(+)-Rimocidin synthetic studies: Construction of the C(1-27) aglycone skeleton

Article abstract of DOI:10.1021/jo900765p

(Chemical Equation Presented) Assembly of the C(1-27) macrocyclic skeleton of rimocidinolide, the aglycone of (+)-rimocidin (1), has been achieved in convergent fashion. Key features of the synthetic strategy entail application of multicomponent Type I Anion Relay Chemistry (ARC), in conjunction with the S_N2/S_N2′ reaction manifolds of vinyl epoxides, both employing 2-substituted 1,3-dithianes to construct the C(1-19) carbon backbone. Yamaguchi union of a C(20-27) vinyl borate ester, possessing the all-trans triene, with an advanced C(1-19) vinyl iodide followed by macrocyclization via Suzuki-Miyaura crosscoupling completed construction of the C(1-27) rimocidinolide skeleton.

Full text of DOI:10.1021/jo900765p

pubs.acs.org/joc
(þ)-Rimocidin Synthetic Studies: Construction of the C(1-27) Aglycone
Skeleton
Amos B. Smith III,* Megan A. Foley, Shuzhi Dong, and Alia Orbin
Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of
Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104
smithab@sas.upenn.edu
Received April 13, 2009
Assembly of the C(1-27) macrocyclic skeleton of rimocidinolide, the aglycone of (þ)-rimocidin (1),
has been achieved in convergent fashion. Key features of the synthetic strategy entail application of
multicomponent Type I Anion Relay Chemistry (ARC), in conjunction with the SN2/SN20 reaction
manifolds of vinyl epoxides, both employing 2-substituted 1,3-dithianes to construct the C(1-19)
carbon backbone. Yamaguchi union of a C(20-27) vinyl borate ester, possessing the all-trans triene,
with an advanced C(1-19) vinyl iodide followed by macrocyclization via Suzuki-Miyaura cross-
coupling completed construction of the C(1-27) rimocidinolide skeleton.
Introduction
of (þ)-rimocidin (1), initially carried out in the laboratory
of Cope5 and co-workers, established the absolute config-
uration of the C(27) stereocenter as well as the presence of
a conjugated tetraene. Subsequent studies, first by the
Rinehart6 group and then Borowski and co-workers,7
led to assignment of the complete structure including
relative and absolute stereochemistry.
Rimocidin (Figure 1), a member of a family of clinically
important polyene macrolide antifungals first isolated in
1951 from the fermentation broths of Streptomyces rimo-
sus,1 embodies an architecturally interesting 28-membered
macrocyclic skeleton comprised of an all-trans tetraene, an
internal hemiketal, and nine stereogenic centers. Related
members of this antifungal family include (þ)-amphoteri-
cin B,2 nystatin,3 and (þ)-candidin.4 Structural studies
(1) Davisson, J. W.; Tanner, F. W., Jr.; Finlay, A. C.; Solomons, I. A.
Antibiot. Chemother. 1951, 1, 289.
(2) (a) Gold, W.; Stout, H. A.; Pagano, J. F.; Donovick, R. Antibiot.
Annu. 1955-1956, 579. (b) Vandeputte, J.; Wachtel, J. L.; Stiller, E. T.
Antibiot. Annu. 1955-1956, 587. (c) Dutcher, J. D.; Young, M. B.; Sherman,
J. H.; Hibbits, W.; Walters, D. R. Antibiot. Annu. 1956-1957, 866. (d)
Mechlinsker, W.; Schaffner, C. P.; Ganis, P.; Avitabile, G. Tetrahedron Lett.
1970, 11, 3873.
FIGURE 1. (þ)-Rimocidin.
(3) (a) Hazel, E. L.; Brown, R. Science 1950, 112, 423. (b) Lancelin, J.-M.;
Beau, J.-M. Tetrahedron Lett. 1989, 30, 4521.
Earlyinterestinthis class of architecturallycomplex natural
products by the synthetic community resulted in pioneering
(4) (a) Taber, W. A.; Vining, L. C.; Waksman, S. A. Antibiot. Chemother.
1954, 4, 455. (b) Vining, L. C.; Taber, W. A. Can. J. Chem. 1956, 34, 1163. (c)
Pawlak, J.; Sowinski, P.; Borowski, E. J. Antibiot. 1993, 46, 1598.
(5) (a) Cope, A. C.; Burrows, E. P.; Derieg, M. E.; Moon, S.; Wirth, W. J.
Am. Chem. Soc. 1965, 87, 5452. (b) Cope, A. C.; Axen, U.; Burrows, E. P. J.
Am. Chem. Soc. 1966, 88, 4221.
(6) Pandey, R.; Rinehart, K. L., Jr. J. Antibiot. 1977, 30, 146.
(7) Sowinski, P.; Pawlak, J.; Borowski, E. J. Antibiot. 1995, 48, 1288.
DOI: 10.1021/jo900765p
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Published on Web 07/21/2009
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Smith et al.
JOCArticle
contributions from the Nicolaou8 and Masamune9 groups,
with the total synthesis of (þ)-amphotericin B and the
aglycone amphoterinolide B, respectively. More recently,
Rychnovsky and co-workers disclosed the utility of their
elegant cyanohydrin acetonide union tactic with the total
synthesis of rimocidinolide methyl ester.10 We also became
intrigued with the rimocidin aglycone, specifically as a vehicle
to demonstrate the utility of what we now term Anion Relay
Chemistry (ARC),11 a multicomponent reaction sequence,
and the SN2/SN20 reaction manifolds of vinyl epoxides with
2-substituted-1,3-dithianes,12 two effective tactics recently
introduced by our laboratory.
SCHEME 1. Retrosynthetic Analysis of (þ)-Rimocidin Agly-
cone 2
Synthetic Plan. From a retrosynthetic perspective, discon-
nection of the (þ)-rimocidin aglycone (2) at the C(19-20)
and C(1-27) bonds reveals a C(1-19) carboxylic acid (4)
and a C(20-27) vinyl borate ester (3), the latter possessing an
all-trans triene (Scheme 1). Access to the macrocycle was
envisioned to entail union of 3 with 4 either via esterification
followed by an intramolecular Suzuki-Miyaura cross-coup-
ling reaction13 or the reverse. Oxidation and protecting
group reorganizations of 4 in the retrosynthetic sense,
including removal of the (C18-19) vinyl iodide, reveal
advanced tris-dithiane 6, which we envision would derive
via what we now term the multicomponent Type I ARC
tactic11m involving epoxides 7 and 9, employing 2-tert-bu-
tyldimethylsilyl-1,3-dithiane (8) as the bifunctional linchpin.
In our original synthetic plan reported in 2003,11f the C(1)
comprised a terminal dithiane moiety (cf. 5); however, as
presented in that report, the aldehydic proton was replaced
with a phenyl group (cf. 6) with the expectation of eventual
(8) (a) Nicolaou, K. C.; Chakraborty, T. K.; Daines, R. A.; Simpkins, N.
S. J. Chem. Soc., Chem. Commun. 1986, 5, 413. (b) Nicolaou, K. C.; Daines,
R. A.; Chakraborty, T. K.; Ogawa, Y. J. Am. Chem. Soc. 1987, 109, 2821. (c)
Chemtracts: Org. Chem. 1990, 3, 327.
(9) (a) Masamune, S.; Ma, P.; Okumoto, H.; Ellingboe, J. W.; Ito, Y. J.
Org. Chem. 1984, 49, 2834. (b) Boschelli, D.; Takemasa, T.; Nishitani, Y.;
Masamune, S. Tetrahedron Lett. 1985, 26, 5239. (c) Masamune, S. Ann. N.Y.
Acad. Sci. 1988, 544, 168.
(10) Packard, G. K.; Hu, Y.; Vescvsi, A.; Rychnovsky, S. D. Angew.
Chem., Int. Ed. 2004, 43, 2822.
(11) Anion relay chemistry (ARC) as recently defined11p entails the
migration of a negative charge within a molecule (i.e., through bond or
through space, the latter employing a transfer element such as a trisubstituted
silyl group). Two types of through-space ARC processes are possible. In
Type I ARC, the anion after initial migration returns to the site of origin,
whereas in Type II ARC the anion is relayed to a new remote site. For an
account on the evolution of Type I and Type II ARC, see ref 11p. For early
examples of Type I ARC, see: (a) Matsuda, S. P. T.; et al. J. Chem. Soc.,
Perkin Trans. 1 1979, 1, 26. (b) Tietze, L. F.; Geissler, H.; Gewert, J. A.;
Jakobi, U. Synlett 1994, 511. (c) Shinokubo, H.; Miura, K.; Oshima, K.;
Utimoto, K. Tetrahedron 1996, 52, 503. For examples of Type I and II ARC
developed by Smith and co-workers, see refs 11d-11h: (d) Smith, A. B. III;
Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925. (e) Smith, A. B. III; Pitram, S.
M. Org. Lett. 1999, 1, 2001. (f ) Smith, A. B. III; Pitram, M. S.; Furetes, M. J. Org.
Lett. 2003, 5, 2751. (g) Smith, A. B. III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.;
Sfouggatakis, C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435. (h) Smith,
A. B. III; Duffey, M. O. Synlett. 2004, 1363. (i) Smith, A. B. III; Kim, D.-S. Org.
Lett. 2004, 6, 1493. ( j) Smith, A. B. III; Kim, D.-S. Org. Lett. 2005, 7, 3247.
(k) Smith, A. B. III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547. (l) Smith, A. B. III;
Xian, M. J. Am. Chem. Soc. 2006, 128, 66. (m) Smith, A. B. III; Xian, M.; Kim,
W.-S.; Kim, D.-S. J. Am. Chem. Soc. 2006, 128, 12368. (n) Smith, A. B. III; Kim,
D.-S; Xian, M. Org. Lett. 2007, 9, 3307. (o) Smith, A. B. III; Kim, D.-S. Org.
Lett. 2007, 9, 3311. (p) Smith, A. B. III; Wuest, W. M. Chem. Commun. 2008,
5883. (q) Smith, A. B. III; Kim, W.-S.; Wuest, W. M. Angew. Chem., Int. Ed.
2008, 47, 7082. (r) Bevarie-Baez, N. O.; Kim, W.-S.; Smith, A. B. III; Xian, M.
Org. Lett. 2009, 11, 1861.
access to the requisite C(1) carboxylic acid via Baeyer-
Villiger14 oxidation followed by hydrolysis. As will be pre-
sented here, a further modification of the C(1) terminus
would be required (vide infra). Access to advanced epoxides
7 and 9 in turn was envisioned to rely on the reactivity of the
SN2 and SN20 manifolds of vinyl epoxide enantiomers 14 and
ent-14 with 2-lithio-1,3-dithiane derivatives,11f thus lending a
sense of symmetry to the overall synthetic plan.
Results and Discussion
Execution of the First Synthetic Strategy: Construction of
Vinyl Epoxide (þ)-14 and the Antipode (-)-14. Although
both epoxides could be readily prepared via asymmetric
Sharpless epoxidation15 of commercially available 1,4-pen-
tadien-3-ol, followed by Payne rearrangement16 and TBS
protection of the resulting primary alcohol, the cost of such
(12) Smith, A. B. III; Pitram, S. M.; Gaunt, M. J.; Kozmin, S. A. J. Am.
Chem. Soc. 2002, 124, 14516.
(13) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.1979, 36, 3437.
(14) (a) Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625. (b)
Hawthorne, M. F.; Emmons, W. D.; McCallum, K. S. J. Am. Chem. Soc.
1958, 80, 6393.
(15) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Romero, A.; Wong, C.-H. J. Org. Chem. 2000, 65, 8264.
(16) Payne, G. J. Org. Chem. 1962, 27, 3819.
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an approach was prohibitive. An alternative method that
proved both scalable and considerably less expensive
entailed the known condensation of malonic acid (15)
with acrolein to furnish (E)-2,4-pentadieneoic acid (16;
Scheme 2)17 followed by reduction to the corresponding
SCHEME 3. Construction of Epoxide (þ)-20 Employing the
SN2 Reaction Manifold of Vinyl Epoxides with 1,3-Dithianes
SCHEME 2. Preparation of Vinyl Epoxides (þ)- and (-)-14 via
Sharpless Asymmetric Epoxidation
For construction of dithiane 11, reaction of vinyl epoxide
(þ)-14 with 1,3-dithiane 21, now carrying the sterically
demanding TIPS group led to the SN20 product.12
A mixture of primary and secondary silyl ethers, (þ)-22
and (þ)-23, resulted due to silyl group migration (Scheme 4).
SCHEME 4. Construction of Dithiane (þ)-11 Employing the
SN20 Reaction Manifold of Vinyl Epoxides with 1,3-Dithianes
alcohol and a “one-flask” Sharpless epoxidation/TBS pro-
tection protocol.18 Absolute stereochemical assignments for
(þ)- and (-)-14 were based on the Sharpless model, in
conjunction with subsequent X-ray analysis of an advanced
intermediate.19 When this route was employed, over 50 g of
(þ)-14 and over 190 g of (-)-14 were prepared.
Elaboration of Vinyl Epoxide (þ)-14 Exploiting the SN2/
SN20 Reaction Manifolds of Vinyl Epoxides: Construction
of Epoxide 7. With both vinyl epoxide enantiomers in hand,
we turned first to access epoxide 7. In what would prove to
be the first of six planned dithiane coupling reactions,
lithiation of 2-phenyl-1,3-dithiane (18), followed by treat-
ment with (þ)-14, as anticipated,12 furnished the SN2
product (þ)-19 in good yield (Scheme 3). As previously
reported, the phenyl substituent behaves as a small group
providing the desired homoallylic alcohol.12 In a modifi-
cation of the previously published synthetic sequence,11f
the olefin was next reduced using tosyl hydrazide20 rather
than trisyl hydrazide,21 since on a larger scale the latter
requires additional expenses in conjunction with both
careful handling and storage. Treatment with methano-
lic HCl (1%) followed by the Fraser-Reid epoxidation22
led to (þ)-20. The overall yield for the six-step sequence
was 17%. Confirmation of the anticipated syn relation-
ship between the ethyl and the C(3) hydroxy sub-
stituents was achieved via single-crystal X-ray analysis of
(þ)-20.19
Pleasingly, the reaction was both efficient and amenable to
large scale. Acid-mediated removal of the TBS group in the
presence of the TIPS group employing p-toluenesulfonic acid
next provided the corresponding diol which in turn was
converted to the acetonide using 2,2-dimethoxypropane
(2,2-DMP) and then treated with TBAF to furnish alkene
(þ)-24. Hydrogenation of the olefin promoted by the Wilkin-
son catalyst23 completed the construction of dithiane (þ)-11,
with an overall yield for the six steps of 18%.
With both the epoxide and dithiane fragments in hand,
their union was achieved via lithiation of (þ)-11 employing
n-butyllithium followed by addition of (þ)-20 (Scheme 5).
Bis-dithiane (-)-25 comprising the C(1-10) (þ)-rimocidin
(17) (a) Kohler, E. P.; Butler, F. R. J. Am. Chem. Soc. 1926, 48, 1036. (b)
Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W.
Tetrahedron 1958, 2, 1. (c) Cannizzaro, C. E.; Ashley, J. A.; Janda, K. D.;
Houk, K. N. J. Am. Chem. Soc. 2003, 125, 2489.
(18) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(19) See the Supporting Information.
(20) Dewey, R. S.; van Tamelen, E. E. J. Am. Chem. Soc. 1961, 83, 3729.
(21) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetra-
hedron. 1976, 32, 2157.
(22) (a) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203. (b) Corey, E.
J.; Weigel, L. O.; Chamberlin, A. R.; Lipshutz, B. J. Am. Chem. Soc. 1980,
102, 1439.
(23) (a) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J.
Chem. Soc. A 1966, 1711. (b) Birch, A. J.; Walker, K. A. M. Tetrahedron Lett.
1967, 20, 1935.
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SCHEME 5. Initial Synthesis of Advanced Epoxide (-)-7
SCHEME 6. Preparation of the Revised C(5-10) Dithiane 30
aglycone backbone was obtained in good yield. At this stage,
we envisioned that protection of the C(3) oxygen prior to
removal of the acetonide would lead to the corresponding
diol. This transformation, however, proved problematic due
to the lability of the C(3) TBS ether. Performing these
transformations in revised order, that is removal of the
acetonide to furnish triol (þ)-26 prior to epoxide formation
and then protection of the secondary alcohol led to the
desired epoxide (-)-7, albeit the yield was modest. In addi-
tion, on preparative scale, removal of the acetonide proved
highly variable, with epoxide formation remaining ineffi-
cient. We therefore chose to replace the acetonide with a
more readily removable protecting group.
We selected a p-methoxybenzylidene (PMP) group based
on two advantages. First, PMP acetals are more acid labile
than acetonides, benefiting from a resonance-stabilized ox-
ocarbenium intermediate during the hydrolysis.24 Second,
removal via a two-step protocol involving reduction to the
PMB ether and oxidative removal25 serves as backup, in the
event that the hydrolysis proved problematic. To arrive at
the PMP acetal, the SN20 adduct mixture of (þ)-22 and (þ)-
23 was treated with HCl in methanol (2%) to provide diol
(þ)-27 in near quantitative yield (Scheme 6). Formation of
the acetal then proceeded smoothly to furnish a diastereo-
meric mixture of (-)-28 and (þ)-29 (2:1) at the acetal carbon.
The acetals were readily separable via column chromatog-
raphy and the relative stereochemistries determined by 1-D
NMR NOE studies. In practice, however, the diastereomeric
mixture was carried forward without separation. Treatment
with TBAF followed by hydrogenation in the presence of
the Wilkinson catalyst23 then furnished the modified
dithiane (30) as a mixture of diastereomers.
without Et3N buffering. A two-step acetal removal protocol
was therefore developed. First, the secondary hydroxy group in
31 was protected as the TBS ether and the acetal reduced with
DIBAL to provide the PMB ether (-)-32. Mesylation of the
primary hydroxy group then proceeded in near quantitative
yield. Oxidative removal of the PMB ether25 and exposure to
K2CO3 in methanol completed construction of advanced cou-
pling epoxide (-)-7 in 41% overall yield from 30. From the
perspective of material advancement, the K2CO3/MeOH reac-
tion proved very clean; moreover the resulting epoxide could be
purified rapidly using silica gel buffered with Et3N. While this
reaction sequence is slightly longer (cf. Scheme 5), the increase
in overall yield represented a significant improvement.
SCHEME 7. An Improved Route for the Preparation of Epoxide
(-)-7
Pleasingly, the anion derived from dithiane 30 proved to be
an excellent nucleophile. Lithiation with tert-butyllithium,
followed by addition of epoxide (þ)-20 furnished 31 in 94%
yield (Scheme 7). In previously unpublished studies we ob-
served that (-)-7 was not stable to silica gel chromatography
(24) Smith, M.; Rammler, D. H.; Goldberg, I. H.; Khorana, H. G. J. Am.
Chem. Soc. 1962, 84, 430.
(25) Oikawa, Y.; Yoshioka, T; Yonemitsu, O. Tetrahedron Lett. 1982, 23,
885.
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Construction of Epoxide 9: A Third Application of the SN2/
SN20 Reaction Manifold. With a scalable route to (-)-7
available, we initiated construction of epoxide 9, the second
epoxide required for the multicomponent ARC tactic.
Here, an SN2 reaction of the lithiated anion derived
from 1,3-dithiane 33 with vinyl epoxide (-)-14 was employed
(Scheme 8). This transformation could be performed on
Application of Type I Multicomponent Anion Relay Chem-
istry (ARC): Construction of Tris-dithiane (þ)-6. With reli-
able routes to epoxides (-)-7 and (þ)-9 achieved, we turned
to the Type
I
multicomponent ARC tactic.11d-11g
As found appropriate in several earlier cases, we first
examined the individual steps of the ARC process. Addi-
tion of epoxide (-)-7 to the lithiated anion derived from 2-
TBS-1,3-dithiane (8) proceeded smoothly to furnish bis-
dithiane (-)-37 in 72% yield (Scheme 9). The second
SCHEME 8. Construction of Advanced Epoxide (þ)-9
SCHEME 9. Stepwise Construction of Tris-dithiane (þ)-6
a 50 g scale to provide the desired adduct in 66% yield.
However, due to silyl migration, the product was again a
mixture of primary and secondary silyl ethers (2.4:1). Protec-
tion of the free hydroxy group was initially achieved
with TBSOTf.11f However, the lower cost and ease of
operation employing TBSCl was viewed as more desirable.
Thus, treatment of the mixture of alcohols with DMAP,
imidazole, and TBSCl in freshly distilled DMF furnished
(-)-12. Lithiation followed by addition of benzyl (R)-(-)-
glycidyl ether (13) then furnished (-)-34 in 88% yield. This
reaction proved highly reliable and was successfully per-
formed on large scale (ca. 35-40 g). Removal of the dithiane
moiety, followed by β-hydroxy-directed reduction of the
resulting ketone next led to syn diol (þ)-35,26 which upon
formation of the acetonide, removal of the TBS groups
with TBAF, and Fraser-Reid epoxide generation22 com-
pleted construction of advanced epoxide (þ)-9 in ten
steps from 2,4-pentadienoic acid 16, with an overall yield
of 8.0%.
reaction in the ARC protocol calls for 1,4-Brook rearran-
gement27 of oxyanion 38, derived in this case via deproto-
nation of (-)-37, followed by reaction with a second
electrophile (þ)-9 in a solution of Et2O and HMPA, a
solvent system which triggers the 1,4-Brook rearrange-
ment. Unfortunately, the intermediate dithiane anion 39
did not react readily with (þ)-9, furnishing the tris-
dithiane (-)-40 in only modest yield (ca. 35%). The major
product (-)-39 resulted from protonation of the inter-
mediate rearranged lithiated anion 39. Notwithstanding
the modest yield of (-)-40, treatment with TBSOTf and
(26) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M.
J. Tetrahedron Lett. 1987, 28, 155.
(27) (a) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886. (b) Brook, A. G.;
Warner, C. M.; McGriskin, M. E. J. Am. Chem. Soc. 1959, 81, 981.
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2,6-lutidine led to the fully protected adduct (þ)-6 posses-
sing the C(1-18) carbon backbone of the rimocidin agly-
cone. The linchpin union of 8 to (-)-7 and (þ)-9 thus
served as the last of six dithiane coupling reactions in the
synthetic sequence to the aglycone skeleton.
SCHEME 11. One-Flask Type I Multicomponent ARC Union
To Provide Tris-dithiane (þ)-43
At this point, completion of the C(1-18) fragment re-
quired removal of the dithiane moieties to reveal the corre-
sponding triketone followed by hydrolysis of the acetonide
with concomitant mixed ketal formation and chemo- and
regioselective Baeyer-Villiger oxidation14 at the C(1)
carbonyl. Unfortunately, removal of the dithianes proved
difficult in the extreme. A number of well-known proto-
cols [cf. tristrifluoracetoxyiodobenzene,28 mercury(II) salts,
CH3I, I2, CAN,29 and NCS/AgNO330] in most cases led only
to a complex mixture of products.
Postulating that steric congestion between the C(1)
dithiane, the C(3) silyl ether, and the C(5) dithiane might
contribute to the observed difficulties, the C(1-10) epoxide
was redesigned by replacement of the large silyl group with a
smaller MOM protecting group. The overall yield for the
five-step sequence to (-)-41 (Scheme 10) was 49%.
the overall synthetic scheme. However, replacement of the
C(1) dithiane with a primary hydroxy group that at a late
stage could be converted to the required carboxylic acid
would have minimal impact on the synthetic sequence, since
only the C(1-4) epoxide would require revision (Scheme 12).
The requisite C(1-10) fragment 44 was envisioned to
arise via addition of epoxide 45 to the anion derived from
dithiane (-)-30 (vide infra).
SCHEME 10. Preparation of Revised Advanced Epoxide (-)-41
SCHEME 12. Retrosynthetic Analysis Revisited: C(1-10) Ep-
oxide
The new epoxide (-)-41 proved to be a competent electro-
phile for the ARC Type I protocol, furnishing the desired
tris-dithiane (-)-42 in 53% yield (Scheme 11). Protection of
the C(9) hydroxy with TBSOTf then provided hydrolysis
substrate (þ)-43. Removal of the dithianes again proved
difficult: use of harsh reagents such as Hg(ClO4)2 led to de-
composition, whereas milder reagents such as Dess-Martin
periodinane31 and 2-iodobenzoic acid (IBX),32 known to
hydrolyze selectively aryl and allyl dithianes in the presence
of alkyl dithianes, resulted in no reaction.
A Second-Generation Strategy. Based on the above results,
a modified approach to the (þ)-rimocidin aglycone was
required. We reasoned that replacing either the C(1) or the
C(5) dithiane with a moiety that could later be converted
to the required functional group would be appropriate.
A different ketone surrogate to replace the C(5) dithiane
was not viewed as feasible without significantly altering
Execution of the Second-Generation Strategy. To construct
epoxide 45 we began with an Evans aldol reaction33 between
known oxazolidinone (þ)-4634 and benzyloxyacetaldehyde
(47); the reaction proceeded in good yield with excellent
selectivity (Scheme 13). Reductive removal of the auxiliary
and protection of the primary alcohol furnished alcohol (-)-
49, which upon removal of the benzyl ether via hydrogeno-
lysis, followed by epoxide formation led to epoxide (þ)-45 in
47% yield for the five steps. Pleasingly, lithiation of (-)-30
followed by addition of (þ)-45 afforded the coupled product
(-)-50 in 94% yield; the latter was converted to the required
advanced epoxide (-)-44 in five steps (62% overall yield),
(28) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
ꢀ
(29) Cristau, H.-J.; Chabaud, B.; Labaudiniere, R.; Christol, H. Synth.
Commun. 1981, 11, 423.
(30) Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553.
(31) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575.
(32) Wu, Y.; Shen, X.; Huang, J.-H.; Tang, C.-J.; Liu, H.-H.; Hu, Q.
Tetrahedron Lett. 2002, 43, 6443.
(33) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127. (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099.
(34) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. J. Org.
Chem. 1990, 55, 6260.
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SCHEME 14. Type I ARC Tactic and Dithiane Hydrolysis To
Reveal Diketone (þ)-54
SCHEME 13. Construction of the Revised C(1-10) Advanced
Epoxide (-)-44
SCHEME 15. Acetonide Hydrolysis
employing the same reaction sequence as employed for (-)-7
in Scheme 7.
Construction of the Second-Generation C(1-18) Linear
Fragment. With both epoxides available, we turned to
the three-component ARC Type I union. Lithiation of
2-TBS-1,3-dithiane (8) was followed by addition of (-)-44
dissolved in Et2O -78 °C. After being stirred at -20 °C for 1 h,
the reaction was recooled to -78 °C and (þ)-9 added as a
solution in THF with HMPA, a solvent system known to
trigger the 1,4-Brook rearrangement (Scheme 14). The desired
three-component coupling product (-)-52 was isolated in 50%
yield. While the ARC union was viewed as a strategic level
transformation, the required dithiane hydrolysis would also
prove crucial for further synthetic advancement. Toward this
end, (-)-52 was treated with TBSOTf to furnish the fully pro-
tected bis-dithiane (þ)-53, which when subjected to Hg(ClO4)2
and 2,6-di-tert-butyl-4-methylpyridine (DtBMP)35 furnished
diketone (þ)-54 in 59% yield.
Elaboration of the C(11-16) Tetrahydropyran Mixed
Methyl Ketal. Construction of the C(11-16) tetrahydropyran
hemiketal next called for removal of the acetonide from
(þ)-54. To this end, treatment of (þ)-54 with PPTS in
methanol furnished mixed methyl ketal (-)-55, albeit in
modest yield along with 15% recovered diketone (þ)-54
(Scheme 15). Extended reaction times only led to significant
formation of the bis-ketal (-)-56, resulting from loss of the
C(9) TBS group followed by cyclization at C(5). A number of
related hydrolysis conditions (cf. HCl in methanol, Dowex,
CSA, p-toluenesulfonic acid) were examined without signifi-
cant improvement.
Given the modest overall yield of (-)-55, in conjunction
with the need for material advancement, an alternative diol
protecting group was introduced at the level of diol (þ)-35
(Scheme 8). The PMP benzylidene acetal was again selected
to facilitate the eventual hydrolysis process (vide infra).
(35) 2,6-Di-tert-butyl-4-methylpyridine is a non-nucleophilic pyridine
derivative that is also relatively nonpolar, allowing for facile purification
of diketone (þ)-54.
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SCHEME 16. Preparation of Advanced Epoxide (-)-57
SCHEME 18. Type I ARC Tactic: Inverse Order of Epoxide
Addition
Preparation of epoxide (-)-57 was straightforward, requir-
ing three steps from (þ)-35 (Scheme 16).
Revised epoxide (-)-57 was then subjected to the Type I
ARC reaction conditions employed to unite success-
fully epoxides (þ)-9 with (-)-41 (Scheme 11) and (-)-44
(Scheme 14). The results in this case were, however, disap-
pointing; adduct 58 was obtained in only 6% yield
(Scheme 17). The major product (40%) was derived from
initial dithiane addition followed by proton capture. In
addition, diene (þ)-60 was produced in 24% yield. The
presence of diene (þ)-60 suggested that the dithiane anion
[Li-59], rather than acting as a nucleophile, deprotonated the
allylic position of epoxide (-)-57, thereby leading, via ring-
opening, to diene (þ)-60.
2-TBS-1,3-dithiane anion36 to react first with epoxide
(-)-57, followed in turn by triggering the 1,4-Brook rear-
rangement by solvent polarity change (i.e., HMPA) and
addition of epoxide (-)-44, led to tricomponent adduct
(-)-61 in 65% yield (Scheme 18). Importantly, this revised
ARC protocol permitted the production of over 21 g of bis-
dithiane (-)-61.
Protection of the secondary hydroxy group in (-)-61 as
a TBS ether and exposure to Hg(ClO4)2 then led to diketone
(þ)-62 in 77% yield for the two steps (Scheme 19). Turn-
ing next to the required acetal hydrolysis, a number of
acid-mediated conditions were explored. Ultimately, PPTS
in anhydrous solvents (THF/MeOH, 4:1) at 10 °C over a
period of 14 h furnished (-)-55 in 47% yield (cf. 74% yield
SCHEME 17. Type I ARC Union Exploiting Revised Epoxide
(-)-57
SCHEME 19. Conversion of Bis-dithiane (-)-61 into Ketal (-)-
63
While unexpected, in the end this result served to highlight
the versatility of the Type I ARC chemistry. Simply reversing
the order of epoxide additions to permit the less basic 2-Li-
(36) Streitwiesser, A.; Xie, L.; Wang, P.; Bachrach, S. M. J. Org. Chem.
1993, 58, 1778.
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SCHEME 21. Hydrogenolysis and Takai Olefination: Vinyl
based on recovered starting material). By recycling the
recovered starting material, the yield of ketal (-)-55 could
be increased to 63% yield. Protection of the liberated
hydroxy group was then achieved in pyridine, employing
DMAP and TBSOTf to furnish the fully protected cyclic
methyl ketal (-)-63.
Iodide (-)-67
Conversion of the C(14) pendent olefin to the requisite
methyl ester began with catalytic OsO4 dihydroxylation,37
followed by oxidative cleavage to furnish aldehyde (-)-64
(Scheme 20).38 Pinnick oxidation39 and esterification with
trimethylsilyldiazomethane (TMSCHN2) completed construc-
tion of methyl ester (-)-65 in 58% yield for the four steps.
SCHEME 20. Elaboration of the Pendent C(14) Olefin to the
Requisite Methyl Ester
olefination produced vinyl iodide (-)-67 in 54% yield for the
two steps with excellent E to Z selectivity (>20:1).
Removal of the primary TBDPS ether in the presence of
the secondary TBS ethers was next required. Such selectivity
usually entails use of either hydroxide ion,43 buffered TBAF,44
tris(diethylaminosulfonium difluorotrimethylsilicate (TAS-F),45
or sodium hydride in HMPA.46 These conditions proved
unsuccessful, most often leading to removal of one or more of
the secondary silyl ethers. Several alternative tactics were
explored, including global desilylation followed by selective
oxidation of the C(1) primary alcohol or selective protection
of the C(1) alcohol. Hemiketal formation between the C(5)
ketone and the C(1) and C(9) hydroxy groups again complicated
the outcome.
Return to an Earlier Intermediate: Access to the C(1)
Carboxylic Acid C(18,19) Vinyl Iodide. At this juncture, we
were forced to return to an earlier intermediate. Global
desilylation of bis-dithiane (-)-61 (Scheme 18) followed in
turn by selective protection of the primary alcohol as the
pivalate ester and silylation of the remaining secondary
hydroxy groups employing TBSOTf in pyridine furnished
bis-dithiane (-)-69 (Scheme 22). Notably, while the reac-
tions of primary alcohols with acid chlorides are generally
facile, formation of this pivalate ester proved surprisingly
slow, requiring over 24 h at room temperature. The next five
Elaboration of the C(18,19) Vinyl Iodide and C(1) Car-
boxylic Acid: Nontrivial Operations. Generation of the
C(18,19) vinyl iodide proved to be surprisingly problematic.
Hydrogenolysis of the benzyl ether using the Pearlman
catalyst in ethanol afforded the debenzylated product albeit
as a mixture of methyl and ethyl ketals at C(11) (1:1). Using
methanol as a reaction solvent led to decomposition products,
while ethyl acetate resulted in elimination of the methoxy
group. Eventually, we discovered that addition of a bulky
amine, 2,6-di-tert-butyl-4-methylpyridine (DtBMP), employ-
ing a mixture of methanol and ethyl acetate (1:1) provided
primary alcohol (-)-66 in modest yield (Scheme 21). The
latter was then subjected to Parikh-Doering oxidation40 to
furnish the corresponding aldehyde. Unfortunately, Takai
olefination41 initially resulted in a mixture of products along
with decomposition. After significant experimentation, we
discovered that slow addition of a solution of the aldehyde,
CHI3 (1.7 equiv), and DtBMP (2 equiv) in 1,4-dioxane to
chromium dichloride (5 equiv) suspended in THF42 sup-
pressed decomposition (Scheme 21). Use of DtBMP as a base
proved necessary to prevent the formation of the olefin-
containing byproduct analogous to those seen in the hydro-
genolysis. With the DtBMP modification in place, the Takai
(43) Smith, A. B. III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J.
Am. Chem. Soc. 2001, 123, 10942.
(44) (a) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2003, 5,
3583. (b) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531.
(45) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D.
S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(37) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
(38) Criegee, R. Ber. 1931, 64, 260.
(39) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron. 1981, 37,
2091.
(40) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
(41) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
(42) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(46) (a) Shekhani, M. S.; Khan, K. M.; Mahmood, K.; Shah, P. M.;
Malik, S. Tetrahedron Lett. 1990, 31, 1669. (b) Marshall, J. A.; Eidam, P. M.
Org. Lett. 2008, 10, 93.
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SCHEME 22. Construction of C(1) Pivalate (-)-71
SCHEME 23. Oxidation of the C(14) Aldehyde and Removal of
the C(1) Pivalate Ester To Afford Diol (-)-72
screened several oxidants; however, tetrapropylammonium per-
ruthenate (TPAP)47 employing NMO as the stoichiometric
oxidant proved optimal, providing lactone (-)-74 in 94% yield.
Removal of the benzyl group via hydrogenolysis then proce-
eded smoothly to furnish the corresponding alcohol, which
upon Parikh-Doering oxidation40 and Takai olefination41,42
exploiting our previously optimized reaction sequence
(cf. Scheme 21) furnished vinyl iodide (-)-75 with excellent
E/Z selectivity in 50% overall yield. Not surprisingly, opening
the δ-lactone to reveal the carboxylic acid proved challenging,
as the derived β-hydroxy acid quickly relactonized. Use of
SCHEME 24. Construction of Keto-Acid (-)-4
operations were then achieved in similar fashion as employed
previously for the production of (-)-64 (cf. Schemes 19 and
20). Removal of the dithianes employing Hg(ClO4)2 pro-
vided the diketone in good yield, which upon exposure to
PPTS furnished mixed methyl ketal (-)-70 in 44% yield. As
with the previous route (cf. Scheme 19), the ketone could be
recovered in 37% yield and resubjected to the reaction
conditions, thus permitting material advancement. Protec-
tion of the C(17) hydroxy group, followed by dihydroxyla-
37
tion of the pendent olefin employing catalytic OsO4 and
Criegee oxidative cleavage38 completed construction of al-
dehyde (-)-71.
At this juncture, Pinnick oxidation39 of aldehyde (-)-71
was followed by DIBAL-H-mediated removal of the
pivalate ester, which proceeded with concomitant reduction
of the C(5) ketone. Esterification with TMSCHN2 led to a
diastereomeric mixture of diols [(-)-72; 3:1] that could be
readily separated via silica gel chromatography (Scheme 23).
Recognizing that the C(5) hydroxy group would ultimately
be oxidized, the configuration of the C(5) diastereomers was
not established. For material advancement, however, both
isomers were carried forward independently. We describe
here the results only for the major diastereomer.
Oxidation of (-)-72 to the desired ketoacid employing a
number of oxidants not surprisingly was interrupted by the
formation of lactol 73, which was then further oxidized to lactone
(-)-74 (Scheme 24). Reasoning that the lactone could serve as a
de facto protecting group for the carboxylic acid moiety, we
(47) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.
(48) Ivanov, I. V.; Romanov, S. G.; Shevchenko, V. P.; Rozhkova, E. A.;
Maslov, M. A.; Groza, N. V.; Myasoedov, N. F.; Kuhn, H.; Myagkova, G. I.
Tetrahedron 2003, 59, 8091.
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SCHEME 26. Completion of the Fully Functionalized Macro-
cyclic Core of (þ)-Rimocidin Aglycone
aqueous lithium hydroxide in THF, followed in turn by
careful dilution with CH2Cl2, removal of the aqueous
layer, and immediate oxidation with TPAP and NMO fur-
nished the advanced C(1)-keto-acid (-)-4 in 54% yield for the
two steps.
Vinyl Borate Ester (-)-3: The C(20-27) Northwest Frag-
ment. The requisite vinyl borate ester 3 required to complete
the carbon skeleton of the rimocidin aglycone was prepared
in five steps from the known alkyne (þ)-7648 exploiting the
bidirectional linchpin of Coleman (cf. 77).49 Toward this
end, alcohol (þ)-76 was protected as the TBS ether, followed
by removal of the TMS group (Scheme 25). Hydrozircona-
tion followed by iodination and removal of the silyl group
furnished vinyl iodide (-)-79. The latter was then subjected
to Stille cross-coupling with diene 77 to provide the C(20-
27) borate ester (-)-3. The overall yield for the five-step
sequence was 30%.
SCHEME 25. Construction of Trienol (-)-3
mechanical stirrer. Diethyl ether (2 L) was added to the flask,
and the suspension was cooled to 0 °C in an ice bath. Triethyl-
amine (31.4 mL, 225.7 mmol) was added followed by methyl
chloroformate (17.5 mL, 225.7 mmol) and the solution stirred
for 30 min. Water was added to the flask to dissolve the salts,
and the remaining solids were filtered off as the solution was
added to a separatory funnel. The layers were separated, and the
aqueous layer was extracted with Et2O until TLC showed the
absence of product. The organic layer was returned to the flask
and recooled to 0 °C. Sodium borohydride (15.5 g, 410.4 mmol)
was added to chilled MeOH (155 mL). This solution was added
rapidly with vigorous stirring to the flask. After being stirred for
15 min, the reaction was quenched with saturated NH4Cl. The
layers were separated, and the aqueous layer was extracted until
TLC showed that no product remained. The combined organic
layers were washed with brine, and the solvent was evaporated
using a stream of air. The allylic alcohol was purified using silica
gel chromatography (100% hexanes to 1:1 hexanes/ether). The
resulting liquid was distilled using a Kugelrohr distillation
apparatus (40 mm, 85 °C) affording 9.40 g of 17 (54% yield,
111.8 mmol) as a colorless liquid: the analytical data were
consistent with data previously reported for this compound;51
IR (film) 3331, 3087, 3040, 3007, 2864, 1604, 1414, 1086, 1004,
904 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.36 (ddd, J=10.3,
10.3, 16.8 Hz, 1H), 6.26 (dd, J=10.6, 15.2 Hz, 1H), 5.86 (ddd,
J=5.8, 5.8, 11.6 Hz, 1H), 5.22 (d, J=16.5 Hz, 1H), 5.11 (d, J=
9.6 Hz, 1H), 4.19 (s, 2H), 1.66 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 141.8, 138.1, 137.5, 123.2, 68.8.
Final Elaboration of (-)-80: The Macrocyclic Core of the
(þ)-Rimocidin Aglycone. Union of (-)-3 with acid (-)-4 was
successfully achieved employing the Yamaguchi esterifica-
tion protocol (Scheme 26).50 Intramolecular Suzuki-
Miyaura cross-coupling13,48 then provided macrocycle
(-)-80 in 29% yield for the two steps, possessing the pro-
tected macrocyclic skeleton of the rimocidin aglycone.
The spectral data for the macrocycle including 500 MHz
1H NMR, 125 MHz 13C NMR, and 2D NMR (COSY,
NOESY, HSQC) spectra and the high-resolution mass spec-
trum are fully consistent with structure (-)-80.19
Summary. A convergent synthesis of the C(1-19) car-
boxylic acid/vinyl iodide fragment of (þ)-rimocidin aglycone
(-)-4 has been achieved in 31 steps (longest linear sequence).
This fragment was then successfully united with vinyl borate
ester (-)-3 to form the macrocyclic core of the aglycone
of (þ)-rimocidin. The synthetic strategy highlights the utility
of six dithiane coupling reactions, specifically the multicom-
ponent Type I ARC tactic and the SN2/SN20 reaction mani-
folds of vinyl epoxides with 2-substituted 1,3-dithianes. Studies
to extend the utility of ARC and the reactivity of the SN2/SN20
manifold of vinyl epoxides continues in our laboratory.
(-)-tert-Butyldimethyl(((2S,3S)-3vinyloxiran-2-yl-)methoxy)
silane (14). A flask was charged with 55 g of flame-dried 4 A
˚
mesh molecular sieves and dry CH2Cl2 (1.7 L). The flask was
cooled to -25 °C in a dry ice/2-propanol/water bath. (þ)-
Diisopropyl tartrate (11.98 g, 50.92 mmol), freshly distilled
titanium(IV) isopropoxide (12.00 g, 42.43 mmol), and tert-
butylhydroperoxide (stored over freshly activated molecular
sieves for 24 h, 154.3 mL, 848.6 mmol) were added sequentially
to the flask. The solution was stirred for 30 min at -25 °C.
Allylic alcohol 17 (35.69 g, 424.3 mmol) was placed in a flask and
stored over activated sieves for 30 min. The alcohol was then
added neat to the reaction mixture. After 1 h, the epoxidation
Experimental Section
2,4-Pentadien-1-ol (17). Acid 16 (20.13 g, 205.2 mmol) was
placed in a 3-necked round-bottom flask equipped with a
(49) Coleman, R. S.; Walczak, M. C. Org. Lett. 2005, 7, 2289.
(50) Inanaga, J.; Hirara, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
J. Org. Chem. Vol. 74, No. 16, 2009 5997

Smith et al.
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was judged complete via TLC. Trimethyl phosphite (79.00 g,
636.5 mmol) was added dropwise to quench the remaining
peroxide. The reaction stirred for 1 h at -25 °C. A second flask
was charged with TBSCl (95.90 g, 636.5 mmol), DMAP (2.59 g,
21.22 mmol), anhydrous CH2Cl2 (250 mL), and Et3N (89.3 mL,
636.5 mmol). The TBSCl solution was added to the reaction in
one portion. The reaction was allowed to warm slowly to 0 °C
and then was placed in a 0 °C refrigerator overnight. The
following morning, Et2O (500 mL) and silica gel (500 mL) were
added to the flask, and the slurry was filtered through Celite
and rinsed with Et2O. The filtrate was refiltered to remove
the remaining solids. The filtrate was concentrated, and the
desired vinyl epoxide was purified using flash chromatography
(0.5% Et2O in hexanes). Epoxide (-)-14 was isolated as a
colorless oil in 72% yield (68.54 g, 319.8 mmol): [R]23D -16.56
(c=1.25, CHCl3); IR (film) 2955, 2931, 2890, 2858, 1468, 1255,
1139, 1109, 838, 779 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.60
(ddd, J=7.5, 10.3, 17.3 Hz, 1H), 5.48 (dd, J=2.2, 17.8 Hz, 1H),
5.29 (dd, J=1.5, 10.6 Hz, 1H), 3.86 (dd, J=3.2, 12.0 Hz, 1H),
3.72 (dd, J=4.5, 12.0 Hz, 1H), 3.28 (dd, J=2.1 7.5 Hz, 1H), 3.00
(ddd, J=2.2, 3.3, 4.5 Hz, 1H), 0.90 (s, 9H), 0.083 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 135.2, 119.4, 63.0, 60.3, 56.1, 25.8
(3C), 18.4, -5.3 (2C); high resolution mass spectrum (CIþ) m/z
215.1464 [(MHþ) calcd for C11H22OSi þ H 215.1467].
for 30 min before addition of saturated NH4Cl (9 mL). The
reaction was partitioned between Et2O (125 mL) and water
(5 mL). The organic layer was washed twice with water and once
with brine. The organic layer was dried over MgSO4 and
concentrated. Flash chromatography (3:1 hexanes/EtOAc)
afforded coupled product 31 as a 2:1 mixture of diastereomers
at the acetal carbon (1.38 g, 2.22 mmol) in 94% yield. The
compounds were characterized as a mixture: IR (film) 3464,
1
2928, 1614, 1517, 1440, 1249, 1170, 1081, 1030, 831 cm-1; H
NMR (500 MHz, C6D6) δ 7.51 (m, 2H), 7.47 (m, 1H), 7.41
(m, 3H), 7.15 (m, 3H), 7.05 (m, 1.5H), 6.80 (m, 3H), 5.94 (s, 0.5H),
5.75 (s, 1H), 3.95 (m, 0.5H), 3.91 (m, 1H), 3.85, (m, 1H), 3.73 (dd,
J=7.3, 7.3 Hz, 1H), 3.45 (dd, J=7.0, 7.0 Hz, 1H), 3.32 (m, 0.5H),
3.31 (s, 1.5H), 3.30 (s, 3H), 3.15 (m, 1.5H), 3.05 (m, 4H),
2.53-2.38 (m, 7H), 2.17 (m, 3H), 2.04 (m, 4.5H), 1.88 (m, 3H),
1.70 (m, 4.5H), 1.54 (m, 4.5H), 1.32 (m, 1H), 1.21 (m, 3H), 1.17 (dd,
J=6.3, 6.3 Hz, 4.5H), 1.16 (m, 1H); 13C NMR (125 MHz, C6D6) δ
160.5, 160.3, 141.8, 131.5, 130.8, 130.5, 128.3, 128.0, 126.7, 113.6,
104.1, 103.2, 76.8, 75.9, 70.4, 69.8, 62.9, 54.6, 43.12, 43.08, 39.7,
34.8, 33.5, 33.2, 32.0, 31.0, 30.8, 28.7, 27.2, 25.0, 22.7, 21.1, 14.1;
high-resolution mass spectrum (ESþ) m/z 643.2016 [(Mþ Naþ)
calcd for C32H44O4S4 þ Na 643.2020].
Dithiane (12). Epoxide (-)-14 (51.35 g, 239.6 mmol) and 1,3-
dithiane 33 (43.21 g, 359.6 mmol) were both azeotroped three
times with toluene. The dithiane was placed under high va-
cuum for 2 h before being dissolved in dry THF (1400 mL)
and transferred into a dry three-necked flask equipped
with an addition funnel. Hexamethylphosphoramide (111 mL,
638 mmol) was added, and the flask was cooled to -78 °C in a
dry ice/acetone bath. The addition funnel was charged with a
solution of n-BuLi in hexanes (1.37 M, 245 mL, 335 mmol) and
added to the reaction mixture dropwise over 1 h, after which the
reaction mixture stirred an additional 30 min. The same funnel
was then charged with (-)-14 and anhydrous THF (120 mL).
This solution was added to the reaction mixture over 1 h, and the
bath was then allowed to warm to room temperature over 3 h.
The reaction was quenched with saturated NH4Cl (100 mL), and
Et2O (500 mL) was added. The layers were separated, and
the aqueous layer was extracted with Et2O (3ꢀ100 mL). The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated to afford an orange oil. Using flash
chromatography (97:3 to 9:1 hexanes/EtOAc) the alcohol
was isolated as a 2.4:1 mixture of primary, and secondary silyl
ethers in 66% total yield. Data for the major isomer is presented:
Phenyl Dithiane (þ)-19. 2-Phenyl-1,3-dithiane (18) (7.23 g,
36.82 mmol) was azeotroped three times with benzene and
placed under high vacuum overnight. Epoxide (þ)-14 (6.34 g,
29.58 mmol) was azeotroped twice with benzene, dissolved in
THF (50 mL), and allowed to stand with CaH2 for 30 min.
Dithiane 18 was dissolved in dry THF (130 mL), and HMPA
(15.4 mL, 88.7 mmol) was added. The solution was cooled to
-78 °C before n-BuLi (2.15 M, 17.2 mL, 38.0 mmol) was
added dropwise, turning the solution orange. After the solu-
tion was stirred at -78 °C for 30 min, the epoxide solution was
added via cannula. The reaction turned red and was allowed to
warm slowly in the dry ice bath over the course of 2 h. The bath
was removed and the reaction stirred at room temperature for
and additional 1 h before being quenched by addition of
saturated NH4Cl (9 mL) and Et2O (230 mL). The layers were
separated, and the aqueous layer was extracted once with
Et2O. Water (200 mL) was run through the combined organic
layers to remove HMPA. The organic layer was washed with
brine, dried over MgSO4, and concentrated. Flash chroma-
tography (98:2 hexanes/EtOAc) afforded (þ)-19 (10.88 g,
26.49 mmol) in 72% yield: [R]23 þ21.00 (c=1.19, CH2Cl2);
[R]23 -21.22 (c = 0.47, CHCl3); IR (film) 3414, 2927, 1466,
D
D
1
IR (film) 3500, 3075, 2928, 2856, 1472, 1442, 1255, 1116, 838,
1250, 1101, 836, 777, 668 cm-1; H NMR (CDCl3, 500 MHz)
1
776 cm-1; H NMR (500 MHz, CDCl3) δ 7.99 (m, 2H), 7.40
δ 5.87 (ddd, J=10.0, 10.0, 17.1 Hz, 1H), 5.26 (dd, J=1.8, 10.1
Hz, 1H), 5.16 (dd, J=1.8, 17.1 Hz, 1H), 4.33 (d, J=4.3 Hz, 1H),
4.10 (dddd, J=3.4, 3.4, 6.2, 6.2 Hz, 1H), 3.56 (m, 2H), 2.95-2.83
(m, 4H), 2.45 (ddd, J=3.4, 7.9, 11.0 Hz, 1H), 2.34 (d, J=3.4 Hz,
1H), 2.10 (m, 1H), 1.90-1.85 (m, 1H), 0.90 (s, 9H), 0.07 (s, 6H);
13C NMR (CDCl3, 125 MHz), δ 133.9, 119.5, 70.6, 65.3, 51.1,
49.3, 30.7, 30.6, 26.0 (3C), 25.8, 19.2, -5.37, -5.42; high-
resolution mass spectrum (ESþ) m/z 357.1362 [(M þ Naþ) calcd
for: C15H30O2S2Si þ Na 357.1354].
(m, 2H), 7.27 (m, 1H), 6.02 (ddd, J=11.0, 11.0, 17.1 Hz, 1H),
5.24 (dd, J=2.0, 10.1 Hz, 1H), 5.00 (dd, J=2.0, 17.1 Hz, 1H),
4.06 (dddd, J=2.4, 3.6, 6.8, 6.8 Hz, 1H), 3.36 (dd, J=6.9,
9.8 Hz, 1H), 3.27 (dd, J=6.8, 9.8 Hz, 1H), 2.76-2.62 (m, 5H),
1.98 (d, J=3.4 Hz, 1H), 1.91 (m, 2H), 0.83 (s, 9H), -0.036 (s,
3H), -0.050 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 140.5,
132.1, 129.8 (2C), 128.6 (2C), 127.1, 120.5, 70.0, 64.7, 62.7,
58.4, 27.6, 27.5, 25.9 (3H), 24.9, 18.1, -5.4, -5.5; high-resolu-
tion mass spectrum (ESþ) m/z 433.1650 [(M þ Naþ) calcd for
C21H34OS2Si þ Na 433.1667].
The mixture of alcohols (13.19 g, 39.42 mmol) was placed
in a flask with TBSCl (8.91 g, 59.13 mmol), DMAP (1.20 g,
9.85 mmol), and imidazole (5.37 g, 78.84 mmol). The flask was
Alcohol 31. A mixture of dithiane 30 diastereomers (987 mg,
2.90 mmol) and epoxide (þ)-20 (662 mg, 2.36 mmol) was
azeotroped three times with toluene and placed under high
vacuum overnight. The dithiane mixture was dissolved in dry
THF (29 mL), and HMPA (1.23 mL, 7.08 mmol) was added.
The solution was cooled to -78 °C in a dry ice/acetone bath, and
t-BuLi (1.35 M, 2.09 mL, 2.83 mmol) was added slowly, turning
the solution dark orange, and stirred for 30 min. The epoxide in
dry THF (15 mL) was added to the reaction mixture via cannula,
and the mixture was allowed to warm in the bath for 2.5 h. The
bath was removed and the reaction stirred at room temperature
˚
then charged with 60 mL of freshly distilled DMF from 4 A
molecular sieves and allowed to stir at room temperature. After
3 days, the reaction was diluted with EtOAc and saturated
NH4Cl. The layers were separated, and the aqueous layer was
extracted three times with EtOAc. Distilled water (∼300 mL)
was run through the combined organic layers to remove
the DMF. The organic layer was then washed with brine, dried
over MgSO4, and concentrated to afford a yellow oil. Flash
chromatography (99:1 hexanes/EtOAc) afforded the desired
product (-)-12 (16.10 g, 35.87 mmol, 91%): [R]23 -3.47 (c=
D
5998 J. Org. Chem. Vol. 74, No. 16, 2009

Smith et al.
JOCArticle
0.30, CHCl3); IR (film) 2953, 2929, 2895, 2857, 1472, 1255, 1096,
diluted with Et2O. The aqueous layer was extracted twice with
Et2O. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated. Flash chromatography
afforded the desired coupled product (-)-42 in 53% yield (188
1
836, 776 cm-1; H NMR (CDCl3, 500 MHz) δ 5.70 (ddd, J=
10.0, 10.0, 17.2 Hz, 1H), 5.22 (dd, J=2.1, 10.0 Hz, 1H), 5.14 (dd,
J=2.0, 17.2 Hz, 1H), 4.17 (m, 1H), 4.14 (d, J=10.8 Hz, 1H), 3.46
(dd, J=5.4, 9.8 Hz, 1H), 3.40 (dd, J=7.9, 9.7 Hz, 1H), 2.88-2.75
(m, 4H), 2.59 (ddd, J=1.9, 10.4, 10.4 Hz, 1H), 2.12-2.07 (m,
1H), 1.92, 1.84 (m, 1H), 0.89 (s, 18H), 0.14 (s, 3H), 0.08 (s, 3H),
0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 134.1,
119.0, 71.1, 64.8, 50.9, 47.9, 30.3, 30.0, 26.1, 25.94 (3C), 25.88
(3C), 18.2, 18.1, -4.2, -4,8, -5.35, -5.41; high-resolution
mass spectrum (ESþ) m/z 471.2202 [(M þ Naþ) calcd for
C21H44O2S2Si2 þ Na 471.2219].
mg, 0.174 mmol): [R]23 -9.75 (c = 0.16, CH2Cl2); IR (film)
D
3502, 2928, 2856, 1456, 1436, 1379, 1257, 1200, 1173, 1107, 1049,
837, 775, 700 cm-1-; 1H NMR (500 MHz, C6H6) δ 7.47 (m, 2H),
7.30 (m, 1H), 7.17 (m, 5H), 7.09 (m, 2H), 6.01 (ddd, J=10.1,
10.1, 17.3 Hz, 1H), 5.16 (dd, J=2.2, 10.3 Hz, 1H), 5.05 (dd,
J=2.1, 17.3 Hz, 1H), 4.86 (d, J=8.3 Hz, 1H), 4.42 (d, J=6.5 Hz,
1H), 4.41 (m, 1H), 4.39 (d, J=3.8 Hz, 2H), 4.37 (d, J=6.4 Hz,
1H), 4.19 (ddd, J=2.2, 8.4, 13.8 Hz, 1H), 4.02 (dddd, J=2.5,
5.1, 5.1, 11.6 Hz, 1H), 3.51 (dd, J = 5.5, 9.8 Hz, 1H), 3.41
(d, J=2.8 Hz, 1H), 3.26 (dd, J=4.9, 9.8 Hz, 1H), 3.23 (dd, J=
6.0, 10.6 Hz, 1H), 3.12 (dd, J=8.2, 10.6 Hz, 1H), 3.11 (s, 3H),
3.05 (m, 2H), 2.61-2.40 (m, 8H), 2.36 (dd, J=5.0, 15.0 Hz, 1H),
2.32 (m, 2H), 2.19-2.01 (m, 8H), 1.94 (m, 1H), 1.83-1.67 (m,
5H), 1.58-1.31 (m, 7H), 1.54 (s, 3H), 1.40 (s, 3H), 1.18 (ddd, J=
6.8, 6.8, 6.8 Hz, 1H), 1.13 (dd, J=7.4, 7.4 Hz, 3H), 1.09 (s, 9H),
0.33 (s, 3H), 0.28 (s, 3H); 13C NMR (125 MHz, C6D6) δ 141.7,
138.9, 134.8, 130.8 (2C), 128.2 (2C), 128.1 (2C), 128.0 (2C),
127.3, 126.8, 118.7, 98.7, 96.3, 74.0, 73.2, 69.7, 69.0, 68.4, 68.3,
66.2, 63.1, 57.2, 54.7, 52.1, 47.5, 45.3, 43.7, 39.7, 39.3, 33.0, 32.3,
32.1, 31.3, 30.9, 30.2, 28.8, 27.2 (2C), 26.5, 26.2 (3C), 26.0, 25.0,
24.6, 22.8, 20.1, 19.5, 18.2, 14.1, -3.6, -4.0; high-resolution
mass spectrum (ESþ) m/z 1103.4515 [(M þ Naþ) calcd for
C55H88O7S6Si þ Na 1103.4521].
Alcohol (-)-34. Dithiane (-)-12 (13.30 g, 29.63 mmol) was
azeotroped three times with toluene and placed under high
vacuum overnight. Benzyl (R)-(-)-glycidyl ether 13 (2.43 g,
14.81 mmol) was azeotroped three times with toluene and placed
under high vacuum for 1 h. The dithiane was dissolved in dry
THF (420 mL), and HMPA (7.7 mL, 44.4 mmol) was added.
The solution was cooled to -78 °C in a dry ice/acetone bath, and
t-BuLi (1.50 M, 20.7 mL, 31.10 mmol) was added dropwise. The
solution turned orange and was then placed in a -45 °C dry
ice/acetonitrile bath. After 30 min, the solution was recooled to
-78 °C, and epoxide (-)-13 in dry THF (210 mL) was added via
cannula. The solution was allowed to warm to -5 °C over the
course of 3 h after which the reaction was quenched with
saturated NH4Cl (6 mL). The THF was removed under reduced
pressure, and the resulting dark red oil was dissolved in Et2O
(300 mL), and half-saturated brine solution (100 mL) was
added. The layers were separated, and the aqueous layer was
extracted twice with Et2O. The combined organics were washed
with brine, dried over MgSO4, and concentrated to afford a dark
orange oil. The desired alcohol, (-)-34, was isolated as an
amorphous solid via flash chromatography (95:5 hexanes/
Dithiane Adduct (-)-50. Dithianes 30 (6.00 g, 17.62 mmol)
and epoxide (þ)-45 (5.20 g, 14.68 mmol) were both azeotroped
three times with toluene and then placed under high vacuum for
14 h. The dithiane was dissolved in dry THF (100 mL), and
HMPA (7.6 mL, 44.0 mmol) was added. The solution was
cooled to -78 °C in a dry ice/acetone bath. The dithiane was
treated with t-BuLi (1.40 M, 12.7 mL, 17.7 mmol) and allowed
to stir at -78 °C for 30 min. Epoxide (þ)-45 was dissolved in
anhydrous THF (75 mL) and added to the dithiane solution via
cannula. The reaction was allowed to warm to room tempera-
ture over 3 h, during which time the color changed from yellow
to dark orange. The reaction was then quenched by addition of
saturated NH4Cl and diluted with Et2O. The layers were
separated, and the aqueous layer was extracted three times with
ether. The combined organic layers were washed with water to
remove the HMPA and with brine prior to drying with MgSO4
and concentration under reduced pressure. The product mixture
was isolated as a colorless oil in 94% yield (9.59 g, 13.80 mmol)
via flash chromatography (9:1 hexanes/EtOAc): (major) (-)-50
EtOAc) in 88% yield (8.05 g, 13.13 mmol): [R]23 -18.56 (c=
D
1.4, CHCl3); IR (film) 3471, 2927, 2855, 1257, 1104, 836,
1
775 cm-1; H NMR (CDCl3, 500 MHz) δ 7.37-7.27 (m, 5H),
5.93 (ddd, J=10.0, 10.0, 17.2 Hz, 1H), 5.30 (dd, J=2.3, 10.0 Hz,
1H), 5.15 (dd, J=2.2, 17.2 Hz, 1H), 4.57 (d, J=2.4 Hz, 2H), 4.46
(dd, J=4.6, 9.8 Hz, 1H), 4,43 (m, 1H), 3.47 (dd, J=4.6, 9.0 Hz,
1H), 3.43 (m, 2H), 3.32 (dd, J=9.5, 9.5 Hz, 1H), 3.22 (d, 9.8 Hz,
1H), 2.99 (ddd, J=3.0, 10.8, 17.4 Hz, 1H), 2.90 (ddd, J=3.1, 10.6,
17.5 Hz, 1H), 2.72-2.65 (m, 2H), 2.27 (dd, J=2.1, 15.8 Hz, 1H),
2.03 (dd, J=8.5, 15.8 Hz, 1H), 1.97 (m, 1H), 1.89 (m, 1H), 0.92 (s,
9H), 0.83 (s, 9H), 0.061 (s, 3H), 0.057 (s, 3H), 0.048 (s, 3H), 0.034
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.3, 133.0, 128.3 (2C),
127.8 (2C), 127.5, 119.6, 74.5, 73.3, 72.1, 67.6, 64.5, 55.9, 44.5,
40.3, 26.01, 25.94 (3C), 25.9 (3C), 25.5, 24.4, 18.2, 18.0, -3.4, -
3.8, -5.38, -5.44; high-resolution mass spectrum (ESþ) m/z
635.3078 [(M þ Naþ) calcd for C31H56O4S2Si2 þ Na 635.3056].
Linchpin Product (-)-42. Epoxide (-)-41 (174 mg, 0.329
mmol) and epoxide (þ)-9 (164 mg, 0.515 mmol) were both
azeotroped three times with benzene and placed under high
vacuum overnight. 2-TBS-1,3-dithiane 8 (91 mg, 0.39 mmol)
was azeotroped three times with benzene and left under high
vacuum for 1 h before being dissolved in dry Et2O (1.6 mL)
and cooled to -78 °C in a dry ice/acetone bath. A solution of
t-BuLi (1.40 M, 0.26 mL, 0.36 mmol) was added and the reac-
tion remained colorless. After 3 min, the flask was placed in a
-45 °C dry ice/acetonitrile bath and stirred for 1 h. The flask
was recooled to -78 °C, and epoxide (-)-41 in anhydrous
Et2O (2.6 mL) was added via cannula. The reaction was stirred
at -20 °C (dry ice/acetone) for 1 h and was then cooled back
down to -78 °C. The solution was pale yellow. Epoxide (þ)-9 in
dry Et2O (4 mL) and HMPA (0.18 mL, 0.98 mmol) was added
via cannula, and the reaction turned dark orange. The solution
was warmed to -20 °C and stirred 1 h before being warmed to
0 °C for 30 min and then room temperature for an additional
30 min. The reaction was quenched with saturated NH4Cl and
[R]23 -21.03 (c = 0.145, C6H6); IR (film) 3493, 2932, 1613,
D
1
1428, 1304, 1248, 1080, 826, 741 cm-1; H NMR (500 MHz,
C6D6) δ 7.81 (m, 4H), 7.45 (m, 2H), 7.24 (m, 6H), 6.80 (m, 2H),
5.80 (s, 1H), 4.50 (m, 1H), 3.94 (m, 1H), 3.90 (dd, J = 4.2,
10.1 Hz, 1H), 3.87 (dd, J=7.0, 10.3 Hz, 1H), 3.78 (dd, J=7.3, 7.3
Hz, 1H), 3.51 (dd, J=7.2, 7.2 Hz, 1H), 3.26 (s, 3H), 2.50 (m, 3H),
2.23 (m, 2H), 2.18 (m, 2H), 2.09 (m, 1H), 1.87 (m, 2H), 1.67 (m,
1H), 1.59 (m, 1H), 1.52-1.35 (m, 6H), 1.19 (s, 9H), 0.80 (dd, J=
7.5, 7.5 Hz, 3H); 13C NMR (125 MHz, C6D6) δ 160.8, 136.1
(2C), 136.0 (2C), 134.0, 133.8, 131.3, 130.1, 130.0, 128.5 (2C),
127.9 (4C), 113.9 (2C), 104.3, 77.2, 70.2, 69.3, 64.5, 54.7, 53.4,
49.4, 43.1, 39.8, 34.1, 27,2 (3C), 26.3, 26,1, 25.4, 21.4, 19.5, 19.2,
12.6; (minor) [R]23D þ6.25 (c=0.16, C6H6); IR (film) 3510, 2933,
1
1612, 1248, 1172, 1087, 825, 703 cm-1; H NMR (500 MHz,
C6D6) δ 7.82 (m, 4H), 7.51 (m, 2H), 7.24 (m, 6H), 6.79 (m, 2H),
6.00 (s, 1H), 4.52 (ddd, J=3.1, 3.1, 7.3 Hz, 1H), 4.04 (m, 1H),
3.96 (dd, J=6.2, 7.9 Hz, 1H), 3.88 (dd, J=4.4, 6.2 Hz, 1H), 3.88
(m, 1H), 3.38 (dd, J=7.7, 7.7 Hz, 1H), 3.28 (dd, J=3.1, 17.1 Hz,
1H), 3.27 (s, 3H), 2.51 (m, 3H), 2.39-2.28 (m, 2H), 2.25 -2.09
(m, 3H), 1.86 (m, 2H), 1.62 (m, 2H), 1.50 (m, 3H), 1.38 (ddd,
J=7.4, 7.4, 9.4 Hz, 1H), 1.34 (m, 2H), 1.19 (s, 9H), 0.80 (dd, J=
7.5, 7.5 Hz, 3H); 13C NMR (125 MHz, C6D6) δ 160.6, 136.1
J. Org. Chem. Vol. 74, No. 16, 2009 5999

Smith et al.
JOCArticle
(2C), 136.0 (2C), 133.9, 133.8, 131.9, 130.1, 130.0, 128.3 (2C),
127.5 (4C), 113.9 (2C), 103.5, 76.3, 70.8, 69.3, 64.5, 54.7, 53.4,
49.4, 43.0, 39.8, 33.9, 27.2 (3C), 26.3, 26.1, 25.4, 21.4, 19.4, 19.2,
12.6; high-resolution mass spectrum (ESþ) m/z 717.3096 [(M þ
Naþ) calcd for C39H54O5S2Si þ Na 717.3080].
ished diketone (þ)-62 as a colorless oil in 83% yield (562 mg,
0.454 mmol): [R]23 þ1.52 (c=0.17, CDCl3); IR (film) 2955,
D
2930, 2857, 1716, 1616, 1516, 1467, 1428, 1385, 1251, 1108, 833,
777, 740, 703 cm -1; 1H NMR (500 MHz, C6D6) δ 7.84 (m, 4H),
7.72 (m, 2H), 7.28 (m, 6H), 7.17 (m, 4H), 7.10 (m, 1H), 6.83 (m,
2H), 5.79 (ddd, J=10.2, 10.2, 17.3 Hz, 1H), 5.63 (s, 1H), 5.15
(dd, J=2.2, 10.2 Hz, 1H), 5.13 (m, 1H), 5.05 (dd, J=2.1, 17.4 Hz,
1H), 4.70 (ddd, J=3.7, 3.7, 7.7 Hz, 1H), 4.44 (d, J=12.2 Hz, 1H),
4.41 (d, J=12.2 Hz, 1H), 4.30 (m, 1H), 3.97 (m, 2H), 3.89 (dd,
J=5.0, 10.1 Hz, 1H), 3.85 (dd, J=5.3, 10.8 Hz, 1H), 2.87 (dd,
J=5.7, 10.1 Hz, 1H), 3.39 (dd, J=4.7, 10.1 Hz, 1H), 3.27 (s, 3H),
2.62 (m, 3H), 2.52 (dd, J = 6.1, 16.3 Hz, 1H), 2.37 (m, 3H),
2.16 (dd, J=7.2, 7.2 Hz, 2H), 1.70-1.58 (m, 4H), 1.57-1.40 (m,
4H), 1.33 (m, 1H), 1.22 (s, 9H), 1.01 (s, 9H), 0.98 (s, 9H), 0.95 (s,
9H), 0.87 (dd, J = 7.5, 7.5 Hz, 3H), 0.19 (s, 3H), 0.16 (s, 3H).
0.15 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.12 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 209.5, 207.1, 159.7, 138.2, 135.60 (2C),
135.58 (2C), 133.73, 133.65, 133.5, 131.2, 129.5 (2C), 128.3 (2C),
127.73 (2C), 127.72 (2C), 127.54 (4C), 127.49, 119.9, 113.4 (2C),
100.4, 76.2, 74.0, 73.4, 73.1, 69.0, 68.2, 64.9, 62.0, 55.6, 55.2,
51.0, 50.5, 48.4, 47.0, 44.5, 36.8, 32.8, 26.9 (3C), 26.1, 25.9 (3C),
25.8 (6C), 19.9, 19.2, 18.9, 18.1, 17.9, 12.3, -4.3, -4.67, -4.71,
-4.76, -4.83, -5.0; high-resolution mass spectrum (ESþ)
m/z 1259.7169 [(M þ Naþ) calcd for C71H112O10Si4 þ Na
1259.7230].
Bis-dithiane (-)-61. 2-tert-Butyldimethylsilyl-1,3-dithiane 8
(1.72 g, 7.34 mmol), epoxide (-)-57 (2.9 1 g, 7.34 mmol), and
epoxide (-)-44 (3.53 g, 5.24 mmol) were each azeotroped
three times with toluene and dried under high vacuum for
12 h. The dithiane was dissolved in dry Et2O (43 mL) and was
cooled to -78 °C in a dry ice/acetone bath. tert-Butyllithium
(1.49 M, 4.9 mL, 7.4 mmol) was added dropwise, and the
colorless solution turned pale yellow. The -78 °C bath was
removed and the reaction stirred at -45 °C (dry ice/acetonitrile)
for 55 min. The reaction was recooled to -78 °C, and epoxide
(-)-57 in anhydrous Et2O (43 mL) was added via cannula. The
now yellow reaction mixture was placed in an ice-water bath
for 3 h after which it was recooled to -78 °C. Epoxide (-)-44
was then added via cannula in THF (43 mL) with HMPA
(3.8 mL, 22.0 mmol); the reaction turned orange upon addition.
The flask warmed slowly to -45 °C over 1 h. The dry ice/acetone
bath was removed and the reaction stirred for 1 h at -45 °C in a
dry ice/acetonitrile bath after which the bath was allowed to
warm to room temperature over the course of 3 h. The reaction
was quenched with saturated NH4Cl (6 mL) and distilled H2O
(10 mL). The mixture was poured into a separatory funnel, and
Et2O (30 mL) was added. The layers were separated, and the
aqueous layer was extracted once with Et2O. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated to afford a yellow oil. The desired bis-dithiane (-)-
61 was isolated as a white foam in 65% yield (4.48 g, 3.43 mmol)
following flash column chromatography (9:1 hexanes/EtOAc):
[R]23D -11.71 (c=0.35, C6H6); IR (film) 3453, 3069, 2952, 2859,
1615, 1517, 1467, 1427, 1250, 1108, 1007, 933, 831, 776, 740,
Ketal (-)-55. Diketone (þ)-62 (1.34 g, 1.08 mmol) was
dissolved in dry THF (12 mL), and dry MeOH (48 mL) was
added. The solution was cooled to 10 °C before the addition of
PPTS (0.50 g, 2.16 mmol). The reaction stirred at 10 °C for 14 h
at which point TLC indicated that the reaction was about 50%
complete and that formation of byproduct (-)-56 had begun.
The reaction was quenched with saturated NaHCO3 and the
solvent was removed under reduced pressure. The resulting
slurry was partitioned between distilled water and EtOAc. The
aqueous layer was extracted twice with EtOAc and the com-
bined organic layers were washed with brine, dried over MgSO4,
and concentrated to afford a colorless oil. Flash chromatogra-
phy (95:5 to 9:1 hexanes/EtOAc) provided ketal (-)-55 in 44%
yield (533 mg, 0.470 mmol) along with 38% recovered diketone
(þ)-62 (507 mg, 0.409 mmol). Resubjection of the starting
material to the same reaction conditions gave an additional
221 mg of (-)-55 along with 209 mg of recovered (þ)-62 bring-
ing the total yield to 63%: [R]23D -4.19 (c=0.43, toluene); IR
(film) 3515, 2955, 2928, 2856, 1717, 1467, 1375, 1254, 1093, 836,
775, 739, 703 cm-1; 1H NMR (C6D6, 500 MHz) δ 7.85 (m, 4H),
7.30 (m, 7H), 7.21 (m, 3H), 7.10 (m, 1H), 5.28 (ddd, J=9.9, 9.9,
17.1 Hz, 1H), 5.10 (dd, J=2.1, 17.1 Hz, 1H), 5.05 (dd, J=2.1,
10.1 Hz, 1H), 4.72 (ddd, J=3.6, 3.6, 7.8 Hz, 1H), 4.39 (s, 2H),
4.19 (m, 1H), 4.00 (m, 2H), 3.91 (dd, J=5.0, 10.1 Hz, 1H), 3.87
(dd, J=5.2, 10.1 Hz, 1H), 3.67 (dd, J=2.4, 10.1 Hz, 1H), 3.56
(dd, J=5.8, 9.3 Hz, 1H), 3.43 (dd, J=6.3, 9.3 Hz, 1H), 3.31 (s,
1H), 3.07 (s, 3H), 2.67 (dd, J=8.3, 16.1 Hz, 1H), 2.38 (dd, J=3.7,
16.1 Hz, 1H), 2.34 (dd, J=4.8, 13.1 Hz, 1H), 2.23 (apt t, J=
7.0 Hz, 2H), 2.13 (ddd, J=2.6, 3.7, 14.6 Hz, 1H), 2.02 (m, 2H),
1.90 (dd, J=5.5, 14.9 Hz, 1H), 1.79 (dd, J=10.9, 13.1 Hz, 1H),
1.76-1.61 (m, 5H), 1.57-1.48 (m, 2H), 1.34 (m, 1H), 1.23 (s,
9H), 1.04 (s, 9H) 1.01 (s, 9H), 0.97 (s, 9H), 0.89 (dd, J=7.5,
7.5 Hz, 3H), 0.19 (s, 3H), 0.175 (s, 3H), 0.166 (s, 6H), 0.15 (s,
3H), 0.068 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 209.5, 138.2,
136.6, 135.6 (4C), 133.75, 133.67, 129.4 (2C), 128.3 (2C), 127.2
(2C), 127.54 (4C), 127.48, 119.3, 100.6, 74.1, 72.1, 70.4, 69.0,
68.4, 67.9, 62.1, 55.7, 48.4, 47.6, 47.0, 44.6, 43.1, 42.7, 37.1,
37.0, 26.93, 26.86 (3C), 26.1, 25.9 (3C), 25.8 (6C), 19.9, 19.2,
19.1, 18.0, 17.8, 12.3, -4.2 (4C), -4.7, -4.8; high-resolution
mass spectrum (ESþ) m/z 1155.6967 [(M þ Naþ) calcd for
C64H108O9Si4 þ Na 1155.6968].
1
703 cm-1; H NMR (500 MHz, CDCl3) δ 7.70 (m, 4H), 7.54
(m, 2H), 7.37 (m, 10H), 7.28 (m, 1H), 6.88 (m, 2H), 5.38 (ddd, J=
10.2, 10.2, 17.3 Hz, 1H), 5.51 (s, 1H), 5.29 (dd, J=2.1, 10.4 Hz,
1H), 5.25 (dd, J=2.1, 17.4 Hz, 1H), 4.79 (d, J=9.0 Hz, 1H), 4.61
(d, J=12.2 Hz, 1H), 4.56 (d, J=12.2 Hz, 1H), 4.38 (ddd, J=2.6,
5.5, 5.5 Hz, 1H), 4.04 (m, 1H), 3.94 (m, 1H), 3.88 (m, 1H), 3.80 (s,
3H), 3.68 (m, 2H), 3.63 (dd, J=6.2, 10.4 Hz, 1H), 3.56 (bs, 1H),
3.49 (dd, J=4.6, 10.3 Hz, 1H), 3.01 (dddd, J=2.8, 11.1, 14.1,
25.5 Hz, 2H), 2.74 (m, 7H), 2.51 (dd, J=9.6, 15.4 Hz, 1H), 2.24
(dd, J=9.2, 15.3 Hz, 1H), 2.02 (m, 1H), 1.87 (m, 7H), 1.77 (m,
1H), 1.70 (d, J=14.9 Hz, 1H), 1.64 (m, 2H), 1.46 (m, 1H), 1.37
(m, 2H), 1.30 (m, 3H), 1.07 (s, 9H), 0.89 (s, 9H), 0.86 (dd, J=7.5,
7.5 Hz, 3H), 0.83 (s, 9H), 0.12 (s, 3H), 0.097 (s, 3H), 0.057 (s,
3H), 0.033 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.7, 138.2,
135.69 (2C), 135.65 (2C), 134.0, 133.8, 133.4, 131.4, 129.4 (2C),
128.3 (2C), 127.7 (2C), 127.6, 127.5 (6C), 121.0, 113.3 (2C),
100.0, 76.2, 74.5, 73.5, 73.1, 69.4, 68.4, 66.2, 62.7, 56.6, 55.2,
53.1, 51.2, 49.2, 47.1, 45.7, 42.5, 39.2, 37.7, 32.9, 26.9 (3C), 26.8,
26.5, 26.3, 26.1 (4C), 26.0 (3C), 25.1, 24.3, 21.0, 19.4, 19.2, 18.2,
18.1, 12.6, -3.49, -3.51, -4.2, -4.9; high resolution mass
spectrum (ESþ) m/z 1325.6230 [(M þ Naþ) calcd for C71H110
O8S4Si3 þ Na 1325.6289].
-
Diketone (þ)-62. A round-bottom flask was charged with bis-
dithiane (773 mg, 0.545 mmol), DtBMP (840 mg, 4.08 mmol),
and a THF/H2O solution (4:1, 15 mL). The solution was
cooled to 0 °C prior to portionwise addition of Hg(ClO4)2
(762 mg, 1.91 mmol). The reaction stirred for 1 h at 0 °C, at
which point it was diluted with EtOAc and filtered through
Celite. Saturated NH4Cl was added to the slightly cloudy
filtrate. The layers were separated, and the aqueous layer was
extracted twice with EtOAc. The combined organic extracts
were washed with brine and dried over MgSO4. The solution was
filtered through Celite and concentrated to provide a yellow oil.
Column chromatography (95:5 to 9:1 hexanes/EtOAc) furn-
Carboxylic Acid (-)-4. Lactone (-)-75 (60 mg, 0.056 mmol)
was dissolved in a THF/H2O solution (4:1, 1.6 mL), and LiOH
6000 J. Org. Chem. Vol. 74, No. 16, 2009

Smith et al.
JOCArticle
(27 mg, 1.12 mmol) was added. After being stirred at room
temperature for 5 h, the reaction was partitioned between pH 8
buffer and CH2Cl2. The aqueous layer was extracted with
CH2Cl2 (6 ꢀ 2 mL). The organic layers were washed with brine
and dried over MgSO4. The organic layer was filtered through
cotton into a flask containing CH2Cl2 (5 mL), NMO (19 mg,
3H), 0.011 (s, 3H); 13C (125 MHz, C6D6) δ 207.5, 173.4, 172.8,
150.2, 149.5, 136.3, 133.7, 133.3, 132.1, 127.4, 100.9, 83.0, 75.3,
73.1, 72.3, 70.0, 69.1, 68.2, 66.7, 57.6, 54.4, 51.1, 48.1, 46.9, 44.5,
43.5, 43.2, 38.1, 37.7, 36.4, 26.3 (3C), 26.1 (3C), 25.9 (3C), 25.8
(3C), 24.8 (4C), 22.9, 19.5, 18.9, 18.29, 18.25 (2C), 17.9, 14.0,
12.4, -3.9 (2C), -4.0, -4.46, -4.52, -4.8, -4.9, -5.0; high-
resolution mass spectrum (ES-) m/z 1383.7010 [(M þ Naþ) calcd
for C65H122BIO13Si4 þ Na 1383.6998].
˚
0.17 mmol), and activated 4 A powdered molecular sieves
(60 mg). A catalytic amount of TPAP was added to the flask,
and the reaction mixture was concentrated under reduced
pressure to a volume of approximately 1 mL. After the mixture
was stirred at room temperature for 2 h, the solvent was removed
and the desired acid was isolated using flash chromatography
(high quality silica gel, 9:1 to 4:1 hexanes/EtOAc). Acid (-)-4
and was obtained in 56% yield over two steps (36 mg, 0.033
mmol): [R]23D -35.2 (c=0.05, C6H6); IR (film) 2953, 2929, 2856,
1736, 1715, 1651, 1540, 1460, 1363, 1255, 1095, 837, 776 cm-1; 1H
NMR (500 MHz, C6D6) δ 6.72 (dd, J=5.5, 14.3 Hz, 1H), 6.24
(dd, J=1.3, 14.3 Hz, 1H), 4.67 (ddd, J=4.9, 10.7, 10.7 Hz, 1H),
4.64 (m, 1H), 4.23 (m, 1H), 4.13 (m, 1H), 4.03 (m, 1H), 3.41 (s,
3H), 3.16 (s, 3H), 2.72 (dd, J=7.5, 16.7 Hz, 1H), 2.55 (dd, J=
10.3, 10.3 Hz, 1H), 2.55 (m, 1H), 2.46 (dd, J=3.8, 16.7 Hz, 1H),
2.42 (dd, J=4.8, 13.0 Hz, 1H), 2.16 (m, 2H), 1.93 (dd, J=5.7,
15.0Hz, 1H), 1.81-1.67 (m, 7H), 1.52(m, 1H), 1.39(m, 2H), 1.06
(s, 9H), 1.00 (s, 9H), 0.98 (s, 9H), 0.93 (s, 9H), 0.91 (dd, J=7.6,
7.6, Hz, 3H), 0.21 (s, 3H), 0.20 (s, 3H), 0.183 (s, 3H), 0.180 (s,
The ester (6.6 mg, 0.0048 mmol) was placed in a flask, and
the flask was evacuated and backfilled with argon three times.
Tetrakis(triphenylphosphine)palladium(0) (catalytic) was added,
and the flask was again evacuated and backfilled three times.
Oxygen-free toluene (400 μL) was added followed by a 2 M
oxygen-free aqueous solution of K2CO3 (50 μL) and oxygen-
free EtOH (50 μL). The reaction was heated to 40 °C for 2 h
at which point the reaction was cooled, diluted with Et2O (from
the solvent purification system), and washed with satura-
ted NaHCO3. The organic layer was washed with brine and
dried over MgSO4. The solvent was removed under reduced
pressure, and macrocycle (-)-80 was isolated in 50% yield
(2.7 mg, 0.0024 mmol) following column chromatography (high
quality silica gel, 98:2 to 95:5 hexanes/EtOAc).52 [R]28 -36.1
D
(c=0.08, C6H6); IR (film) 2929, 1733, 1646, 1463, 1383, 1255,
1095, 837, 776 cm-1; 1H NMR (500 MHz, C6D6) δ 6.39-6.14
(m, 6H), 5.77 (dd, J=3.3, 14.0 Hz, 1H), 5.67 (ddd, J=5.3, 9.2,
14.9 Hz, 1H), 5.10-5.06 (m, 1H), 4.73 (ddd, J = 4.7, 10.5,
10.5 Hz, 1H), 4.50 (ddd, J=1.8, 6.2, 9.6 Hz, 1H), 4.38 (br s,
1H), 4.30 (ddd, J=1.6, 10.3, 10.3 Hz, 1H), 4.09-4.06 (m, 1H),
3.50 (s, 3H), 3.24 (s, 3H), 2.97 (dd, J=9.8, 16.0, Hz, 1H), 2.73 (dt,
J=4.9, 11.5 Hz, 1H), 2.64 (ddd, J=3.1, 9.1, 15.7 Hz, 1H), 2.56-
2.50 (m, 2H), 2.41 (dt, J=6.2, 18.9 Hz, 1H), 2.32 (dd, J=1.7,
16.0 Hz, 1H), 2.28-2.22 (m, 1H), 2.18-2.12 (m, 1H), 2.01 (dd,
J=1.2, 15.4 Hz, 1H), 1.86-1.14 (series of m, 14H), 1.10 (s, 9H),
1.07 (s, 9H), 1.02 (s, 9H), 1.01 (s, 9H), 0.87 (t, J=7.4 Hz, 3H),
0.82 (t, J=7.0 Hz, 3H), 0.30 (s, 3H), 0.28 (s, 3H), 0.27 (s, 3H),
0.21 (s, 3H), 0.18 (s, 3H), 0.082 (s, 3H), 0.078 (s, 3H), 0.073 (s,
3H); 13C NMR (125 MHz, C6D6) δ 207.8, 173.2, 171.8, 140.3,
134.5, 134.0, 132.8, 132.3, 130.7, 128.9, 125.6, 101.0, 73.2, 70.1,
69.5, 68.7, 68.5, 66.0, 57.9, 56.6, 51.2, 48.5, 46.6, 45.7, 44.0, 43.7,
41.0, 39.2, 36.8, 35.2, 30.2, 26.5 (3C), 26.3 (3C), 26.1 (3C), 26.0
(3C), 22.9, 19.4, 18.6, 18.5, 18.4, 18.1, 14.0, 12.4, -3.3, -3.8,
-4.0, -4.1, -4.5, -4.8, -4.9, -5.0; high-resolution mass
3H), 0.14 (s, 3H), 0.12 (s, 3H), 0.046 (s, 3H), 0.0084 (s, 3H); 13
C
NMR (125 MHz, C6D6) δ 207.3, 176.8, 172.9, 149.5, 101.0, 75.4,
72.3, 69.7, 69.3, 68.3, 66.8, 57.6, 54.1, 51.2, 48.2, 47.1, 44.2, 43.6,
43.2, 42.0, 37.4, 26.3 (3C), 26.1 (3C), 26.0 (3C), 25.9 (3C), 21.8,
19.7, 18.33, 18.32, 18.2, 18.0, 12.4, -3.8, -3.9, -4.0, -4.4, -4.7
(2C), -4.8, -4.9; high-resolution mass spectrum (ES-) m/z
1109.4865 [(M þ Naþ) calcd for C48H95IO11Si4 þ Na 1109.4894].
Lactone (-)-80. Acid (-)-4 (15 mg, 0.014 mmol), alcohol (-)-
3 (16 mg, 0.055 mmol), and DMAP (7 mg, 0.06 mmol) were each
azeotroped three times with toluene and placed under high
vacuum for 2 h. The acid was then dissolved in dry toluene
(200 μL), and Et3N (8 μL) was added followed by the addition of
a solution of 2,4,6-tricholorbenzoyl chloride in toluene (1.37 M,
20 μL, 2 equiv). After 2 h, DMAP in toluene (100 μL) and
alcohol (-)-3 in toluene (200 μL) were added sequentially. The
reaction was heated to 42 °C overnight. The reaction was then
quenched with a saturated solution of NaHCO3 and diluted
with stabilizer-free ether (solvent purification system). The
aqueous layer was extracted three times with ether, and the
combined organic extracts were washed with brine, dried over
MgSO4, and concentrated. The desired ester was isolated in 58%
yield (11 mg, 0.0081 mmol) following column chromatography
(high quality silica gel, 98:2 hexanes/EtOAc): [R]23D -17.7 (c=
0.12, C6H6); IR (film) 3449, 2955, 2929, 2856, 1735, 1615, 1584,
1471, 1362, 1324, 1156, 1144, 1104, 1035, 1008, 970, 938, 837,
spectrum (ES-) m/z 1129.7023 [(MþNaþ) calcd for C59H110
O11Si4þNa 1129.7003.
-
Acknowledgment. Financial support was provided by the
National Institutes of Health (Institutes of General Medicinal
Sciences) through Grant No. GM-29028. We also thank Drs.
George Furst, R. Kohli, and Patrick Carroll for their assis-
tance in obtaining the NMR spectra, the high-resolution mass
spectra, and the X-ray crystal analyses, respectively.
776 cm-1 1H NMR (500 MHz, C6D6) δ 7.44 (dd, J = 9.7,
;
17.5 Hz, 1 H), 6.72 (dd, J=5.4, 14.3 Hz, 1H), 6.24 (dd, J=1.4,
14.3 Hz, 1H), 6.20 (dd, J=8.7, 9.6 Hz, 1H), 5.99 (m, 1H), 5.92 (d,
J=17.6 Hz, 1H), 5.54 (ddd, J=7.4, 7.4, 14.9 Hz, 1H), 5.04 (m,
1H), 4.68 (ddd, J=4.7, 10.6, 10.6 Hz, 1H), 4.61 (m, 1H), 4.23 (m,
1H), 4.19 (m, 1H), 4.01 (m, 1H), 3.42 (s, 3H), 3.13 (s, 3H), 2.89
(dd, J = 8.2, 16.6 Hz, 1H), 2.61 (m, 2H), 2.54 (dd, J = 10.3,
10.3 Hz, 1H), 2.41 (dd, J=4.8, 13.1 Hz, 1H), 2.23 (m, 4 H), 2.16
(dd, J=4.8, 15.1 Hz, 1H), 1.92 (dd, J=6.1, 15.1 Hz, 1H), 1.80 (m,
2H), 1.74-1.53 (m, 7H), 1.37 (m, 5H), 1.10 (s, 12H), 1.06 (s, 9H),
1.02 (s, 9H), 1.00 (s, 9H), 0.99 (s, 9H), 0.89 (m, 6H), 0.22 (s, 3H),
0.21 (s, 3H), 0.19 (s, 6H), 0.17 (s, 3H), 0.087 (2, 3H), 0.049 (s,
Supporting Information Available: Experimental proce-
dures and analytical and spectroscopic data for all new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
(51) For 1H and IR data, see: Ainsworth, P. J.; Craig, D.; Reader, J. C.;
Slawin, A. M. Z.; White, A. J. P.; Williams, D. J. Tetrahedron 1995, 51, 11601.
For 1H and 13C NMR, see: Constantine, M. G.; de Oliveira, K. T.; Polo, E.
C.; da Silva, G. V. J.; Brockson, T. J. J. Org. Chem. 2006, 71, 9880.
(52) See the Supporting Information for 1H and 13C NMR assignments.
J. Org. Chem. Vol. 74, No. 16, 2009 6001