730 g, 1.10 mmol),
1,10-phenanthroline (0.1 mg), and THF (11 mL) was cooled to
-78 °C. To the vigorously stirring solution was added LiDBB (2
mL, over a 0.5 h period) in a dropwise fashion, directly to the center
of the reaction mixture, whereby the green color of LiDBB was
allowed to dissipate before the addition of the following drop.
Another 3 mL of LiDBB were added over a 40 min period in an
identical manner. The solution was stirred for 5 min at -78 °C,
and then another 2.5 mL of LiDBB were added over a 35 min
period in the same manner as described above. Then 0.8 mL of
LiDBB was added over a 10 min period (8.3 mL total volume).
After addition of the final drop of LiDBB its dark color persisted
for 15 s, and then dissipated to give a red solution. The solution
was allowed to stir at -78 °C for 2 h, and excess LiDBB was
quenched by the addition of MeOH (1 mL). The mixture was
warmed to room temperature, diluted with 40 mL of water, and
extracted with Et2O (3 × 100 mL). The combined organic layers
were washed with brine (1 × 40 mL), dried over anhydrous Na2-
SO4, filtered, and concentrated under reduced pressure. The crude
product was determined to be a 78:1 ratio of spiroacetal 6 and
spiroacetal 47 by GC analysis (Rt-6 ) 21.75 min, Rt-47 ) 19.55
min).47 The resulting residue was purified by silica gel chroma-
tography, eluting first with 100% hexanes (to remove DBB) then
15% Et2O/hexanes. The desired spiroacetal 6 (0.502 g, 94% yield)
was isolated as a colorless oil: Rf 0.44 (15% Et2O/hexanes); [R]D
+20 (c 0.23, CH2Cl2); 1H NMR (500 MHz, C6D6) δ 5.79 (ddt, 1H,
J ) 6.7, 10.2, 16.9 Hz), 5.04 (dq, 1H, J ) 1.6, 17.1 Hz), 4.99 (ddt,
1H, J ) 1.2, 2.2, 10.2 Hz), 4.50 (m, 1H), 4.22 (dq, 1H, J ) 2.8,
6.9 Hz), 4.06-3.99 (m, 2H), 3.82 (t, 1H, J ) 6.8 Hz), 2.74 (dd,
1H, J ) 2.8, 9.3 Hz), 2.00 (app q, 2H, J ) 7.4 Hz), 1.93-1.85 (m,
2H), 1.83-1.75 (m, 2H), 1.67-1.62 (m, 2H), 1.60 (s, 3H), 1.56-
1.51 (m, 2H), 1.50-1.45 (m, 4H), 1.44 (s, 3H), 1.39-1.29 (m,
2H), 1.04 (s, 9H), 0.96 (m, 1H), 0.79 (d, 3H, J ) 6.6 Hz), 0.28 (s,
3H), 0.15 (s, 3H) ppm; 13C NMR (125 MHz, C6D6) δ 139.4, 115.1,
109.6, 108.2, 78.1, 76.4, 75.9, 70.4, 65.7, 44.7, 38.5, 35.1, 34.7,
32.9, 31.6 (2C), 31.5, 27.1, 26.7, 26.6, 24.9, 18.7, 17.6, -3.6, -3.8
ppm; IR (neat) 2933, 1624, 1460, 1251, 1064 cm-1; HRMS (ESI)
calcd for C27H50O5SiNa [M + Na]+ 505.3325, found 505.3335.
Epoxide 5. Spiroacetal 6 (0.150 g, 0.311 mmol), PPTS (0.312
g, 1.24 mmol), and MeOH (3.1 mL) were combined and stirred at
room temperature for 28 h. Then 4 mL of saturated NaHCO3(aq)
was added, and the mixture was vigorously stirred for 5 min and
then extracted with Et2O (2 × 60 mL). The organic layers were
combined, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure to give 0.112 g of an oil that was dried by
azeotropic removal of moisture with benzene.
Experimental Section
Thioketene Acetal 10. The following procedure was adopted
from the protocol developed by Kocienski.27 Flask 1: A solution
of KHMDS (0.5 M in toluene, 24.8 mL, 12.4 mmol) and THF (37
mL) was cooled to -78 °C. A mixture consisting of PhN(Tf)2 (3.80
g, 10.6 mmol), lactone 41 (1.90 g, 8.87 mmol), and THF (44 mL)
was prepared and added dropwise over a 1 h 15 min period. After
the addition was completed, the mixture was stirred at -78 °C for
15 min.
Flask 2: To a suspension of NaH (60% dispersion in mineral,
0.710 g, 17.7 mmol) in THF (8.8 mL), at room temperature, was
added PhSH (1.09 mL, 10.6 mmol) dropwise. After the evolution
of gas had ceased, the mixture was stirred at room temperature for
15 min and then cooled to -78 °C.
Flask 3: To a mixture of Ni(PPh3)2Br2 (0.659 g, 0.887 mmol),
PPh3 (0.465 g, 1.77 mmol), and zinc powder (0.348 g, 5.32 mmol)
was added THF (21 mL). The green suspension was stirred at room
temperature for 20 min, after which the color of the reaction mixture
became deep red.
The contents of flask 1 were transferred to flask 2 (via cannula),
and the contents of flask 3 were transferred to flask 2 by syringe.
The deep red mixture was removed from the cooling bath, warmed
to room temperature, and stirred for 3.5 h. The reaction mixture
was diluted with 5% NaOH(aq) (50 mL) and extracted with Et2O (3
× 100 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product mixture was subsequently purified by silica
gel chromatography (deactivated silica gel, 5-10% Et2O/hexanes)
to afford 2.05 g (75% yield) of the title compound as a colorless
1
oil: Rf 0.43 (15% Et2O/hexanes); [R]D -40 (c 0.36, CH2Cl2); H
NMR (500 MHz, C6D6) δ 7.47 (dd, 2H, J ) 1.5, 8.7 Hz), 7.05 (t,
2H, J ) 7.5 Hz), 6.96 (m, 1H), 5.23 (dd, 1H, J ) 2.7, 4.9 Hz),
3.95 (dt, 1H, J ) 2.4, 7.3 Hz), 3.79 (t, 1H, J ) 7.7 Hz), 3.61 (app
t, 1H, J ) 7.1 Hz), 2.93 (dd, 1H, J ) 2.4, 9.1 Hz), 2.01 (m, 1H),
1.79 (dt, 1H, J ) 5.3, 17.5 Hz), 1.46 (ddd, 1H, J ) 2.7, 10.3, 17.5
Hz), 1.39 (s, 3H), 1.33 (s, 3H), 0.72 (d, 3H, J ) 6.8 Hz) ppm; 13
C
NMR (125 MHz, C6D6) δ 147.6, 135.4, 130.8, 129.4, 127.2, 109.8,
107.7, 81.1, 75.0, 65.3, 31.5, 28.7, 26.7 (2C), 17.2 ppm; IR (neat)
2914, 1634, 1584, 1480, 1379, 1070 cm-1; HRMS (ESI) calcd for
C17H23O3S [M + H]+ 307.1368, found 307.1367.
Orthoester 8. To a solution of thiophenyl ketene acetal 10 (1.07
g, 3.49 mmol), in CH2Cl2 (17 mL), was added a solution of diol 9
(1.16 g, 3.83 mmol), in CH2Cl2 (19 mL), and 4 Å molecular sieves
(700 mg). The mixture was stirred at room temperature for 2 h,
and filtered through a 45 µm Whatman syringe filter into another
flask that had been equipped with a magnetic stir bar. The solution
was treated with CSA (8 mg, 3.49 µmol) then stirred at room
temperature for 40 min. The reaction was quenched with Et3N (0.10
mL, 0.717 mmol), and the solution was concentrated under reduced
pressure. The resulting oil was purified by silica gel chromatography
(15% Et2O/hexanes) to afford 1.49 g (86% yield) of the desired
orthoester 8 as a colorless oil: Rf 0.61 (20% Et2O/hexanes); [R]D
The oil (0.112 g, 0.34 mmol) was dissolved in CH2Cl2 (1.7 mL),
then treated with trimethyl orthoacetate (0.10 mL, 0.82 mmol) and
PPTS (9 mg, 0.034 mmol). The mixture was stirred at room
temperature for 45 min, concentrated under reduced pressure, and
placed under a vacuum (0.2 mmHg) for 2 min. The resulting residue
was dissolved in CH2Cl2 (1.7 mL) then treated with Et3N (0.01
mL, 0.072 mmol), and the reaction vessel was then placed in a
room temperature water bath. The mixture was treated with acetyl
bromide (0.061 mL, 0.82 mmol), stirred for 40 min, and then
concentrated under reduced pressure. The resulting residue was
dissolved in MeOH (3.2 mL), and the solution was then treated
with K2CO3(s) (0.471 g, 3.41 mmol). The mixture was stirred
vigorously at room temperature for 15 h, diluted with 4 mL of brine,
and extracted with Et2O (2 × 20 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The resulting oil was purified by silica gel
chromatography (40% EtOAc/hexanes) to afford 0.0645 g (67%
yield) of the title compound as a colorless oil: Rf 0.38 (40% EtOAc/
1
+2.7 (c 0.75, CH2Cl2); H NMR (500 MHz, C6D6) δ 5.79 (ddt,
1H, J ) 6.7, 10.2, 16.9 Hz), 5.04 (dd, 1H, J ) 1.8, 17.1 Hz), 4.99
(dd, 1H, J ) 1.1, 10.2 Hz), 4.51 (ddt, 1H, J ) 3.5, 7.3, 11.4 Hz),
4.15 (dt, 1H, J ) 3.5, 7.1 Hz), 4.04-3.96 (m, 2H), 3.84 (t, 1H, J
) 6.9 Hz), 3.75 (ddd, 1H, J ) 2.6, 11.0, 13.2 Hz), 3.49 (dd, 1H,
J ) 4.3, 10.9 Hz), 3.18 (dd, 1H, J ) 3.5, 10.1 Hz), 2.04-1.98 (m,
3H), 1.79-1.71 (m, 3H), 1.63-1.52 (m, 8H), 1.51-1.45 (m, 2H),
1.41-1.35 (m, 4H), 1.17-1.11 (m, 1H), 1.05 (s, 9H), 0.73 (d, 3H,
J ) 6.6 Hz), 0.25 (s, 3H), 0.16 (s, 3H) ppm; 13C NMR (125 MHz,
C6D6) δ139.4, 115.1, 110.7, 109.3, 77.2, 76.7, 69.8, 66.8, 65.8,
58.8, 45.1, 38.3, 35.3, 34.7, 32.1, 31.8, 30.2, 27.1, 26.7, 26.3, 24.8,
18.7, 17.4, -3.6, -3.7 ppm; IR (neat) 2930, 1462, 1379, 1256,
1
hexanes); [R]D -32 (c 1.3, CHCl3); H NMR (500 MHz, C6D6) δ
(47) GC conditions are reported in the Supporting Information.
2610 J. Org. Chem., Vol. 72, No. 7, 2007

A ReductiVe Cyclization Approach to Attenol A
5.80 (ddt, 1H, J ) 6.7, 10.2, 17.0 Hz), 5.05 (dq, 1H, J ) 1.7, 17.1
Hz), 4.99 (ddt, 1H, J ) 1.1, 2.3, 10.2 Hz), 4.32 (m, 1H), 3.86 (m,
1H), 3.25 (dd, 1H, J ) 6.9, 10.0 Hz), 2.78 (ddd, 1H, J ) 2.6, 4.0,
6.8 Hz), 2.45 (dd, 1H, J ) 2.6, 5.5 Hz), 2.39 (dd, 1H, J ) 4.0, 5.3
Hz), 2.05-1.97 (m, 3H), 1.96-1.90 (m, 1H), 1.89-1.82 (m, 2H),
1.74-1.68 (m, 1H), 1.65-1.55 (m, 4H), 1.51-1.41 (m, 7H), 0.67
(d, 3H, J ) 6.3 Hz) ppm; 13C NMR (125 MHz, C6D6) δ 139.6,
115.0, 106.1, 78.4, 78.2, 69.8, 53.4, 45.5, 45.0, 39.1, 38.0, 34.6,
34.4, 33.2, 31.0, 29.9, 25.8, 17.9 ppm; IR (neat) 3439, 2927, 1640,
1459, 1373, 1015 cm-1; HRMS (ESI) calcd for C18H30O4Na [M +
Na]+ 333.2042, found 333.2048.
Spiroacetal 51. A solution of vinyl iodide 25 (0.58 g, 1.6 mmol),
in Et2O (3.3 mL), was cooled to -78 °C, then treated with n-BuLi
(2.5 M in hexanes, 0.65 mL, 1.6 mmol). The colorless solution
was stirred at -78 °C for 1 h, then solid CuCN (0.076 g, 0.85
mmol) was added in one portion. The reaction flask was placed in
a -30 °C bath, stirred for 1 h, and recooled to -78 °C. A solution
of epoxide 5 (0.063 g, 0.20 mmol), in Et2O (1 mL), was then added
dropwise. The mixture was again placed in a -30 °C bath and
stirred for 1.5 h, then 5 mL of concentrated NH4OH(aq) was added
in one portion. The mixture was warmed to room temperature,
diluted with saturated NH4Cl(aq) (1 mL), and stirred until the green
copper salts were digested (∼20 min). The blue solution was
extracted with Et2O (3 × 70 mL), and the organic layers were
combined and washed with saturated NaHCO3(aq) (1 × 20 mL) and
then brine (1 × 20 mL). The organic extracts were dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure
to give an oil that was purified by silica gel chromatography (30%
EtOAc/hexanes) to afford 0.093 g (85% yield) of the title compound
as a colorless oil: Rf 0.33 (30% EtOAc/hexanes); [R]D -4.8 (c
1
0.60, CH2Cl2); H NMR (500 MHz, CDCl3) δ 5.80 (ddt, 1H, J )
6.7, 10.2, 16.9 Hz), 5.59-5.52 (m, 2H), 5.00 (dq, 1H, J ) 1.6,
17.1 Hz), 4.94 (ddt, 1H, J ) 1.2, 2.3, 10.1 Hz), 4.32 (m, 1H), 3.84
(m, 1H), 3.71-3.65 (m, 3H), 3.31 (dd, 1H, J ) 1.0, 10.3 Hz), 2.50-
2.43 (m, 1H), 2.38-2.30 (m, 2H), 2.21 (br s, 1H), 2.14-2.05 (m,
3H), 2.04-1.96 (m, 2H), 1.86-1.61 (m, 9H), 1.57-1.41 (m, 5H),
1.08-1.04 (m, 21H), 0.86 (d, 3H, J ) 6.5 Hz) ppm; 13C NMR
(125 MHz, CDCl3) δ138.6, 128.3, 127.7, 114.5, 106.3, 77.7, 77.6,
70.1, 69.9, 63.0, 43.8, 38.5, 36.7, 33.9, 33.7, 32.7, 31.4, 30.9, 30.2,
29.0, 25.1, 18.0, 17.2, 12.0 ppm; IR (neat) 3430, 2942, 1641, 1461,
1380 cm-1; HRMS (ESI) calcd for C31H58O5SiNa [M + Na]+
561.3951, found 561.3946.
Acknowledgment. The National Institutes of Health (GM-
65388) provided support for this project. Novartis Pharmaceu-
ticals is gratefully acknowledged for fellowship support to T.E.L.
Supporting Information Available: Experimental details for
preparation of the cyclization substrates and the characterization
and correlation of the products, and proton and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0626459
J. Org. Chem, Vol. 72, No. 7, 2007 2611