Total syntheses of (+)-acutiphycin and (+)-trans-20,21-didehydroacutiphycin

Article abstract of DOI:10.1021/ja972497r

The first total syntheses of the cytotoxic macrolides (+)-acutiphycin (1) and (+)-trans-20,21-didehydroacutiphycin (2) have been achieved. An acyclic stereocontrol strategy was employed to establish the configurations at C(5), C(10), and C(13) as well as the E geometry of the C(8,9)-trisubstituted olefin. Importantly, the natural source of 1 and 2, the blue-green alga Osillatoria acutissima, no longer produces these metabolites.

Full text of DOI:10.1021/ja972497r

J. Am. Chem. Soc. 1997, 119, 10935-10946
10935
Total Syntheses of (+)-Acutiphycin and
(+)-trans-20,21-Didehydroacutiphycin
Amos B. Smith, III,* Sean S.-Y. Chen, Frances C. Nelson, Janice M. Reichert, and
Brian A. Salvatore
Contribution from the Department of Chemistry, Laboratory for Research on the Structure of
Matter, and Monell Chemical Senses Center, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
ReceiVed July 23, 1997X
Abstract: The first total syntheses of the cytotoxic macrolides (+)-acutiphycin (1) and (+)-trans-20,21-didehy-
droacutiphycin (2) have been achieved. An acyclic stereocontrol strategy was employed to establish the configurations
at C(5), C(10), and C(13) as well as the E geometry of the C(8,9)-trisubstituted olefin. Importantly, the natural
source of 1 and 2, the blue-green alga Osillatoria acutissima, no longer produces these metabolites.
In 1984, Moore and co-workers reported the isolation and
characterization of the architecturally novel macrolides (+)-
acutiphycin (1) and (+)-trans-20,21-didehydroacutiphycin (2).1
The structures and absolute stereochemistries of 1 and 2 were
determined via spectroscopic studies and chemical degradation.
Both compounds exhibited significant in vivo antineoplastic
activity against murine Lewis lung carcinoma and in vitro
cytotoxicity against the KB and NIH/3T3 cell lines.1 Interest-
ingly, the original source, the blue-green alga Osillatoria
acutissima, no longer produces these metabolites;2 further
biological evaluation and confirmation of the assigned structures
therefore mandated synthesis. Our longstanding interest in the
construction of biologically active hemi- and spiroketals led us
to undertake the first total syntheses of 1 and 2.3 Challenging
features of the targets included the anticipated lability of the
â-carboalkoxy hemiketal moiety and the C(10) stereocenter as
well as the considerable steric congestion of the 16-membered
ring.
Scheme 1
Retrosynthetic Analysis. Initial cleavage of targets 1 and
2 at the lactone linkage followed by disconnection between
C(13) and C(14) led to common advanced aldehyde 4 and vinyl
anion precursors 5 and 6 (Scheme 1). Stereocontrolled union
of these fragments was expected to yield seco acids 3,
embodying the complete carbon skeleton of (+)-acutiphycin (1)
and (+)-trans-20,21-didehydroacutiphycin (2) with all requisite
stereochemistry. Alternatively, the C(13) stereocenter could be
introduced by 1,3-anti reduction of the derived ketones, directed
by the C(11) hydroxyl. Common aldehyde 4 in turn was
envisioned to derive from the C(3-11) fragment 7 via oxidation,
Cram addition4 of the enolate derived from ethyl isobutanethi-
olate, and chemoselective thioester reduction.5 The trans-
trisubstituted olefin 7 in turn would arise from tertiary allylic
alcohol 8 in stereocontrolled fashion via a Still [2,3]-sigmatropic
rearrangement.6 To secure the correct configuration of the
tertiary alcohol and the cis olefin geometry in 8, we envisioned
a four-step sequence involving addition of propynyllithium to
aldehyde 9, oxidation of the resultant alcohol, chelation-
controlled incorporation of the methyl group,7 and semireduction
of the acetylene. For the elaboration of aldehyde 9 from L-malic
X Abstract published in AdVance ACS Abstracts, November 1, 1997.
(1) Barchi, J. J., Jr.; Moore, R. E.; Patterson, G. M. L. J. Am. Chem.
Soc. 1984, 106, 8193.
(2) Moore, R. E., University of Hawaii, Ma`noa, private communication.
(3) Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.;
Salvatore, B. A. J. Am. Chem. Soc. 1995, 117, 12013.
(4) Cram, D. J.; Abd Elhafez, F. A. J. Am. Chem. Soc. 1952, 74, 5828.
See also: Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions;
Prentice-Hall: Englewood Cliffs, NJ, 1971.
(6) (a) Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927. (b)
Nakai, T.; Mikami, K. Chem. ReV. 1986, 86, 885.
(7) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(5) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050.
S0002-7863(97)02497-9 CCC: $14.00 © 1997 American Chemical Society

10936 J. Am. Chem. Soc., Vol. 119, No. 45, 1997
Smith et al.
acid (10), a Brown enantioselective allylboration8 would be
utilized to set the C(5) stereocenter.
to aldehyde 9 and subsequent Moffatt oxidation15 afforded
ketone (+)-1512 (80% yield, two steps; Scheme 3). Chelation-
Construction of the C(3-11) Segment 7. The acutiphycin
synthetic venture began with borane reduction9 of L-malic acid
(10) to furnish the corresponding triol; ketal formation10 afforded
predominantly the more stable11 dioxolane (-)-1112a (>10:1,
83% yield from 10; Scheme 2). Oxidation to (+)-1212a with
Scheme 3
Scheme 2
controlled addition of methylmagnesium bromide7 (80% yield)
and semihydrogenation with Lindlar catalyst (95%) then pro-
duced tertiary allylic alcohol (+)-8;12 the relative stereochemistry
was confirmed by X-ray analysis of a derivative.16 The stannyl
ether substrate for the [2,3]-sigmatropic rearrangement was
prepared by deprotonation of 8 with KH and 18-crown-6 in
THF, followed by alkylation with Me3SnCH2I at room temper-
ature.17 The reaction mixture was immediately cooled to -78
°C and treated with n-BuLi, affording the rearranged alcohol
(+)-712 (58% yield) and a significant byproduct, diene (+)-
1612 (41%); only the E isomer of 7 was observed. Kallmerten
has attributed similar E stereoselectivity to chelation of the
lithium cation by an R-alkoxy substituent.18 The formation of
diene 16 may involve E2 elimination of the hindered stannyl
ether or fragmentation of the lithiated intermediate.
buffered pyridinium chlorochromate (PCC)13 (69%) and Brown
asymmetric allylation8 with allyl(diisopinocampheyl)borane
selectively produced homoallylic alcohol (-)-1312 after oxidative
workup [H2O2/NaOH; 75% yield, 92% diastereomeric excess
(de)]; the borane was prepared in situ by addition of allylmag-
nesium bromide to commercially available (+)-B-methoxy-
(diisopinocampheyl)borane.8 Protection with tert-butyldiphe-
nylsilyl chloride (BPSCl) and reductive ozonolysis provided
aldehyde (+)-1412 (ca. 100% yield, two steps). Exposure to
citric acid in MeOH at reflux then induced ketal methanolysis
and cyclization, furnishing the requisite methyl R-pyranoside
and its â-epimer in 62 and 21% yields after chromatography;
the axial disposition of the methoxy group is favored by the
anomeric effect.14 Resubmission of the â-isomer to the citric
acid/methanol protocol afforded the same epimeric mixture.
Moffatt oxidation15 of the R-isomer then produced aldehyde (+)-
912a (89%).
Construction of Common Advanced Aldehyde 4. Acidic
hydrolysis of 7, selective protection of the primary alcohol with
triethylsilyl chloride (TESCl), and oxidation of the resultant
lactol furnished lactone (+)-17 in 64% yield for the three steps
(Scheme 4).12,19 Following addition of the lithium enolate of
ethyl acetate to the lactone carbonyl,20 treatment with acidic
methanol removed the TES ether and installed a mixed methyl
ketal to give (+)-1812a (94%). Dess-Martin oxidation21 and
coupling with the lithium enolate of ethyl isobutanethioate then
provided the epimeric alcohols (+)-1912 and (+)-2012 in 62 and
17% yields (3.6:1 ratio); the requisite C(11) erythro stereo-
To set the stage for the Still [2,3]-sigmatropic rearrangement,6
we next undertook stereocontrolled installation of the allylic
alcohol moiety in 8. To this end, addition of 1-lithio-1-propyne
(8) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(9) Lane, C. F.; Myatt, H. L.; Daniels, J.; Hopps, H. B. J. Org. Chem.
1974, 39, 3052.
(16) Treatment of (+)-8 with TBAF provided the crystalline diol (+)-
i12a (mp 80-82 °C).
(10) Huggins, M. J.; Kubler, D. G. J. Org. Chem. 1975, 40, 2813.
(11) (a) Masamune, S.; Ma, P.; Okumoto, H.; Ellingboe, J. W.; Ito, Y.
J. Org. Chem. 1984, 49, 2834. (b) Meyers, A. I.; Lawson, J. P. Tetrahedron
Lett. 1982, 23, 4883.
(12) (a) The structure assigned to each new compound was in accord
with its infrared, 500 MHz H NMR and 125 MHz 13C NMR spectra, as
1
well as appropriate parent ion identification by high-resolution mass
spectrometry. (b) In addition, an analytical sample of this compound,
obtained by recrystallization or liquid chromatography, gave satisfactory
combustion analysis (within 0.4%).
(17) Seyferth, D.; Andrews, S. B. J. Organomet. Chem. 1971, 30, 151.
(18) (a) Kallmerten, J.; Balestra, M. Tetrahedron Lett. 1988, 29, 6901.
(b) Wittman, M. D.; Kallmerten, J. J. Org. Chem. 1988, 53, 4631.
(19) McKillop, A.; Young, D. W. Synthesis 1979, 401.
(13) Cheng, Y.-S.; Liu, W.-L.; Chen, S.-H. Synthesis 1980, 223.
(14) Delongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Baldwin, J. E., Ed.; Pergamon: New York, 1983; pp 4-21.
(15) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87, 5670.
(20) Duggan, A. J.; Adams, M. A.; Brynes, P. J.; Meinwald, J.
Tetrahedron Lett. 1978, 45, 4323.
(21) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.

Syntheses of Acutiphycin and Dehydroacutiphycin
J. Am. Chem. Soc., Vol. 119, No. 45, 1997 10937
Scheme 4
Secondary alcohol 19 was next masked as TES ether (+)-
2312a in 91% yield (Scheme 6), allowing for selective desily-
Scheme 6
lation in the presence of the BPS ether. Finally, chemoselective
reduction of thiol ester 23 via the Fukuyama method5 furnished
the desired common aldehyde (+)-412a (88%).
Synthesis of Vinyl Bromides 5 and 6. Construction of vinyl
bromide 5 began with Sharpless asymmetric dihydroxylation23
of 1-heptene (24) (Scheme 7), which furnished (2R)-1,2-
chemistry in 19 was predicted by the Cram model4 and verified
via the modified Mosher method.22 The latter exercise entailed
treatment of minor alcohol (+)-20 with both (R)-(-)- and (S)-
(+)-R-methoxy-R-(trifluoromethyl)phenylacetyl (MTPA) chlo-
ride; removal of the BPS group with tetrabutylammonium
fluoride (TBAF) gave Mosher ester derivatives (+)-2112a and
(+)-2212a (Scheme 5). Kakisawa analysis22b-d of the 1H
Scheme 7
Scheme 5
heptanediol [(+)-25]12a in excellent yield with adequate enan-
tioselectivity [94% yield, 84% enantiomeric excess (ee)]. The
1
enantiomeric purity of the diol was determined via H NMR
analysis of the bis Mosher ester prepared from (R)-(-)-MTPA
chloride.24 DIBAL reduction25 of the derived p-methoxyben-
zylidene (PMB) acetal then gave primary alcohol (-)-2612a
(89%, two steps). Bromination with CBr4/Ph3P26 (92% yield)
followed by coupling with 1-lithio-1-propyne provided alkyne
chemical shifts (Figure 1) revealed the S absolute configuration
at C(11) of 20.
(22) (a) Dale, J. A; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Ohtani, I.; Kusumi, T.; Ishitsuka, M. O.; Kakisawa, H. Tetrahedron Lett.
1989, 30, 3147. (c) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Org. Chem. 1991, 56, 1296. (d) Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(23) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(24) Høyer, T.; Kjær, A.; Lykkesfeldt, J. Collect. Czech. Chem. Commun.
1991, 56, 1042.
(25) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983,
1593.
(26) Kocienski, P. J.; Cernigliaro, G.; Feldstein, G. J. Org. Chem. 1977,
42, 353.
Figure 1. Absolute stereochemistry determination: ∆δ values for the
Mosher ester derivatives 21 and 22 (∆δ ) δ21 - δ22 ppm, 500 MHz).

10938 J. Am. Chem. Soc., Vol. 119, No. 45, 1997
Smith et al.
(+)-2712a (82%). Hydrozirconation27 of 27 proceeded with high
regio- and stereoselectivities, affording a 16.4:1 mixture of
regioisomeric bromides after treatment of the vinylzirconium
intermediates with N-bromosuccinimide. Oxidative removal of
the PMB group produced the pure secondary alcohol (-)-2812a
in 61% yield after flash chromatography and HPLC. Protection
of alcohol 28 as the TES ether (98% yield) completed the
synthesis of vinyl bromide (+)-5.12a
Scheme 9
Vinyl bromide 6, required for the unsaturated acutiphycin
congener 2, was prepared from aldehyde (+)-12, employed
earlier en route to common aldehyde 4. Following Corey-
Fuchs dibromomethylenation,28 treatment with n-BuLi and
quenching with iodomethane furnished acetylene (+)-2912a in
75% overall yield (Scheme 8). Selective hydrozirconation/
Scheme 8
bromination27 of 29 and ketal hydrolysis with HOAc/H2O (4:
1) then gave the desired diol (-)-30.12a The Kishi one-step
epoxidation protocol29 generated a volatile oxirane which was
immediately added to the lower-order cuprate prepared from
crotylmagnesium chloride; the resultant 2.2:1 E/Z mixture of
alkenes could be separated by chromatography on silica gel
impregnated with silver nitrate,30 affording pure (-)-3112a
(42%). Silylation with triethylsilyl trifluoromethanesulfonate
(TESOTf) then provided the vinyl bromide subunit (+)-612a in
96% yield.
Assembly of Seco Acids 3a and 3b. With common aldehyde
4 and vinyl bromides 5 and 6 in hand, we turned to the coupling
of the building blocks. Addition of the vinyl Grignard reagent
derived from (+)-5 or (+)-6 (10 equiv) to aldehyde (+)-4 (THF,
-78 °C) gave a 1:1 mixture of epimeric alcohols; excess in the
Grignard reagent was required to drive the reaction to comple-
tion. Dess-Martin oxidation then furnished enones (+)-32a12a
and (+)-32b12a in 77 and 83% yields, respectively, for the two
steps (Scheme 9).21 Selective cleavage of the TES groups with
camphorsulfonic acid (CSA) in methanol unmasked â-hydroxy
ketones (+)-33a12a (97% yield) and (+)-33b12a (84%). Evans
anti reduction31a,b with the Gribble reagent Me4NBH(OAc)3,31c
afforded triols (+)-34a12a (90% yield, 96:4) and 34b12a (94%
yield, >96:4). The C(13) configuration was established in each
case via 13C NMR analysis of the derived 1,3-acetonide.32 Ester
saponification in turn produced seco acids (+)-3a12a and (+)-
3b,12a the macrolactonization substrates, in high yield.
Macrolactonization: A Significant Synthetic Challenge.
Of the many known methods for macrolactone generation,33
three appeared best suited to the sensitive acutiphycin struc-
ture: the Mukaiyama N-methyl-2-chloropyridinium iodide
procedure;33a the Keck cyclization with 1,3-dicyclohexylcarbo-
diimide (DCC), 4-(dimethylamino)pyridine (DMAP), and
DMAP‚HCl,33b and the Yamaguchi mixed anhydride protocol.33c
The Mukaiyama method33a was investigated first. A dilute
solution of seco acid (+)-3 and triethylamine (1.5 equiv) in
methylene chloride was added over 5 h to a dilute solution of
N-methyl-2-chloropyridinium iodide in methylene chloride at
reflux, and the resultant mixture was stirred overnight at room
temperature. No desired macrolactone was isolated. The Keck
method,33b involving slow addition of (+)-3 in THF to a solution
(27) (a) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc.
1975, 97, 679. (b) Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1979, 101,
3521.
(28) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(29) Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9693.
(30) Henrick, C. A. Tetrahedron 1977, 33, 1845.
(31) (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939.
(b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
110, 3560. (c) Nutaitis, C. F.; Gribble, G. W. Tetrahedron Lett. 1983, 24,
4287.
(32) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
(33) (a) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49. (b)
Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394. (c) Inanaga, J.;
Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989.

Syntheses of Acutiphycin and Dehydroacutiphycin
J. Am. Chem. Soc., Vol. 119, No. 45, 1997 10939
Scheme 11
of 1,3-dicyclohexylcarbodiimide, 4-(dimethylamino)pyridine,
and DMAP‚HCl in ethanol-free chloroform at reflux, resulted
only in decomposition of the starting material.
Success was finally realized by exploiting the Yamaguchi
protocol33c (Scheme 10). Treatment of seco acid (+)-3a with
Scheme 10
2,4,6-trichlorobenzoyl chloride and triethylamine (THF, room
temperature) gave the requisite mixed anhydride. After the
triethylamine hydrochloride was removed, the anhydride was
slowly added under high-dilution conditions to a solution of
DMAP in toluene at reflux, providing a (ca. 4.2:1) mixture of
the macrolide triene (-)-3512a and the desired macrolactone (+)-
3612a in 70% yield. Detailed spectroscopic analysis, including
1H decoupling and a 2D COSY experiment, established that
the major product arose via â-elimination of methanol. When
the macrolide mixture was heated in methanolic citric acid for
3 days, reinstallation of the C(3) methoxy group afforded pure
(+)-36a in 75% yield. In similar fashion seco acid (+)-3b was
transformed to (+)-36b (44% yield, two steps).
The Acutiphycin Endgame. Completion of the syntheses
of 1 and 2 required selective protection of the C(13) hydroxyl,
oxidation of the C(11) alcohol, and deprotection (Scheme 11).
Silylation of the less-hindered C(13) secondary hydroxyl in
macrolactones 36a and 36b (TESOTf, -78 °C) generated ethers
(+)-37a12a and (+)-37b12a in 65 and 71% yields. Oxidation
with the Dess-Martin periodinane and pyridine21b then produced
the corresponding ketones (+)-38a12a (96% yield) and (+)-
38b12a (90%) without observable epimerization at C(10) or
migration of the C(8,9) double bond. Exposure to 49% HF/
CH3CN (1:9) for 3-5 min effected removal of the TES group
and hydrolysis of the methyl pyranoside, affording hydroxy
ketones (+)-39a12a and (+)-39b12a (88 and 89%, respectively);
longer reaction times resulted in decomposition. Attempted
removal of the BPS group in 39a and 39b with tetrabutylam-
monium fluoride (TBAF) likewise led to the demise of these
base-sensitive intermediates. However, we were delighted to
find that TBAF buffered with HOAc34 (1:1) smoothly removed
the BPS moiety. Synthetic (+)-acutiphycin (1)12a (95% yield)
and (+)-trans-20,21-didehydroacutiphycin (2)12a (92%) were
identical with the natural materials in all respects (500 MHz
1H and 125 MHz 13C NMR, IR, HRMS, mp, mmp, optical
rotation, and TLC in four solvent systems).35
Summary. The first total syntheses of (+)-acutiphycin (1)
and (+)-trans-20,21-didehydroacutiphycin (2) have verified the
(34) Hayward, C. M.; Yohannes, D.; Danishefsky, S. J. J. Am. Chem.
Soc. 1993, 115, 9345.
(35) We thank Professor Richard E. Moore, University of Hawaii, Ma`noa,
for samples of natural (+)-acutiphycin and (+)-trans-20,21-didehydroacut-
iphycin.

10940 J. Am. Chem. Soc., Vol. 119, No. 45, 1997
Smith et al.
at -78 °C. The reaction mixture was stirred at -78 °C for 1 h, warmed
to room temperature, stirred 1 h further, and treated with aqueous
sodium hydroxide (2 M, 40 mL) and hydrogen peroxide (50%, 50 mL).
The mixture was stirred overnight at room temperature, diluted with
ether (500 mL), washed with water (300 mL) and brine (300 mL), dried
over MgSO4, filtered, and concentrated. Flash chromatography (hex-
anes/ethyl acetate, 24:1) provided (-)-13 (6.2 g, 75% yield, 96:4 by
1H NMR analysis) as a colorless oil: [R]D20 -6.8° (c 1.48, CHCl3); IR
(CHCl3) 3500 (m, br), 3100 (m), 3025 (s), 3000 (s), 2960 (s), 1090
(s), 930 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.84-5.75 (m, 1 H),
5.10 (m, 2 H), 4.28 (m, 1 H), 4.06 (dd, J ) 7.8, 6.0 Hz, 1 H), 3.90 (m,
1 H), 3.50 (t, J ) 8.0 Hz, 1 H), 2.41 (br s, 1 H), 2.30-2.18 (m, 2 H),
1.75 (m, 1 H), 1.67-1.54 (m, 5 H), 0.87 (t, J ) 7.5 Hz, 3 H), 0.86 (t,
J ) 7.5 Hz, 3 H); 13C NMR (62.9 MHz, CDCl3) δ 134.5, 118.1, 112.6,
73.8, 70.1, 68.0, 42.2, 39.2, 29.9, 29.6, 8.2, 7.9; high-resolution mass
spectrum (Cl, NH3) m/z 215.1627 [(M + H)+; calcd for C12H23O3
215.1647].
structures and absolute stereochemistries elucidated by Moore
et al. We anticipate that the successful strategy will provide
material required for further biological evaluation of 1 and 2,
which no longer are available from the original marine source,
and also will prove amenable to the construction of a series of
novel analogs.
Experimental Section36
Hydroxy Ketal (-)-11. A mechanically stirred solution of
borane‚dimethyl sulfide complex (10 M; 130 mL, 1.3 mol) and trimethyl
borate (136 mL, 1.77 mol) in THF (500 mL) was cooled to 0 °C, and
a solution of L-malic acid [(-)-10, 54 g, 0.40 mol] in THF (200 mL)
was added slowly. The resultant suspension was warmed to room
temperature, stirred for two days, cooled to 0 °C, and treated slowly
(2 h) with anhydrous methanol (300 mL). The solution was then
warmed to room temperature, stirred overnight, and concentrated. Flash
chromatography (dichloromethane/methanol, 90:10) afforded the cor-
responding triol (36.5 g, 87% yield) as a colorless oil. A solution of
the triol (30 g, 0.29 mol), 3,3-dimethoxypentane (76.6 mL, 0.58 mol),
and p-toluenesulfonic acid (7.0 g, 0.037 mol) in DMF (100 mL) was
stirred at room temperature overnight. The reaction mixture was then
diluted with ethyl acetate (500 mL) and washed with 10% NaOH (300
mL) and water (300 mL). The combined aqueous layers were extracted
with ethyl acetate (500 mL), and the combined organic solutions were
then washed with brine (400 mL), dried over MgSO4, filtered, and
concentrated. Distillation through a 25 cm Vigreux column furnished
(-)-11 (48.1 g, 95% yield) as a colorless liquid: bp 60-65 °C, 0.1
mmHg.
Aldehyde (+)-12. A mechanically-stirred mixture of pyridinium
chlorochromate (58 g, 0.27 mol), sodium acetate (4.4 g, 0.054 mol),
alumina (70 g), and dichloromethane (400 mL) was cooled to 0 °C,
and a solution of alcohol (-)-11 (11.6 g, 0.066 mol) in dichloromethane
(40 mL) was added over 30 min. The black suspension was then
warmed to room temperature, stirred 2 h further, diluted with ether (1
L), and filtered through a pad of silica gel, and the pad was washed
with CH2Cl2 (400 mL). Concentration furnished a clear, green liquid
which was distilled through a 15 cm Vigreux column to give (+)-12
(7.8 g, 69% yield) as a colorless oil: bp 55-60 °C, 0.2 mmHg.
Homoallylic Alcohol (-)-13. At -78 °C a solution of (+)-B-
methoxy(diisopinocampheyl)borane (16.0 g, 50.6 mmol) in toluene (130
mL) was treated with allylmagnesium bromide (1.0 M in ether; 50.5
mL, 50.5 mmol). After an additional 15 min, the resultant suspension
was warmed to room temperature and stirred for 3 h. The clear upper
layer was then transferred via cannula over 30 min to a flask containing
a solution of aldehyde (+)-12 (6.7 g, 38.8 mmol) in toluene (35 mL)
Anal. Calcd for C12H22O3: C, 67.26; H, 10.35. Found: C, 67.34;
H, 10.25.
Silyloxy Aldehyde (+)-14. A solution of alcohol (-)-13 (9.2 g,
43 mmol), imidazole (7.3 g, 100 mmol), tert-butyldiphenylsilyl chloride
(16 mL, 61 mmol), and 4-(dimethylamino)pyridine (150 mg) in DMF
(50 mL) was stirred overnight at room temperature. The mixture was
then diluted with water (250 mL) and extracted with ether (300 mL),
and the organic phase was washed with brine (250 mL) , dried over
MgSO4, filtered, and concentrated. Flash chromatography (hexane/
ethyl acetate, 95:5) gave the silyl ether (19.5 g, 100% yield) as a
colorless liquid.
Ozone was bubbled through a solution of the silyl ether (19.5 g, 43
mmol) in dichloromethane (300 mL) at -78 °C. When a pale blue
color persisted, dimethyl sulfide (80 mL) was added, and the mixture
was warmed to room temperature and stirred overnight. Concentration
and flash chromatography (hexanes/ethyl acetate, 80:20) provided (+)-
14 (19.5 g, 100% yield) as a colorless liquid.
Acetal Aldehyde (+)-9. A solution of aldehyde (+)-14 (24.0 g,
53 mmol) and citric acid (20.3 g, 0.106 mol) in methanol (200 mL)
was heated at reflux overnight, cooled to room temperature, and
concentrated. The resultant liquid was dissolved in dichloromethane
(400 mL), the solution was washed with saturated aqueous NaHCO3
(300 mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/ethyl
acetate, 80:20) furnished the hydroxy acetal (13.3 g, 62% yield) as a
colorless liquid.
Pyridine (2.5 mL, 31 mmol) was added to a solution of dicyclo-
hexylcarbodiimide (19.1 g, 93 mmol), dimethyl sulfoxide (50 mL), and
the above alcohol (12.4 g, 31 mmol) in benzene (100 mL). Trifluo-
roacetic acid (1.2 mL, 15.5 mmol) was then introduced, and the resultant
suspension was stirred for 5 h at room temperature, diluted with ether
(300 mL), and filtered. The filtrate was washed with water (200 mL)
and brine (200 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexane/ethyl acetate, 80:20) gave (+)-9 (11.0 g, 89%
yield) as a colorless liquid: [R]2D0 +70.4° (c 4.77, CHCl3); IR (CHCl3)
3000 (m), 2940 (s), 2860 (s), 1745 (s), 1430 (s), 1110 (s), 1050 (s),
(36) Reactions were carried out in oven- or flame-dried glassware under
argon, unless otherwise noted. All solvents were reagent grade. Diethyl
ether and tetrahydrofuran (THF) were freshly distilled from sodium/
benzophenone under argon. Dichloromethane, benzene, and diisopropy-
lamine were freshly distilled from calcium hydride under argon. Triethy-
lamine, diisopropylethylamine, and tetramethylethylenediamine were distilled
from calcium hydride under argon and stored over potassium hydroxide.
Hexamethylphosphoramide was distilled from calcium hydride at reduced
pressure and stored over 4 Å molecular sieves. Anhydrous pyridine,
dimethylformamide, and dimethyl sulfoxide were purchased from Aldrich
and used without purification. n-Butyllithium was purchased from Aldrich
and standardized by titration with menthol/triphenylmethane. Except as
otherwise stated, reactions were magnetically stirred and monitored by thin-
layer chromatography with 0.25 mm E. Merck precoated silica gel plates.
Flash chromatography was performed with silica gel-60 (particle size 0.040-
0.062 mm) supplied by E. Merck. Yields refer to chromatographically and
spectroscopically pure compounds, unless otherwise indicated. Melting
points were determined on a Bristoline heated-stage microscope and are
corrected. Infrared spectra were recorded on a Perkin-Elmer Model 283B
spectrometer with polystyrene as external standard. NMR spectra were
recorded on a Bruker AMX-500 spectrometer. Chemical shifts are reported
relative to internal tetramethylsilane (δ 0.00) for 1H and chloroform (δ 77.0)
for 13C. Optical rotations were obtained with a Perkin-Elmer model 241
polarimeter. High-resolution mass spectra were measured at the University
of Pennsylvania Mass Spectrometry Service Center with a VG Micromass
70/70H or VG ZAB-E spectrometer. Microanalyses were performed by
Robertson Laboratories, Madison, NJ. High-performance liquid chroma-
tography (HPLC) was performed with a Ranin component analytical/
semipreparative system.
1
910 (s), 710 (s) cm-1; H NMR (500 MHz, CDCl3) δ 9.57 (s, 1 H),
7.66 (m, 4 H), 7.45-7.37 (m, 6 H), 4.89 (s, 1 H), 4.20 (m, 1 H), 4.00
(dd, J ) 12.0, 2.8 Hz, 1 H), 3.25 (s, 3 H), 1.97 (m, 2 H), 1.67 (m, 1
H), 1.48 (dd, J ) 22.8, 12.2 Hz, 1 H), 1.06 (s, 9 H); 13C NMR (62.9
MHz, CDCl3) δ 200.3, 135.7, 133.9, 129.7, 127.6, 99.4, 73.0, 64.8,
55.0, 39.1, 34.9, 26.8, 19.0; high-resolution mass spectrum (CI, NH3)
m/z 416.2271 [(M + NH4)+; calcd for C23H34NO4Si 416.2257].
Alkynyl Ketone (+)-15. Propyne (30 mL) was condensed in THF
(300 mL) at -78 °C. n-Butyllithium (2.4 M in hexanes; 140 mL, 0.34
mol) was added dropwise over 1 h, and the resultant suspension was
mechanically stirred for an additional 15 min at -78 °C. A solution
of aldehyde (+)-9 (8.4 g, 21 mmol) in THF (25 mL) was then added
dropwise, and the suspension was stirred for 15 min at -78 °C and
warmed to room temperature. After 1 h the mixture was poured into
cold (0 °C) saturated aqueous NH4Cl (200 mL), the combined layers
were separated, and the aqueous phase was extracted thoroughly with
ether (2 × 300 mL). The combined organic layers were washed with
brine (400 mL), dried over MgSO4, filtered, and concentrated. Flash

Syntheses of Acutiphycin and Dehydroacutiphycin
J. Am. Chem. Soc., Vol. 119, No. 45, 1997 10941
chromatography (hexanes/ethyl acetate, 80:20) provided an inseparable
mixture of epimeric alcohols (9.0 g, 96% yield) as a colorless liquid.
A solution of dicyclohexylcarbodiimide (30 g, 149 mmol), dimethyl
sulfoxide (75 mL), and the above alcohols (21.7 g, 49.5 mmol) in
benzene (150 mL) was treated with pyridine (3.9 mL, 49.5 mmol)
followed by dropwise addition of trifluoroacetic acid (1.9 mL, 24.8
mmol). The resultant suspension was stirred for 2 h at room
temperature and then diluted with ether (400 mL) and filtered. The
filtrate was washed with water (300 mL) and brine (300 mL), dried
over MgSO4, filtered, and concentrated. Flash chromatography (hex-
anes/ethyl acetate, 90:10) afforded (+)-15 (18.0 g, 83% yield) as a
colorless liquid.
Allylic Alcohol (+)-8. A suspension of dry magnesium chloride
(18.0 g, 0.19 mol) in THF (200 mL) was treated with ketone (+)-15
(14.0 g, 32 mmol) in THF (70 mL). Upon heating at reflux for 20
min, most of the solid dissolved. The mixture was cooled to room
temperature and then to -78 °C, and methylmagnesium bromide (3.0
M in ether; 21.0 mL, 64 mmol) was then added dropwise over 10 min.
After 1.5 h at -78 °C, the solution was poured into saturated aqueous
NH4Cl (150 mL). The aqueous layer was extracted with ether (300
mL), and the combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated. Flash chromatography (hex-
anes/ethyl acetate, 80:20) gave the desired alcohol (11.7 g, 80% yield)
as a colorless liquid.
The above alcohol (14.5 g, 32 mmol) was dissolved in hexane (175
mL), and 5% palladium on calcium carbonate (2.6 g) and quinoline
(2.6 mL) were added. The flask was flushed three times with hydrogen,
and the mixture was stirred under H2 for 1.5 h. The suspension was
then filtered through a pad of silica gel, and the pad was washed with
EtOAc (150 mL). Concentration and flash chromatography (hexanes/
ethyl acetate, 90:10) furnished (+)-8 (13.8 g, 95% yield) as a colorless
liquid.
Diol (+)-i. Tetra-n-butylammonium fluoride (1.0 M in THF; 0.6
mL, 0.6 mmol) was added to a solution of alcohol (+)-8 (0.15 g, 0.33
mmol) in THF (5 mL). The reaction mixture was stirred overnight at
room temperature, diluted with ether (20 mL), washed with brine (10
mL), dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (hexanes/ethyl acetate, 50:50) afforded (+)-i as a colorless
crystalline solid: mp 80-82 °C.
4.22-4.16 (m, 1 H), 3.95 (d, J ) 11.7 Hz, 1 H), 3.21 (s, 3 H), 1.99-
1.96 (m, 1 H), 1.83-1.77 (m, 1 H), 1.76 (dd, J ) 6.9, 1.7 Hz, 3 H),
1.66-1.61 (m, 1 H), 1.46 (dd, J ) 23.3, 11.8 Hz, 1 H), 1.05 (s, 9 H);
13C NMR (125.8 MHz, CDCl3) δ 144.5, 135.7, 134.5, 134.4, 129.5,
128.1, 127.53, 127.51, 127.3, 113.5, 99.5, 70.4, 65.7, 54.5, 40.3, 39.4,
26.9, 19.1, 14.8.
Anal. Calcd for C27H36O3Si: C, 74.27; H, 8.31. Found: C, 74.00;
H, 8.20.
Lactone (+)-17. A solution of alcohol (+)-7 (0.63 g, 1.34 mmol)
and p-toluenesulfonic acid (0.045 g) in DME (54 mL) and water (20
mL) was heated at reflux for 24 h, cooled to room temperature, and
concentrated. The resultant liquid was saturated with NaCl and
extracted with ethyl acetate (3 × 40 mL), and the combined organic
layers were dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 50:50) gave the corresponding
diol (0.45 g, 74% yield) as a colorless oil.
A solution of the above diol (0.65 g, 1.43 mmol), diisopropylethy-
lamine (0.5 mL, 3.0 mmol), and 4-(dimethylamino)pyridine (50 mg)
in dichloromethane (14 mL) was cooled to 0 °C, and triethylsilyl
chloride (0.24 mL, 1.43 mmol) was added over 10 min. The reaction
mixture was stirred 40 min further, and the reaction was then quenched
with water (2 mL). The mixture was diluted with ether (30 mL),
washed with brine (20 mL), dried over MgSO4, filtered, and concen-
trated. Flash chromatography (hexanes/ethyl acetate, 90:10) afforded
the hydroxy silyl ether (0.73 g, 90% yield) as a colorless oil.
A mixture of the above alcohol (0.73 g, 1.28 mmol), silver carbonate
on Celite (50% w/w; 3.5 g, 6.4 mmol), and benzene (43 mL) was heated
at reflux for 19 h with azeotropic removal of water via a Dean-Stark
trap. The suspension was then cooled to room temperature and filtered
through a pad of Celite. The solids were washed thoroughly with ether,
and the combined filtrates were concentrated. Flash chromatography
(hexanes/ethyl acetate, 80:20) furnished lactone (+)-17 (0.70 g, 96%
yield) as a colorless oil.
Hydroxy Ester (+)-18. n-Butyllithium (2.4 M in hexanes; 88 µL,
0.21 mmol) was added dropwise to a cold (0 °C) solution of
diisopropylamine (33 µL, 0.24 mmol) in THF (4 mL). The solution
was stirred for 20 min and then cooled to -78 °C. Ethyl acetate (21
µL, 0.22 mmol) was added. After 40 min at -78 °C, a solution of
lactone 17 (0.11 g, 0.19 mmol) in THF (1 mL) was added. The solution
was stirred at -78 °C for 1 h, and then ethanol (1 mL) was added.
The solution was concentrated, and flash column chromatography, using
hexane/ethyl acetate (90:10) as eluant, afforded the intermediate
hemiketal (0.11 g, 87%) as a colorless liquid.
A solution of the hemiketal (0.28 g, 0.43 mmol) and citric acid (0.19
g, 1.0 mmol) in methanol (10 mL) was heated at reflux for 1.5 h; the
solution was then cooled to room temperature and concentrated. The
resulting liquid was diluted with ethyl acetate, washed with saturated
NaHCO3 and brine, dried over magnesium sulfate, and filtered. The
solvent was removed, and the product was purified by flash column
chromatography, using hexane/ethyl acetate (70:30) as eluant, to afford
ketal (+)-18 (0.22 g, 94%) as a colorless liquid.
Thioesters (+)-19 and (+)-20. The Dess-Martin periodinane (0.74
g, 1.74 mmol) was dissolved in CH2Cl2 (7.0 mL) and treated with
pyridine (0.31 mL, 3.83 mmol) to produce a clear solution. At room
temperature alcohol (+)-18 (0.48 g, 0.87 mmol) in CH2Cl2 (1.5 mL)
was then added over 5 min. After 160 min, the reaction mixture was
diluted with diethyl ether (25 mL), and the reaction was quenched with
saturated aqueous NaHCO3/NaHSO3 (1:1, 20 mL). The resultant
mixture was stirred for 5 min, diluted with additional diethyl ether (40
mL), and separated. The organic layer was washed with saturated
aqueous NaHCO3 (2 × 25 mL) and brine (25 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexane/ethyl acetate,
6:1) furnished the corresponding aldehyde (0.42 g, 88% yield) as a
colorless oil.
A solution of diisopropylamine (0.24 mL, 1.72 mmol) in THF (6.7
mL) was cooled to 0 °C, and n-BuLi (2.47 M in hexanes; 0.67 mL,
1.64 mmol) was added dropwise. After 25 min, the reaction was cooled
to -78 °C, a solution of S-ethyl isobutanethioate (0.23 g, 1.72 mmol)
in THF (2.1 mL) was added via a cannula, and the mixture was stirred
for an additional 1.25 h. A solution of the above aldehyde (0.79 g,
1.43 mmol) in THF (4 mL) was then introduced via a cannula, and the
reaction was stirred at -78 °C for 1 h, quenched with saturated aqueous
Rearranged Alcohol (+)-7 and Diene (+)-16. Potassium hydride
(35% dispersion in mineral oil; 2.8 g, 24 mmol) was washed with dry
hexane (3 × 5 mL), dried under vacuum, and suspended in THF (175
mL). Following the addition of 18-crown-6 (2.0 g, 7.8 mmol), the
mixture was cooled to 0 °C, treated dropwise with a solution of alcohol
(+)-8 (7.10 g, 15.6 mmol) in THF (25 mL), warmed to room
temperature, and stirred for 45 min. (Trimethylstannyl)methyl iodide
(5.70 g, 18.7 mmol) was then added, and the suspension was stirred
for an additional 45 min and cooled to -78 °C. n-Butyllithium (2.3
M in hexanes; 7.5 mL, 17.2 mmol) was introduced dropwise over 15
min, the reaction mixture was stirred at -78 °C for 1.5 h, and the
reaction was quenched with saturated aqueous NH4Cl (2 mL). The
organic layer was washed with brine (100 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/ethyl
acetate, 80:20) gave alcohol (+)-7 (4.20 g, 58% yield) as a colorless
oil and diene (+)-16 (3.0 g, 41% yield) as a colorless liquid.
For 7: [R]2D0 +53.4° (c 2.47, CHCl3); IR (CHCl3) 3440 (w, br),
3065 (w), 3000 (m), 2960 (s), 2940 (s), 2860 (m), 1260 (s), 1110 (s),
1
1045 (s) cm-1; H NMR (500 MHz, CDCl3) δ 7.67 (m, 4 H), 7.43-
7.36 (m, 6 H), 5.10 (d, J ) 9.4 Hz, 1 H), 4.77 (d, J ) 3.3 Hz, 1 H),
4.19 (m, 1 H), 3.84 (d, J ) 11.6 Hz, 1 H), 3.46 (dd, J ) 10.2, 7.7 Hz,
1 H), 3.36 (dd, J ) 10.2, 7.8 Hz, 1 H), 3.19 (s, 3 H), 2.65-2.59 (m,
1 H), 1.95 (dd, J ) 12.9, 4.9 Hz, 1 H), 1.73 (m, 1 H), 1.64 (s, 3 H),
1.60 (m, 2 H), 1.48 (dd, J ) 23.3, 11.7 Hz, 1 H), 1.05 (s, 9 H), 0.93
(d, J ) 6.6 Hz, 3 H); 13C NMR (62.9 MHz, CDCl3) δ 136.8, 135.7,
134.4, 134.3, 129.5, 128.9, 127.5, 99.4, 72.3, 67.5, 65.7, 54.5, 39.9,
39.3, 35.0, 26.9, 19.0, 16.8, 13.0.
Anal. Calcd for C28H40O4Si: C, 71.75; H, 8.60. Found: C, 72.06;
H, 8.55.
For 16: [R]2D0 +87.0° (c 2.27, CHCl3); IR (CHCl3) 1600 (w), 1110
1
(s), 970 (m), 900 (m), 700 (m) cm-1; H NMR (500 MHz, CDCl3)
7.67 (m, 4 H), 7.44-7.36 (m, 6 H), 5.79 (d, J ) 11.8 Hz, 1 H), 5.72-
5.66 (m, 1 H), 5.24 (s, 1 H), 4.97 (s, 1 H), 4.81 (d, J ) 3.2 Hz, 1 H),

10942 J. Am. Chem. Soc., Vol. 119, No. 45, 1997
Smith et al.
NH4Cl (10 mL), and diluted with ethyl acetate (30 mL). The aqueous
phase was extracted with ethyl acetate (3 × 10 mL), and the combined
organic layers were washed with brine (30 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/ether/
methylene chloride, 3:1:1) provided the desired â-alcohol (+)-19 (0.605
g, 62% yield) and undesired R-epimer (+)-20 (0.174 g, 17% yield) as
colorless oils.
The mixture was stirred overnight at room temperature, diluted with
ether (10 mL), washed with H2O (10 mL) and brine (10 mL), dried
over MgSO4, filtered, and concentrated. Flash chromatography (hex-
anes/ethyl acetate, 2:1) gave (+)-21 (4.5 mg, 71% yield) as a colorless
oil: [R]2D5 +24° (c 0.41, CHCl3); IR (CHCl3) 3480 (w, br), 3010 (m),
2920 (s), 2850 (m), 1740 (s), 1670 (m), 1015 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 7.58-7.56 (m, 2 H), 7.42-7.39 (m, 3 H), 5.59 (dd, J
) 2.3, 0.5 Hz, 1 H), 5.35 (d, J ) 9.9 Hz, 1 H), 4.15 (m, 2 H), 4.10 (m,
1 H), 3.78 (apparent d, J ) 11.5 Hz, 1 H), 3.52 (s, 3 H), 3.17 (d, J )
0.7 Hz, 3 H), 2.84 (m, 2 H), 2.77 (m, 1 H), 2.65 (ABq, JAB ) 13.8 Hz,
∆υAB ) 102.6 Hz, 2 H), 2.32 (apparent dd, J ) 12.7, 4.3 Hz, 1 H),
1.82 (ddt, J ) 12.1, 4.0, 2.0 Hz, 1 H), 1.58 (s, 3 H), 1.52 (m, 1 H),
1.30 (m, 1H), 1.27 (td, J ) 7.2, 0.9 Hz, 3 H), 1.23 (td, J ) 7.4, 0.9 Hz,
3 H), 1.18 (s, 3 H), 1.14 (s, 3 H), 0.92 (d, J ) 7.0 Hz, 3 H); 13C NMR
(125.8 MHz, CDCl3) δ 204.6, 169.2, 165.8, 133.8, 131.9, 129.6, 128.4,
127.8, 127.4, 99.4, 82.9, 74.2, 65.0, 60.5, 55.3, 54.2, 47.8, 42.7, 42.1,
38.3, 34.0, 23.5, 23.2, 20.5, 19.8, 14.4, 14.2, 12.2; high-resolution mass
spectrum (FAB, NBA matrix) m/z 685.2620 [(M + Na)+; calcd for
C32F3H45O9SNa 685.2634].
For (+)-19: [R]2D5 +33° (c 1.0, CHCl3); IR (CHCl3) 3495 (w, br),
2955 (s), 2930 (s), 2890 (m), 2855 (m), 1730 (s), 1650 (m), 1460 (m),
1425 (m), 1375 (m), 1365 (m), 1305 (m), 1230 (m), 1145 (m), 1110
1
(s), 1035 (s), 995 (m), 940 (m), 815 (w), 695 (s), 600 (w) cm-1; H
NMR (500 MHz, CDCl3) δ 7.67-7.64 (m, 4 H), 7.42-7.34 (m, 6 H),
5.26 (d, J ) 9.7 Hz, 1 H), 4.17-4.09 (m, 1 H), 4.11 (qd, J ) 7.2, 1.2
Hz, 2 H), 3.63 (dd, J ) 11.7, 1.1 Hz, 1 H), 3.51 (dd, J ) 7.6, 6.0 Hz,
1 H), 3.06 (s, 3 H), 2.86-2.78 (m, 2 H), 2.68 (d, J ) 7.7 Hz, 1 H),
2.60 (ABq, JAB ) 13.5 Hz, ∆υAB ) 49.9 Hz, 2 H), 2.60-2.53 (m, 1
H), 2.17 (ddd, J ) 12.9, 4.8, 1.6 Hz, 1 H), 1.68 (dd, J ) 12.8, 10.8
Hz, 1 H), 1.62-1.59 (m, 1 H), 1.54 (d, J ) 1.0 Hz, 3 H), 1.39 (apparent
q, J ) 12.0 Hz, 1 H), 1.244 (s, 6 H), 1.237 (t, J ) 7.0 Hz, 3 H), 1.22
(t, J ) 7.4 Hz, 3 H), 1.04 (s, 9 H), 0.91 (d, J ) 6.7 Hz, 3 H); 13C NMR
(125.8 MHz, CDCl3) δ 208.2, 169.3, 135.7, 134.6, 134.4, 132.6, 130.6,
129.5, 127.51, 127.49, 99.5, 80.9, 73.9, 66.6, 60.4, 54.0, 47.8, 42.6,
42.2, 38.8, 34.9, 27.0, 24.5, 23.1, 21.8, 19.1, 16.6, 14.3, 14.2, 12.3;
high-resolution mass spectrum (FAB, NBA matrix) m/z 707.3438 [(M
+ Na)+; calcd for C38H56O7SSiNa 707.3414].
Hydroxy Mosher Ester Derivative (+)-22. Via the procedure
described for the preparation of (+)-21, alcohol (+)-20 (11.2 mg, 16.4
µmol) was acylated with (S)-(+)-R-methoxy-R-(trifluoromethyl)phe-
nylacetyl chloride (15.3 µL, 82.0 µmol). Workup and flash chroma-
tography as before furnished the Mosher ester (12 mg, 81% yield) as
a colorless oil: [R]2D5 +48.0° (c 0.60, CHCl3); IR (CHCl3) 1740 (s),
For (+)-20: [R]2D5 +28.2° (c 1.0, CHCl3); IR (CHCl3) 3500 (w, br),
2960 (s), 2925 (s), 2890 (m), 2850 (m), 1730 (s), 1660 (m), 1460 (m),
1425 (m), 1365 (m), 1305 (m), 1225 (m), 1145 (m), 1110 (s), 1035
(s), 990 (m), 940 (m), 810 (m), 690 (s), 600 (m) cm-1; 1H NMR (500
MHz, CDCl3) δ 7.67-7.64 (m, 4 H), 7.42-7.34 (m, 6 H), 5.33 (d, J
) 10.0 Hz, 1 H), 4.17-4.10 (m, 1 H), 4.12 (q, J ) 7.1 Hz, 2 H), 3.64
(apparent d, J ) 12.6 Hz, 1 H), 3.62 (dd, J ) 5.8, 3.3 Hz, 1 H), 3.07
(s, 3 H), 2.87-2.71 (m, 2 H), 2.63 (d, J ) 5.9 Hz, 1 H), 2.61-2.57
(m, 1 H), 2.59 (ABq, JAB ) 13.5 Hz, ∆υAB ) 49.0 Hz, 2 H), 2.17
(ddd, J ) 12.8, 4.8, 1.7 Hz, 1 H), 1.69 (dd, J ) 12.9, 10.8 Hz, 1 H),
1.61 (ddt, J ) 12.2, 4.1, 1.8 Hz, 1 H), 1.55 (d, J ) 1.3 Hz, 3 H), 1.38
(apparent q, J ) 12.0 Hz, 1 H), 1.24 (t, J ) 7.1 Hz, 3 H), 1.23 (s, 3
H), 1.22 (s, 3 H), 1.20 (t, J ) 7.5 Hz, 3 H), 1.04 (s, 9 H), 0.97 (d, J
) 6.9 Hz, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 208.0, 169.2, 135.7,
134.6, 134.4, 134.3, 129.5, 127.5, 127.4, 99.5, 80.7, 74.0, 66.6, 60.4,
53.7, 47.7, 42.6, 42.2, 38.8, 34.3, 27.0, 23.0, 22.7, 22.1, 19.7, 19.1,
14.22, 14.17, 12.5; high-resolution mass spectrum (FAB, NBA matrix)
m/z 707.3432 [(M + Na)+; calcd for C38H56O7SSiNa 707.3414].
Hydroxy Mosher Ester (+)-21. A stock solution was prepared by
dissolving Et3N (0.17 mL, 1.2 mmol) and 4-(dimethylamino)pyridine
(6.4 mg, 52 µmol) in dry CH2Cl2 (2.2 mL). A portion of this solution
(0.24 mL) was transferred to a vial containing alcohol (+)-20 (11.8
mg, 17.2 µmol). (R)-(-)-R-Methoxy-R-(trifluoromethyl)phenylacetyl
chloride (16 µL, 86 µmol) was then added. The reaction mixture was
stirred at room temperature overnight, diluted with ether (10 mL),
washed with saturated aqueous NaHCO3 (2 × 10 mL) and brine (15
mL), dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (hexanes/ethyl acetate, 9:1) furnished the corresponding Mosher
ester (13 mg, 84% yield) as a colorless oil: [R]2D5 +33.8° (c 0.65,
CHCl3); IR (CHCl3) 1740 (s), 1665 (m), 1460 (m), 1225 (s), 1165 (s),
1
1665 (m), 1225 (s), 1180 (s), 1165 (s), 1105 (s), 1030 (s) cm-1; H
NMR (500 MHz, CDCl3) δ 7.68-7.65 (m, 4 H), 7.54 (d, J ) 7.8 Hz,
2 H), 7.42-7.27 (m, 9 H), 5.54 (d, J ) 2.7 Hz, 1 H), 5.16 (d, J ) 9.6
Hz, 1 H), 4.17-4.10 (m, 1 H), 4.11 (q, J ) 7.1 Hz, 2 H), 3.52 (apparent
d, J ) 12.5 Hz, 1 H), 3.49 (s, 3 H), 3.04 (s, 3 H), 2.85-2.78 (m, 2 H),
2.73-2.66 (m, 1 H), 2.58 (ABq, JAB ) 13.6 Hz, ∆υAB ) 68.9 Hz, 2
H), 2.21 (ddd, J ) 12.9, 4.8, 1.4 Hz, 1 H), 1.67 (dd, J ) 12.9, 10.8
Hz, 1 H), 1.57-1.53 (m, 1 H), 1.49 (d, J ) 0.9 Hz, 3 H), 1.36 (apparent
q, J ) 11.7 Hz, 1 H), 1.24 (t, J ) 7.1 Hz, 3 H), 1.21 (t, J ) 7.4 Hz,
3 H), 1.12 (s, 3 H), 1.05 (s, 12 H), 0.86 (d, J ) 7.0 Hz, 3 H); 13C
NMR (125.8 MHz, CDCl3) δ 204.5, 169.2, 165.8, 135.8, 134.6, 134.4,
134.3, 131.9, 129.6, 128.4, 127.7, 127.53, 127.52, 127.1, 99.5, 82.9,
73.9, 66.5, 60.4, 55.3, 54.1, 47.6, 42.7, 42.2, 38.6, 34.1, 27.0, 24.0,
23.1, 19.9, 19.7, 19.1, 14.4, 14.2, 12.2; high-resolution mass spectrum
(FAB, NBA matrix) m/z 923.3810 [(M + Na)+; calcd for C48F3H63O9-
SiSNa 923.3812].
Desilylation, workup, and flash chromatography as described above
then gave (+)-22 (7.4 mg, 84% yield) as a colorless oil: [R]2D5 +49°
(c 0.80, CHCl3); IR (CHCl3) 3500 (w, br), 3005 (s), 2970 (s), 2930
(s), 1735 (s), 1670 (m), 1230 (s), 1185 (s), 1165 (s), 1010 (s) cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.59-7.56 (m, 2 H), 7.42-7.39 (m, 3 H),
5.59 (d, J ) 3.0 Hz, 1 H), 5.37 (d, J ) 9.7 Hz, 1 H), 4.15 (m, 2 H),
4.11 (m, 1 H), 3.80 (dd, J ) 11.7, 1.4 Hz, 1 H), 3.52 (s, 3 H), 3.19 (s,
3 H), 2.83 (m, 2 H), 2.76 (m, 1 H), 2.66 (ABq, JAB ) 13.9 Hz, ∆υAB
) 96.8 Hz, 2 H), 2.32 (ddd, J ) 12.7, 4.7, 1.8 Hz, 1 H), 1.82 (ddt, J
) 12.1, 4.5, 1.9 Hz, 1 H), 1.59 (d, J ) 1.1 Hz, 3 H), 1.53 (dd, J )
12.6, 11.2 Hz, 1 H), 1.31 (m, 1 H), 1.27 (t, J ) 7.1 Hz, 3 H), 1.22 (t,
J ) 7.4 Hz, 3 H), 1.18 (s, 3 H), 1.08 (s, 3 H), 0.92 (d, J ) 7.1 Hz, 3
H); 13C NMR (125.8 MHz, CDCl3) δ 204.5, 169.1, 165.8, 134.2, 131.9,
129.6, 128.4, 127.7, 127.6, 99.4, 83.0, 74.2, 64.9, 60.5, 55.4, 54.1, 47.8,
42.7, 42.0, 38.3, 34.2, 24.2, 23.2, 19.9, 19.7, 14.4, 14.2, 12.2; high-
resolution mass spectrum (FAB, NBA matrix) m/z 685.2631 [(M +
Na)+; calcd for C32F3H45O9SNa 685.2634].
TES Ether (+)-23. A solution of alcohol (+)-19 (0.42 g, 0.61
mmol) in CH2Cl2 (12.1 mL) was cooled to 0 °C and treated dropwise
with 2,6-lutidine (0.42 mL, 3.6 mmol) and triethylsilyl trifluo-
romethanesulfonate (0.55 mL, 2.4 mmol). After 20 min, the reaction
mixture was quenched with MeOH (0.5 mL), diluted with ethyl acetate
(40 mL), washed with 0.1 M aqueous NaHSO4 (20 mL) and brine (20
mL), dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (hexanes/ethyl acetate, 97:3) provided (+)-23 (0.44 g, 91% yield)
as a colorless oil.
Aldehyde (+)-4. TES ether (+)-23 (95 mg, 0.12 mmol) was
dissolved in CH2Cl2 (0.6 mL) and triethylsilane (0.12 mL, 0.77 mmol)
and 10% Pd on carbon (16.5 mg, 16.0 µmol) were then added. The
mixture was stirred for 2 h at room temperature, diluted with ethyl
acetate (3 mL), filtered through Celite, and concentrated. Flash
1
1105 (s) cm-1; H NMR (500 MHz, CDCl3) δ 7.68-7.65 (m, 4 H),
7.53 (d, J ) 7.6 Hz, 2 H), 7.42-7.26 (m, 9 H), 5.55 (d, J ) 2.3 Hz,
1 H), 5.15 (d, J ) 9.8 Hz, 1 H), 4.16-4.10 (m, 1 H), 4.11 (q, J ) 7.1
Hz, 2 H), 3.50 (s, 3 H), 3.49 (apparent d, J ) 12.9 Hz, 1 H), 3.03 (s,
3 H), 2.88-2.77 (m, 2 H), 2.74-2.68 (m, 1 H), 2.58 (ABq, JAB
)
13.6 Hz, ∆υAB ) 75.1 Hz, 2 H), 2.21 (ddd, J ) 12.9, 4.8, 1.5 Hz, 1
H), 1.66 (dd, J ) 12.9, 10.8 Hz, 1 H), 1.56-1.52 (m, 1 H), 1.48 (d, J
) 1.2 Hz, 3 H), 1.36 (apparent q, J ) 12.0 Hz, 1 H), 1.24 (t, J ) 7.1
Hz, 3 H), 1.21 (t, J ) 7.4 Hz, 3 H), 1.13 (s, 3 H), 1.11 (s, 3 H), 1.05
(s, 9 H), 0.87 (d, J ) 7.1 Hz, 3 H); 13C NMR (125.8 MHz, CDCl3) δ
204.6, 169.2, 165.7, 135.8, 134.6, 134.4, 134.0, 131.9, 129.6, 128.3,
127.7, 127.5, 127.0, 99.5, 82.8, 73.8, 66.5, 60.4, 55.4, 54.1, 47.6, 42.7,
42.2, 38.5, 33.9, 27.0, 23.4, 23.2, 20.6, 19.8, 19.1, 14.3, 14.2, 12.2;
high-resolution mass spectrum (FAB, 1-thioglycerol matrix) m/z
923.3836 [(M + Na)+; calcd for C48F3H63O9SiSNa 923.3812].
A solution of the silyloxy Mosher ester (8.6 mg, 9.5 µmol) in THF
(1.9 mL) was treated with TBAF (1.0 M in THF; 95 µL, 95 µmol).

Syntheses of Acutiphycin and Dehydroacutiphycin
J. Am. Chem. Soc., Vol. 119, No. 45, 1997 10943
chromatography (hexanes/ethyl acetate, 95:5) furnished (+)-4 (77 mg,
88% yield) as a colorless oil: [R]2D5 +36° (c 1.0, CHCl3); IR (CHCl3)
3030 (m), 3010 (m), 2970 (s), 2940 (s), 2920 (m), 2880 (m), 2860
(m), 1730 (s), 1465 (m), 1115 (s), 1040 (s) cm-1; 1H NMR (500 MHz,
CDCl3) δ 9.59 (s, 1 H), 7.67-7.65 (m, 4 H), 7.42-7.34 (m, 6 H), 5.14
(d, J ) 9.7 Hz, 1 H), 4.19-4.13 (m, 1 H), 4.12 (q, J ) 7.1 Hz, 2 H),
3.68 (d, J ) 4.1 Hz, 1 H), 3.63 (apparent d, J ) 11.7 Hz, 1 H), 3.09
(s, 3 H), 2.64-2.53 (m, 1 H), 2.61 (ABq, JAB ) 13.6 Hz, ∆υAB ) 73.8
Hz, 2 H), 2.20 (ddd, J ) 11.3, 3.2, 1.6 Hz, 1 H), 1.67 (dd, J ) 12.8,
10.9 Hz, 1 H), 1.61 (ddt, J ) 12.4, 4.5, 2.2 Hz, 1 H), 1.52 (d, J ) 0.8
Hz, 3 H), 1.40 (apparent q, J ) 11.9 Hz, 1 H), 1.24 (t, J ) 7.1 Hz, 3
H), 1.05 (s, 15 H), 0.97 (t, J ) 7.9 Hz, 9 H), 0.87 (d, J ) 6.7 Hz, 3 H),
0.64 (q, J ) 7.9 Hz, 6 H); 13C NMR (125.8 MHz, CDCl3) δ 206.0,
169.2, 135.8, 135.7, 134.6, 134.4, 134.0, 130.3, 129.5, 127.51, 127.48,
99.5, 81.4, 73.9, 66.5, 60.4, 51.5, 47.7, 42.7, 42.2, 38.8, 34.7, 27.0,
20.0, 19.8, 19.1, 15.9, 14.2, 12.5, 7.1, 5.6; high-resolution mass
spectrum (FAB, NBA matrix) m/z 761.4253 [(M + Na)+; calcd for
C42H66O7Si2Na 761.4245].
with brine (50 mL), dried over MgSO4, filtered through a pad of silica
gel supported by a pad of Celite, and washed with hexane/ethyl acetate
(4:1, 200 mL). Concentration and flash chromatography (hexanes/ethyl
acetate, 95:5) provided a 16.4:1 mixture of bromo ethers (1.52 g, 78%
yield) as a colorless oil.
Water (1.09 mL) was added to solution of the bromo ethers (1.47 g,
4.15 mmol) in CH2Cl2 (19.6 mL). The biphasic mixture was cooled
to 7 °C with vigorous stirring, and solid 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ, 1.23 g, 5.40 mmol) was introduced in one portion.
The resultant black slurry containing orange water droplets gave rise
to an orange slurry within 10 min. After an additional 20 min, the
reaction mixture was diluted with CH2Cl2 (200 mL) and then washed
with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried
over MgSO4, filtered, and concentrated. Flash chromatography (hex-
anes/ethyl acetate, 9:1) gave a mixture of alcohols. Further purification
by normal-phase HPLC (Rainin 60-Å silica column; hexane/ethyl
acetate, 85:15) afforded (-)-28 (0.59 g, 61% yield) as a colorless
oil.
(+)-(2R)-Heptane-1,2-diol (25). To a solution of AD-mix-â (59.9
g) in t-BuOH and H2O (1:1, 428 mL) at 0 °C was added 1-heptene
(6.0 mL, 42.8 mmol). The heterogeneous slurry was stirred vigorously
at 0 °C, and after 40 h, solid sodium sulfite (54 g) was slowly introduced
at 0 °C. The resultant suspension was allowed to warm to room
temperature, stirred for an additional 1 h, and diluted with CH2Cl2 (400
mL). The aqueous phase was extracted with CH2Cl2 (3 × 200 mL),
and the combined organic extracts were dried over MgSO4, filtered,
and concentrated. Removal of t-BuOH by distillation at atmospheric
pressure then gave (+)-25 (5.3 g, 94% yield) as a colorless oil.
PMB Ether (-)-(26). A solution of diol (+)-25 (5.73 g, 43.3 mmol)
in benzene (140 mL) was treated with p-methoxybenzaldehyde dimethyl
acetal (15.8 g, 86.6 mmol) and p-toluenesulfonic acid monohydrate
(0.75 g, 4.3 mmol). The reaction mixture was stirred at ambient
temperature for 18 h and then concentrated. The residue was used
without purification in the next step.
The crude acetonide (maximum 43.3 mmol) dissolved in CH2Cl2
(217 mL) was cooled to -78 °C and treated with diisobutylaluminum
hydride (1.0 M in hexane; 147.2 mL, 147.2 mmol). After 30 min, the
reaction mixture was gradually warmed to room temperature, quenched
with MeOH (4 mL), diluted with ether (300 mL), and treated with a
saturated solution of Rochelle’s salt (200 mL). The resultant biphasic
mixture was stirred vigorously at room temperature until the organic
phase turned clear. The organic phase was then dried with MgSO4,
filtered through Na2SO4, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 3:1) afforded (-)-26 (9.7 g, 89% yield for two
steps) as a colorless liquid.
Alkyne (+)-(27). A solution of alcohol (-)-26 (1.3 g, 5.3 mmol)
in CH2Cl2 (22 mL) was treated with triphenylphosphine (2.8 g, 10.5
mmol) and cooled to 0 °C. After 15 min, carbon tetrabromide (3.5 g,
10.5 mmol) was added, and the reaction mixture was gradually warmed
to room temperature, stirred further for 4 h, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 97:3) gave the corresponding
bromide (1.5 g, 92% yield) as a colorless oil.
THF (33.8 mL) was cooled to -78 °C, and n-BuLi (2.5 M in hexane;
14.2 mL, 35.4 mmol) was slowly added. Propyne was then bubbled
into the mixture until the clear solution became milky white. The
suspension was slowly warmed to 0 °C, treated with HMPA (8.4 mL)
and recooled to -78 °C, and then the above bromide (3.72 g, 11.8
mmol) in THF (4 mL) was introduced via cannula over 15 min. After
an additional 15 min, the reaction mixture was warmed to room
temperature, stirred for 3 h, and poured into ice-cold saturated aqueous
NH4Cl (50 mL). The organic phase was then washed with brine (40
mL), dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (hexanes/ethyl acetate, 95:5) furnished (+)-27 (2.66 g, 82% yield)
as a colorless liquid.
TES Ether (+)-(5). At 0 °C, a solution of alcohol (-)-28 (1.04 g,
4.40 mmol) in CH2Cl2 (17.6 mL) was treated with 2,6-lutidine (2.30
mL, 19.8 mmol) and triethylsilyl trifluoromethanesulfonate (2.09 mL,
9.24 mmol). After 30 min, the reaction was quenched with MeOH
(0.3 mL), diluted with ethyl acetate (80 mL), washed with 0.1 M
aqueous NaHSO4 (40 mL) and brine (40 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes) furnished
(+)-5 (1.50 g, 98% yield) as a colorless oil.
Alkyne (+)-(29). At 0 °C, a solution of triphenylphosphine (18.3
g, 69.6 mmol) in CH2Cl2 (75.5 mL) was treated with carbon tetrabro-
mide (11.5 g, 34.8 mmol) dissolved in CH2Cl2 (26.0 mL), and the
resultant suspension was stirred for 15 min. A solution of aldehyde
(+)-12 (3.0 g, 17.4 mmol) in CH2Cl2 (10.2 mL) was then introduced
via a cannula over 15 min. After 70 min, the reaction mixture was
concentrated in Vacuo and filtered through a pad of silica gel.
Concentration and flash chromatography (hexanes/ethyl acetate, 95:5)
provided the dibromomethylene derivative (4.7 g, 82% yield) as a
colorless oil.
A solution of the dibromide (4.67 g, 14.2 mmol) in THF (95 mL)
was cooled to -78 °C and n-BuLi (2.5 M in hexane; 12.5 mL, 31.2
mmol) was added dropwise. The reaction mixture was stirred for 1 h,
warmed to room temperature, stirred 1 h further, recooled to -78 °C,
and treated with iodomethane (4.42 mL, 71.0 mmol) slowly. After an
additional 30 min at -78 °C and 75 min at room temperature, the
mixture was concentrated. The resultant liquid was then dissolved in
ether (200 mL), and the solution was washed with water (100 mL)
and brine (100 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 95:5) afforded (+)-29 (2.35
g, 91% yield) as a colorless liquid.
Bromo Diol (-)-(30). A solution of alkyne (+)-29 (1.18 g, 6.47
mmol) in benzene (43 mL) was treated with zirconocene chloride
hydride (5.00 g, 19.4 mmol) in one portion, warmed to 40-45 °C for
1 h, and cooled to room temperature. N-Bromosuccinimide (2.30 g,
12.9 mmol) was then added, and the reaction was stirred for 30 min
and quenched with saturated aqueous NaHCO3 (20 mL). The biphasic
mixture was stirred vigorously for 5 min and extracted with hexane/
ethyl acetate (9:1, 2 × 40 mL). The combined organic solutions were
washed with brine (50 mL), dried over MgSO4, and filtered through a
pad of silica gel supported by a pad of Celite, and the pad was washed
with hexanes/ethyl acetate (4:1, 200 mL). Concentration gave a mixture
of crude bromo acetonides which was used in the next step without
purification.
The bromo acetonides were treated with acetic acid/H2O (4:1, 20
mL). The reaction mixture was stirred at room temperature overnight
and then poured into saturated aqueous NaHCO3/ether (1:1, 40 mL).
The organic layer was washed with brine (20 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/ethyl
acetate, 2:1) furnished the desired diol (-)-30 as a mixture of
regioisomers [0.92 g, 73% (2 steps), ca. 17:1 by 1H NMR] as a colorless
oil.
Alkene (-)-(31). A solution of diol (-)-30 (0.58 g, 2.97 mmol) in
THF (9.9 mL) was cooled to 0 °C, and sodium hydride (60% dispersion
in mineral oil; 0.36 g, 8.91 mmol) was added all at once. After 15
min, the reaction was warmed to room temperature, diluted with THF
Bromo Alcohol (-)-(28). A solution of acetylene (+)-27 (1.51 g,
5.50 mmol) in benzene (36.7 mL) was treated with zirconocene chloride
hydride (4.30 g, 16.5 mmol) in one portion, warmed to 40-45 °C for
1 h, and cooled to room temperature. N-Bromosuccinimide (1.96 g,
11.0 mmol) was then added, and the reaction was stirred for 15 min
and quenched with saturated aqueous NaHCO3 (15 mL). The biphasic
mixture was stirred vigorously for 5 min and extracted with hexane/
ethyl acetate (9:1, 2 × 30 mL). The combined extracts were washed

10944 J. Am. Chem. Soc., Vol. 119, No. 45, 1997
Smith et al.
(19.8 mL), stirred for 30 min, and recooled to 0 °C. Solid 1-(p-
toluenesulfonyl)imidazole (0.99 g, 4.46 mmol) was then introduced in
one portion. The reaction mixture was stirred for 15 min, warmed to
room temperature, stirred an additional 2 h, and transferred via a cannula
to another flask containing copper(I) iodide (0.28 g, 1.49 mmol) and
crotylmagnesium chloride (0.3 M in THF; 49.5 mL, 14.9 mol) at -23
°C. After an additional 5 min, the reaction was quenched with 10%
aqueous NH4OH and saturated aqueous NH4Cl (1:1, 40 mL) and diluted
with ether (50 mL). The organic phase was washed with brine (50
mL), dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (hexanes/ethyl acetate, 95:5) afforded a mixture of alcohols (0.42
g, 61% yield; ca. 2.2:1 by 1H NMR). Further chromatography on 10%
AgNO3/silica gel (hexanes/ethyl acetate, 95:5) then provided (-)-31
(0.29 g, 42% yield) as a colorless oil.
TES Ether (+)-(6). A solution of alcohol (-)-31 (67.0 mg, 0.29
mmol) in CH2Cl2 (1.15 mL) was cooled to 0 °C and treated with 2,6-
lutidine (0.15 mL, 1.29 mmol) and triethylsilyl trifluoromethane-
sulfonate (0.14 mL, 0.60 mmol). After 30 min, the reaction mixture
was quenched with MeOH (0.2 mL), diluted with ethyl acetate (15
mL), washed with 0.1 M aqueous NaHSO4 (8 mL) and brine (10 mL),
dried over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes) furnished (+)-6 (98.3 mg, 98% yield) as a colorless oil.
Enone (+)-32a. To a slurry of powdered magnesium (0.26 g, 10.7
mmol), in ether (7.5 mL) was added a solution of 1,2-dibromoethane
(0.86 mL, 10.0 mmol) in benzene (2.5 mL) dropwise over 30 min so
as to maintain a gentle reflux. The resulting solution was stirred for
an additional 45 min and then allowed to stand for 1-2 h before use
in the coupling reaction. The concentration of magnesium bromide
was assumed to be 1.0 M.
At -78 °C a solution of vinyl bromide (+)-5 (0.96 g, 2.76 mmol)
in THF (10.1 mL) was treated dropwise with t-BuLi (1.7 M in pentane;
3.72 mL, 6.32 mmol), and the resultant yellow solution was stirred for
an additional 35 min. A freshly prepared (Vide supra) solution of
magnesium bromide [1 M in Et2O/benzene (3:1); 3.16 mL, 3.16 mmol]
was added, affording a heterogeneous mixture which was stirred for
an additional 1 h and then transferred via a cannula into a solution of
(+)-4 (0.19 g, 0.26 mmol) in THF (2.0 mL) at -78 °C. The reaction
was stirred for 1 h at -78 °C and quenched with saturated aqueous
NH4Cl (20 mL). After dilution with ethyl acetate (20 mL), the aqueous
phase was extracted with ethyl acetate (3 × 20 mL) and the organic
solutions were washed with brine (50 mL), dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes/ethyl acetate, 9:1)
provided a mixture of alcohols (0.21 g, 82% yield; ca. 1:1 by 1H NMR)
as a colorless oil.
The Dess-Martin periodinane (0.68 g, 1.6 mmol) and pyridine (0.28
mL, 3.5 mmol) were dissolved in CH2Cl2 (5.7 mL); the resultant clear
stock solution which was used within 5 min. At room temperature a
solution of the above alcohols (0.21 g, 0.21 mmol) in CH2Cl2 (1.2 mL)
was treated with a portion of the periodinane solution (3.2 mL). After
1 h, the reaction mixture was diluted with ether (15 mL) and quenched
with saturated aqueous NaHCO3 and NaHSO3 solutions (1:1, 10 mL).
The resultant mixture was stirred for 5 min, diluted with additional
ether (10 mL), washed with saturated aqueous NaHCO3 (2 × 10 mL)
and brine (15 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 95:5) furnished (+)-32a (0.20
g, 94% yield) as a colorless oil.
(+)-33a. Workup and flash chromatography as before furnished (+)-
33b (0.14 g, 84% yield) as a colorless oil.
Triol (+)-34a. A stock solution was prepared by dissolving
tetramethylammonium triacetoxyborohydride (310 mg, 1.18 mmol) in
anhydrous acetic acid (3.9 mL), and a portion (0.52 mL) was stirred at
room temperature for 1 h to effect complete mixing and cooled to 0
°C. Following the addition of dihydroxy ketone (+)-33a (12 mg, 15.4
µmol) in acetonitrile (0.8 mL), the reaction was stirred at -25 °C for
17 h and at 0 °C for 2 h and then quenched with methanol (0.5 mL).
The mixture was allowed to warm slowly to room temperature and
concentrated. The residue was diluted with ethyl acetate (10 mL) and
washed with saturated aqueous NaHCO3 (2 × 5 mL). The combined
aqueous layers were extracted with ethyl acetate (2 x 10 mL), and the
combined organic solutions were washed with brine (15 mL), dried
over MgSO4, filtered, and concentrated. Flash chromatography (hex-
anes/ethyl acetate, 2:1) gave (+)-34a (10.8 mg, 90% yield; 96:4 by 1H
NMR analysis) as a colorless oil.
Triol (+)-34b. Dihydroxy ketone (+)-33b (34 mg, 43.8 µmol) was
reduced as described above for the preparation of (+)-34a. Workup
and flash chromatography as before afforded (+)-34b (32 mg, 94%
1
yield; >92% ee by H NMR analysis) as a colorless oil.
Seco Acid (+)-3a. A solution of ester (+)-34a (25.2 mg, 0.032
mmol) in THF/MeOH/H2O (2:2:1, 4.60 mL) was treated with LiOH
(33.9 mg, 0.81 mmol), and the mixture was stirred at room temperature
overnight and then extracted with ethyl acetate (15 mL). The aqueous
layer was acidified to pH 1-2 with 0.1 M aqueous NaHSO4 and
extracted with ethyl acetate (2 × 10 mL). The combined organic phases
were washed with brine (20 mL), dried over MgSO4, and concentrated,
providing (+)-3a (23.0 mg, 95% yield; pure by 1H NMR) as a colorless
oil.
Seco Acid (+)-3b. Ester (+)-34b (25.0 mg, 0.032 mmol) was
saponified via the procedure described above for the preparation of
(+)-39. Workup as before furnished (+)-3b (23.0 mg, 96% yield; pure
1
by H NMR) as a colorless oil.
Macrolides (-)-35a and (+)-36a. A stock solution was prepared
by dissolving Et3N (91.5 µL, 0.66 mmol) and 2,4,6-trichlorobenzoyl
chloride (93.0 µL, 0.60 mmol) in THF (16.6 mL), and a portion (3.13
mL) was added to a flask containing seco acid (+)-3a (28.0 mg, 37.2
µmol). The resultant cloudy solution was stirred at room temperature
for 15 h and then filtered through a plug of cotton. The filtrate was
concentrated, and the resultant yellow oil was dissolved in toluene (9.3
mL). The solution was added over 7 h via a syringe pump to a solution
of 4-(dimethylamino)pyridine (27.2 mg, 0.22 mmol) in toluene (37 mL)
at reflux. The suspension was stirred for an additional 0.5 h and then
cooled to room temperature, diluted with ethyl acetate (50 mL), washed
with 0.1 M aqueous NaHSO4 (30 mL) and brine (30 mL), dried over
MgSO4, filtered, and concentrated. Flash chromatography (hexanes/
ethyl acetate, 5:1) gave a mixture of (-)-35a and(+)-36a (18.4 mg,
1
69.7% yield; ca. 4.2:1 by H NMR).
A solution of the macrolides (18.4 mg) in MeOH (63 mL) was treated
with anhydrous citric acid (6.0 mg, 31.2 µmol). The reaction mixture
was then heated at reflux for 72 h and cooled to room temperature,
and the reaction was quenched with solid NaHCO3 (10 mg). Concen-
tration and flash chromatography (hexanes/ethyl acetate, 5:1) afforded
(+)-36a (14.4 mg, 75% yield) and 35a (minor component) as a colorless
oil: (-)-35a: [R]2D5 -16° (c 0.30, CHCl3); IR (CHCl3) 3495 (w, br),
2995 (m), 2955 (s), 1730 (s), 1675 (m), 1250 (s), 1205 (s), 1105 (s),
Enone (+)-32b. Via the procedure described above for the
preparation of (+)-32a, vinyl bromide (+)-6 (1.06 g, 3.05 mmol) was
coupled with aldehyde (+)-4 (0.23 g, 0.30 mmol). Workup and flash
chromatography as before afforded a mixture of alcohols (0.29 g, 94%
yield) as a colorless oil. Dess-Martin oxidation of the alcohols (0.25
g, 0.24 mmol), workup, and flash chromatography as described for
32a then furnished (+)-32b (0.22 g, 88% yield) as a colorless oil.
Diol (+)-33a. A solution of bis TES ether (+)-32a (0.20 g, 0.20
mmol) in MeOH (39.3 mL) was cooled to 0 °C and treated with solid
10-camphorsulfonic acid (0.011 g, 0.049 mmol) in one portion. The
reaction mixture was stirred for 2 h and allowed to stand at 4°C in a
refrigerator overnight, and the reaction was then quenched with solid
NaHCO3 (0.02 g) and concentrated in Vacuo. Flash chromatography
(hexanes/ethyl acetate, 3:1) gave (+)-33a (0.15 g, 97% yield) as a
colorless oil.
1
1005 (s) cm-1; H NMR (500 MHz, CDCl3) δ 7.68-7.65 (m, 4 H),
7.46-7.36 (m, 6 H), 5.22 (d, J ) 10.8 Hz, 1 H), 5.18 (apparent d, J )
9.8 Hz, 1 H), 4.76-4.71 (m, 1 H), 4.62-4.58 (m, 1 H), 4.61 (s, 1 H),
4.16 (s, 1 H), 4.12 (dd, J ) 12.4, 1.3 Hz, 1 H), 3.19 (apparent d, J )
14.8 Hz, 1 H), 2.95 (apparent t, J ) 8.9 Hz, 1 H), 2.87 (d, J ) 14.8
Hz, 1 H), 2.80 (d, J ) 8.4 Hz, 1 H), 2.66-2.59 (m, 1 H), 2.38-2.30
(m, 2 H), 2.07 (apparent t, J ) 13.0 Hz, 1 H), 1.96 (td, J ) 12.7, 9.5
Hz, 1 H), 1.80-1.77 (m, 1 H), 1.68 (d, J ) 1.1 Hz, 3 H), 1.62 (s, 3 H),
1.55-1.45 (m, 2 H), 1.32-1.20 (m, 6 H), 1.07 (s, 3 H), 1.06 (s, 12 H),
0.86 (t, J ) 7.0 Hz, 3 H), 0.69 (s, 3 H); 13C NMR (125.8 MHz, CDCl3)
δ 170.0, 149.3, 135.8, 135.7, 135.5, 134.1, 134.04, 134.00, 130.6,
129.69, 129.66, 127.6, 125.5, 104.3, 86.8, 82.7, 81.7, 74.2, 65.8, 42.1,
40.6, 38.7, 35.5, 35.4, 32.3, 31.7, 27.0, 26.8, 24.7, 22.7, 22.5, 19.7,
19.1, 14.0, 12.7, 10.6; high-resolution mass spectrum (FAB, 1-thioglyc-
erol matrix) m/z 725.4200 [(M + Na)+; calcd for C43H62O6SiNa
725.4213].
Diol (+)-33b. Bis TES ether (+)-32b (0.21 g, 0.21 mmol) was
desilylated via the procedure described above for the preparation of

Syntheses of Acutiphycin and Dehydroacutiphycin
J. Am. Chem. Soc., Vol. 119, No. 45, 1997 10945
For (+)-36a: [R]2D5 +19° (c 0.91, CHCl3); IR (CHCl3) 3470 (w,
br), 2990 (m), 2950 (s), 2920 (s), 1720 (s), 1460 (m), 1105 (s), 1005
(s), 690 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.68-7.65 (m, 4 H),
7.44-7.35 (m, 6 H), 5.38 (apparent t, J ) 7.0 Hz, 1 H), 5.20 (apparent
dd, J ) 11.1, 0.9 Hz, 1 H), 4.70-4.65 (m, 1 H), 4.27 (s, 1 H), 4.10-
4.03 (m, 1 H), 3.90 (dd, J ) 11.9, 2.5 Hz, 1 H), 2.98 (apparent t, J )
8.6 Hz, 1 H), 2.95 (s, 3 H), 2.79 (d, J ) 7.9 Hz, 1 H), 2.67-2.59 (m,
1 H), 2.52 (ABq, JAB ) 13.1 Hz, ∆υAB ) 29.1 Hz, 2 H), 2.42-2.37
(m, 2 H), 2.13-2.07 (m, 1 H), 1.99 (ddd, J ) 11.2, 4.5, 1.5 Hz, 1 H),
1.72 (d, J ) 1.1 Hz, 3 H), 1.72-1.68 (m, 1 H), 1.62 (apparent q, J )
12.1 Hz, 1 H), 1.62 (s, 3 H), 1.47-1.40 (m, 1 H), 1.34 (dd, J ) 12.7,
10.9 Hz, 1 H), 1.31-1.22 (m, 7 H), 1.08 (d, J ) 6.3 Hz, 3 H), 1.08 (s,
3 H), 1.05 (s, 9 H), 0.87 (t, J ) 7.0 Hz, 3 H), 0.72 (s, 3 H); 13C NMR
(125.8 MHz, CDCl3) δ 169.2, 135.9, 135.8, 134.3, 133.6, 130.7, 129.65,
129.63, 127.60, 127.59, 125.4, 100.2, 87.0, 81.5, 76.8, 74.7, 66.1, 49.9,
44.5, 43.1, 42.0, 38.7, 38.4, 34.3, 31.7, 30.9, 27.0, 26.3, 25.0, 22.52,
22.48, 19.9, 19.1, 14.0, 12.3, 11.5; high-resolution mass spectrum (FAB,
NBA matrix) m/z 757.4491 [(M + Na)+; calcd for C44H66O7SiNa
757.4476].
ethyl acetate, 9:1) furnished (+)-37a (6.0 mg, 65% yield) as a colorless
oil: [R]2D5 +25° (c 0.54, CHCl3); IR (CHCl3) 2975 (s), 2940 (s), 2880
(s), 2870 (s), 1720 (s), 1460 (m), 1230 (s), 1215 (s), 1200 (s), 1115
1
(s), 1060 (s), 1040 (s), 1005 (s), 700 (s) cm-1; H NMR (500 MHz,
CD3OD) δ 7.72-7.65 (m, 4 H), 7.45-7.36 (m, 6 H), 5.59 (apparent t,
J ) 6.4 Hz, 1 H), 5.40 (d, J ) 10.8 Hz, 1 H), 4.81 (m, 1 H), 4.18 (s,
1 H), 4.13 (m, 1 H), 3.71 (d, J ) 11.6 Hz, 1 H), 3.06 (d, J ) 8.8 Hz,
1 H), 2.95 (s, 3 H), 2.64-2.57 (m, 1 H), 2.62 (ABq, JAB ) 14.1 Hz,
∆υAB ) 190.3 Hz, 2 H), 2.49-2.43 (m, 1 H), 2.31-2.25 (m, 1 H),
1.96 (ddd, J ) 12.6, 4.6, 1.6 Hz, 1 H), 1.92-1.86 (m, 1 H), 1.82 (dd,
J ) 12.5, 10.9 Hz, 1 H), 1.71-1.63 (m, 1 H), 1.63 (s, 3 H), 1.58 (d,
J ) 0.8 Hz, 3 H), 1.52-1.45 (m, 1 H), 1.41-1.27 (m, 8 H), 1.05 (s,
9 H), 0.96 (t, J ) 7.9 Hz, 9 H), 0.948 (s, 3 H), 0.947 (d, J ) 7.8 Hz,
3 H), 0.89 (t, J ) 6.9 Hz, 3 H), 0.89 (s, 3 H), 0.61 (q, J ) 7.9 Hz, 6
H); 13C NMR (125.8 MHz, CD3OD) δ 171.1, 139.0, 136.92, 136.88,
135.4, 131.7, 131.1, 130.9, 128.73, 128.72, 126.8, 101.0, 83.4, 76.3,
74.9, 68.0, 46.0, 44.3, 43.8, 40.3, 37.9, 35.1, 33.0, 31.9, 27.6, 26.6,
23.6, 22.6, 20.2, 19.9, 14.4, 14.1, 13.8, 7.5, 6.2; high-resolution mass
spectrum (FAB, NBA matrix) m/z 871.5334 [(M + Na)+; calcd for
C50H80O7Si2Na 871.5341].
Macrolides (-)-35b and (+)-36b. Seco acid (+)-3b (25.0 mg, 33.3
µmol) was cyclized via the basic procedure described above for the
preparation of (+)-36a; in this case, the mixed anhydride was added
to the solution of 4-(dimethylamino)pyridine over 6 h. Workup and
flash chromatography as before afforded a mixture of (-)-35b and (+)-
TES Ether (+)-37b. Diol (+)-36b (7.5 mg, 10.2 µmol) was
selectively monosilylated as described above for the preparation of (+)-
37a. Workup as before gave (+)-37b (6.1 mg, 71% yield) as a colorless
oil: [R]2D5 +22° (c 0.41, CHCl3); IR (CHCl3) 3470 (w, br), 2990 (m),
2950 (s), 2920 (s), 2870 (s), 2850 (s), 1715 (s), 1455 (m), 1210 (s),
1
36b (18.4 mg, 69.7% yield; ca. 3.3:1 by H NMR). Treatment of the
1
1105 (s), 1035 (s), 1000 (s), 690 (s) cm-1; H NMR (500 MHz, CD3-
macrolides (15.5 mg) with methanolic citric acid, workup, and flash
chromatography as before furnished the desired macrolide (+)-36b (10.9
mg, 68% yield) and 35b (minor component) as a colorless oil: (-)-
35b: [R]2D5 -13° (c 0.44, CHCl3); IR (CHCl3) 3490 (w, br), 3000 (m),
2955 (s), 2925 (s), 1730 (s), 1675 (m), 1215 (s), 1105 (s), 1005 (s),
695 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.68-7.65 (m, 4 H), 7.44-
7.36 (m, 6 H), 5.45-5.34 (m, 2 H), 5.22 (d, J ) 10.8 Hz, 1 H), 5.17
(apparent d, J ) 10.2 Hz, 1 H), 4.77-4.72 (m, 1 H), 4.61-4.58 (m, 1
H), 4.60 (s, 1 H), 4.15 (s, 1 H), 4.12 (d, J ) 12.3 Hz, 1 H), 3.19
(apparent d, J ) 14.9 Hz, 1 H), 2.97-2.93 (m, 1 H), 2.86 (d, J ) 14.8
Hz, 1 H), 2.80 (d, J ) 8.4 Hz, 1 H), 2.66-2.58 (m, 1 H), 2.37-2.27
(m, 2 H), 2.07 (apparent t, J ) 13.4 Hz, 1 H), 2.01-1.93 (m, 3 H),
1.81-1.77 (m, 1 H), 1.67 (s, 3 H), 1.62 (s, 6 H), 1.26 (s, 2 H), 1.06 (d,
J ) 11.7 Hz, 3 H), 1.06 (s, 12 H), 0.69 (s, 3 H); 13C NMR (125.8
MHz, CDCl3) δ 170.0, 149.3, 135.78, 135.74, 135.6, 134.2, 134.1,
134.0, 130.6, 130.1, 129.70, 129.67, 127.6, 125.5, 125.3, 104.4, 86.9,
82.8, 81.7, 73.8, 65.8, 42.1, 40.5, 38.7, 35.5, 35.2, 32.2, 28.2, 27.0,
26.8, 22.7, 19.7, 19.1, 17.9, 12.7, 10.6; high-resolution mass spectrum
(FAB, NBA matrix) m/z 723.4068 [(M + Na)+; calcd for C43H60O6-
SiNa 723.4057].
For (+)-36b: [R]2D5 +19° (c 0.3, CHCl3); IR (CHCl3) 3500 (w, br),
3000 (m), 2950 (m), 2920 (s), 1715 (m), 1455 (m), 1195 (s), 1105 (s),
1005 (s), 695 (s), 655 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.67-
7.65 (m, 4 H), 7.44-7.36 (m, 6 H), 5.45-5.34 (m, 3 H), 5.19 (d, J )
11.1 Hz, 1 H), 4.72-4.67 (m, 1 H), 4.27 (s, 1 H), 4.09-4.03 (m, 1 H),
3.90 (dd, J ) 11.7, 2.4 Hz, 1 H), 2.98 (apparent t, J ) 8.4 Hz, 1 H),
2.95 (s, 3 H), 2.75 (d, J ) 7.9 Hz, 1 H), 2.66-2.60 (m, 1 H), 2.51
(ABq, JAB ) 13.1 Hz, ∆υAB ) 26.1 Hz, 2 H), 2.40 (ddd, J ) 15.1, 8.1,
3.2 Hz, 1 H), 2.36 (s, 1 H), 2.13-2.07 (m, 1 H), 2.01-1.94 (m, 3 H),
1.72 (d, J ) 0.9 Hz, 3 H), 1.68-1.65 (m, 1 H), 1.62 (d, J ) 6.0 Hz,
3 H), 1.62 (s, 3 H), 1.52-1.45 (m, 1 H), 1.34 (dd, J ) 12.7, 10.9 Hz,
1 H), 1.30-1.20 (m, 2 H), 1.26 (s, 3 H), 1.08 (d, J ) 5.0 Hz, 3 H),
1.05 (s, 9 H), 0.71 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 169.1,
136.0, 135.8, 134.3, 133.5, 130.8, 130.2, 130.0, 129.7, 129.6, 127.6,
125.5, 125.2, 100.2, 87.0, 81.5, 76.8, 74.2, 66.1, 49.9, 44.5, 43.1, 42.0,
38.7, 38.5, 34.0, 30.8, 28.5, 27.0, 26.3, 22.5, 19.9, 19.1, 17.9, 12.3,
11.4; high-resolution mass spectrum (FAB, NBA matrix) m/z 755.4336
[(M + Na)+; calcd for C44H64O7SiNa 755.4319].
OD) δ 7.68-7.65 (m, 4 H), 7.45-7.36 (m, 6 H), 5.58 (apparent t, J )
6.6 Hz, 1 H), 5.49-5.39 (m, 2 H), 5.39 (d, J ) 10.8 Hz, 1 H), 4.84-
4.77 (m, 1 H), 4.19 (s, 1 H), 4.13 (m, 1 H), 3.72 (d, J ) 10.8 Hz, 1 H),
3.06 (d, J ) 8.7 Hz, 1 H), 2.95 (s, 3 H), 2.62 (ABq, JAB ) 14.1 Hz,
∆υAB ) 185.0 Hz, 2 H), 2.60 (ddd, J ) 15.3, 8.7, 6.6 Hz, 1 H), 2.50-
2.43 (m, 2 H), 2.31-2.24 (m, 1 H), 2.06-1.99 (m, 1 H), 1.96 (ddd, J
) 11.2, 4.9, 1.8 Hz, 1 H), 1.92-1.70 (m, 3 H), 1.63 (s, 3 H), 1.62 (d,
J ) 4.7 Hz, 3 H), 1.59 (d, J ) 0.8 Hz, 3 H), 1.57-1.50 (m, 1 H), 1.39
(apparent q, J ) 11.9 Hz, 1 H), 1.05 (s, 9 H), 0.954 (t, J ) 8.0 Hz, 9
H), 0.949 (s, 3 H), 0.948 (d, J ) 5.6 Hz, 3 H), 0.89 (s, 3 H), 0.60 (q,
J ) 7.9 Hz, 6 H); 13C NMR (125.8 MHz, CD3OD) δ 171.0, 139.0,
136.92, 136.89, 135.41, 135.35, 131.7, 131.4, 131.1, 130.9, 128.8, 128.7,
126.7, 126.5, 101.0, 83.4, 75.9, 75.0, 68.9, 68.0, 46.0, 44.3, 43.8, 40.3,
38.0, 34.9, 31.8, 29.9, 27.6, 26.5, 22.6, 20.2, 19.9, 18.1, 14.1, 13.7,
7.5, 6.2; high-resolution mass spectrum (FAB, 1-thioglycerol matrix)
m/z 869.5170 [(M + Na)+; calcd for C50H78O7Si2Na 869.5184].
Ketone (+)-38a. The Dess-Martin periodinane (0.15 g, 0.34 mmol)
was dissolved in CH2Cl2 (10.7 mL), and pyridine (0.14 mL, 1.71 mmol)
was added, producing a clear stock solution which was used within 5
min. At room temperature alcohol (+)-37a (8.4 mg, 9.9 µmol) was
treated with a portion of the periodinane solution (5.01 mL). After an
additional 20 min, the reaction mixture was diluted with ether (5 mL),
and the reaction was quenched with saturated aqueous NaHCO3 and
NaHSO3
(1:1, 5 mL). The resultant mixture was stirred for 5 min,
diluted with ether (20 mL), washed with saturated aqueous NaHCO3
(2 × 10 mL) and brine (15 mL), dried over MgSO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate, 9:1)
furnished (+)-38a (8.0 mg, 96% yield) as a colorless oil: [R]2D5 +112°
(c 0.73, CHCl3); IR (CHCl3) 1705 (s), 1455 (m), 1205 (s), 1110 (s),
1070 (s), 1040 (s), 695 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.68-
7.63 (m, 4 H), 7.44-7.35 (m, 6 H), 5.40 (d, J ) 10.3 Hz, 1 H), 5.25
(apparent t, J ) 6.8 Hz, 1 H), 4.90-4.86 (m, 1 H), 4.18 (s, 1 H), 4.14-
4.08 (m, 1 H), 3.99-3.93 (m, 1 H), 3.67 (d, J ) 11.8 Hz, 1 H), 2.94
(s, 3 H), 2.62 (ABq, JAB ) 14.3 Hz, ∆υAB ) 244.0 Hz, 2 H), 2.27-
2.25 (m, 2 H), 1.97 (ddd, J ) 12.8, 4.8, 1.6 Hz, 1 H), 1.96 (ddt, J )
12.3, 4.4, 2.2 Hz, 1 H), 1.78 (dd, J ) 12.8, 10.7 Hz, 1 H), 1.68-1.57
(m, 1 H), 1.59 (s, 3 H), 1.56 (d, J ) 1.0 Hz, 3 H), 1.41-1.35 (m, 1 H),
1.31-1.23 (m, 6 H), 1.29 (s, 3 H), 1.18 (apparent q, J ) 12.0 Hz, 1
H), 1.04 (s, 9 H), 1.00 (d, J ) 6.7 Hz, 3 H), 0.99 (s, 3 H), 0.96 (t, J
) 8.0 Hz, 9 H), 0.87 (t, J ) 7.0 Hz, 3 H), 0.60 (q, J ) 7.9 Hz, 6 H);
13C NMR (125.8 MHz, CDCl3) δ 214.5, 169.3, 137.6, 135.8, 135.7,
134.5, 134.2, 133.7, 129.7, 127.58, 127.57, 125.2, 123.2, 99.3, 80.1,
74.4, 72.4, 66.4, 56.2, 48.1, 43.5, 42.0, 40.4, 38.7, 33.1, 31.8, 30.7,
26.9, 25.5, 24.2, 22.6, 19.3, 19.0, 18.6, 14.0, 13.5, 13.1, 7.0, 4.9; high-
resolution mass spectrum (FAB, NBA matrix) m/z 869.5168 [(M +
Na)+; calcd for C50H78O7Si2Na 869.5184].
TES Ether (+)-37a. A stock solution was prepared at 0 °C by
dissolving 2,6-lutidine (57 µL, 0.49 mmol) and triethylsilyl trifluo-
romethanesulfonate (50 µL, 0.22 mmol) in CH2Cl2 (14.7 mL), and a
portion (2.2 mL) was then added to a flask containing diol (+)-36a
(8.0 mg, 10.9 µmol) at -78 °C. The reaction mixture was stirred for
an additional 20 min, and the reaction was quenched with MeOH (15
µL) and diluted with Et2O (10 mL). The organic phase was washed
with 0.1 M aqueous NaHSO4 (4 mL) and brine (4 mL), dried over
MgSO4, filtered, and concentrated. Flash chromatography (hexanes/

10946 J. Am. Chem. Soc., Vol. 119, No. 45, 1997
Smith et al.
Ketone (+)-38b. Alcohol (+)-37b (10.0 mg, 11.8 µmol) was
oxidized via the same procedure described above for the preparation
of (+)-38a; in this case, the reaction mixture was stirred for 15 min
after the addition of the periodinane. Workup and flash chromatography
(+)-Acutiphycin (1). A stock solution was prepared by addition
of HOAc (0.15 mL) to a solution of tetrabutylammonium fluoride in
THF (1.0 M, 2.5 mL). BPS ether (+)-39a (6.0 mg, 8.3 µmol) was
dissolved in THF (3.3 mL) and treated with a portion of the stock
solution (1.5 mL). After 42 h at room temperature, the reaction mixture
was diluted with ethyl acetate (25 mL), washed with saturated aqueous
NaHCO3 (2 × 15 mL) and brine (15 mL), dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexane/ethyl acetate, 2:1)
afforded (+)-1 (3.8 mg, 95% yield) as a colorless, amorphorus solid:
mp 156-158 °C (lit.1 155-156 °C); mmp 155-158 °C; [R]2D5 +158°
as before afforded (+)-38b (9.0 mg, 90% yield) as a colorless oil: [R
25
D
]
+119° (c 0.20, CHCl3); IR (CHCl3) 1705 (s), 1455 (m), 1200 (s),
1105 (s), 1065 (s), 1040 (s), 695 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.68-7.63 (m, 4 H), 7.44-7.35 (m, 6 H), 5.46-5.34 (m, 3 H), 5.23
(apparent t, J ) 6.8 Hz, 1 H), 4.92-4.87 (m, 1 H), 4.19 (s, 1 H), 4.14-
4.07 (m, 1 H), 3.99-3.93 (m, 1 H), 3.68 (d, J ) 11.8 Hz, 1 H), 2.94
(s, 3 H), 2.61 (ABq, JAB ) 14.2 Hz, ∆υAB ) 240.4 Hz, 2 H), 2.27-
2.22 (m, 2 H), 2.02-1.89 (m, 3 H), 1.86 (ddt, J ) 12.4, 4.4, 2.2 Hz,
1 H), 1.78 (dd, J ) 12.7, 10.7 Hz, 1 H), 1.73-1.65 (m, 1 H), 1.61
(apparent d, J ) 5.7 Hz, 3 H), 1.59 (s, 3 H), 1.57 (d, J ) 1.0 Hz, 3 H),
1.48-1.41 (m, 1 H), 1.28 (s, 3 H), 1.19 (apparent q, J ) 12.0 Hz, 1
H), 1.04 (s, 9 H), 1.00 (d, J ) 6.6 Hz, 3 H), 0.99 (s, 3 H), 0.96 (t, J
) 8.0 Hz, 9 H), 0.60 (q, J ) 8.0 Hz, 6 H); 13C NMR (125.8 MHz,
CDCl3) δ 214.5, 169.2, 137.7, 135.8, 135.7, 134.4, 134.2, 133.7, 130.1,
129.7, 127.6, 125.4, 125.3, 123.0, 99.3, 80.0, 73.9, 72.5, 66.4, 56.2,
48.2, 43.4, 41.9, 40.4, 38.7, 32.9, 30.7, 28.8, 26.9, 24.2, 19.2, 19.0,
18.6, 17.9, 13.5, 13.1, 7.0, 4.9; high-resolution mass spectrum (FAB,
1-thioglycerol matrix) m/z 867.5039 [(M + Na)+; calcd for C50H76O7-
Si2Na 867.5027].
(c 0.35, CH2Cl2) {lit.1 [R]25 +107° (c 1.0, CH2Cl2)}; IR (CHCl3) 3605
D
(w), 3460 (w, br), 3015 (m), 2960 (m), 2935 (s), 2855 (m), 1705 (s),
1470 (w), 1450 (m), 1430 (m), 1415 (m), 1370 (m), 1330 (w), 1280
(w), 1220 (s), 1200 (s), 1150 (m), 1060 (m), 1030 (m), 1015 (m), 1000
1
(m), 900 (m), 700 (m) cm-1; H NMR [500 MHz, C6D6/CDCl3 (1:1)]
δ 5.35 (d, J ) 2.0 Hz, 1 H), 5.21 (apparent d, J ) 9.6 Hz, 1 H), 5.16
(apparent dd, J ) 11.0, 1.3 Hz, 1 H), 4.90 (dddd, J ) 11.4, 8.2, 4.5,
2.1 Hz, 1 H), 4.52 (br s, 1 H), 4.17 (dd, J ) 11.9, 2.1 Hz, 1 H), 4.00
(tt, J ) 11.1, 4.6 Hz, 1 H), 3.86 (dq, J ) 11.1, 6.6 Hz, 1 H), 2.40 (d,
J ) 14.5 Hz, 1 H), 2.27 (d, J ) 14.5 Hz, 1 H), 2.20 (ddd, J ) 15.2,
10.6, 2.1 Hz, 1 H), 1.96 (apparent d, J ) 13.1 Hz, 1 H), 1.90 (ddd, J
) 11.9, 4.6, 1.6 Hz, 1 H), 1.62 (d, J ) 1.4 Hz, 3 H), 1.54 (ddt, J )
14.3, 4.5, 1.8 Hz, 1 H), 1.44 (t, J ) 1.2 Hz, 3 H), 1.30 (m, 1 H), 1.17
(m, 8 H), 1.10 (s, 3 H), 1.03 (d, J ) 6.5 Hz, 3 H), 0.99 (td, J ) 12.9,
2.0 Hz, 1 H), 0.85 (s, 3 H), 0.80 (t, J ) 7.0 Hz, 3 H); 13C NMR (125.8
MHz, DMSO-d6) δ 214.4, 170.8, 136.1, 134.9, 128.1, 123.6, 96.1, 77.3,
74.1, 73.7, 62.6, 53.0, 45.9, 43.5, 41.2, 38.2, 34.3, 31.7, 30.9, 24.3,
23.3, 21.8, 20.5, 16.6, 13.8, 12.8, 11.8; high-resolution mass spectrum
(FAB, NBA matrix) m/z 503.2972 [(M + Na)+; calcd for C27H44O7Na
503.2985].
(+)-trans-20,21-Didehydroacutiphycin (2). BPS ether (+)-39b (6.0
mg, 8.4 µmol) was desilylated via the general procedure described above
for the preparation of (+)-1; in this case, the reaction time was 50 h.
Workup and flash chromatography as before furnished (+)-2 (3.7 mg,
92% yield) as a colorless, amorphorus solid: mp 155-156 °C (lit.1
153-154 °C); mmp 154-156 °C; [R]2D5 +130.9° (c 0.23, CHCl3) {lit.1
[R]2D5 +110° (c 1.0, MeOH)}; IR (CHCl3) 3600 (w), 3440 (w, br),
3010 (m), 2930 (s), 2850 (m), 1735 (m), 1700 (s), 1510 (w), 1445
(m), 1425 (m), 1370 (m), 1325 (w), 1205 (s), 1145 (m), 1100 (m),
1055 (m), 1025 (m), 1015 (m), 995 (m), 900 (s), 710 (s, br), 655 (m)
cm-1; 1H NMR [500 MHz, C6D6/CDCl3 (1:1)] δ 5.35-5.23 (m, 2 H),
5.31 (d, J ) 2.5 Hz, 1 H), 5.18 (apparent d, J ) 9.5 Hz, 1 H), 5.14
(apparent dd, J ) 11.1, 1.2 Hz, 1 H), 4.89 (dddd, J ) 11.0, 8.4, 4.3,
2.1 Hz, 1 H), 4.49 (d, J ) 2.7 Hz, 1 H), 4.15 (dd, J ) 12.0, 2.2 Hz, 1
H), 3.99 (tt, J ) 11.1, 4.9 Hz, 1 H), 3.84 (dq, J ) 11.1, 6.6 Hz, 1 H),
2.39 (d, J ) 14.6 Hz, 1 H), 2.26 (d, J ) 14.6 Hz, 1 H), 2.19 (ddd, J
) 13.1, 10.6, 2.1 Hz, 1 H), 1.94 (apparent d, J ) 13.3 Hz, 1 H), 1.90
(ddd, J ) 11.9, 4.6, 1.7 Hz, 1 H), 1.85 (apparent q, J ) 7.0 Hz, 2 H),
1.60 (d, J ) 1.3 Hz, 3 H), 1.54 (ddt, J ) 12.2, 4.2, 1.9 Hz, 1 H), 1.52
(dd, J ) 5.8, 0.8 Hz, 3 H), 1.42 (s, 3 H), 1.40-1.33 (m, 1 H), 1.13 (m,
2 H), 1.07 (s, 3 H), 1.01 (d, J ) 6.5 Hz, 3 H), 0.99 (td, J ) 11.7, 2.5
Hz, 1 H), 0.82 (s, 3 H); 13C NMR (125.8 MHz, DMSO-d6) δ 214.4,
170.7, 136.2, 134.9, 130.2, 128.0, 124.9, 123.4, 96.1, 77.3, 74.1, 73.3,
62.6, 53.0, 45.9, 43.5, 41.2, 38.2, 34.1, 31.5, 27.9, 23.2, 20.6, 17.6,
16.7, 12.9, 11.8; high-resolution mass spectrum (FAB, 1-thioglycerol
matrix) m/z 501.2806 [(M + Na)+; calcd for C27H42O7Na 501.2828].
Alcohol (+)-39a. At ambient temperature, TES ether (+)-38a (8.0
mg, 9.4 µmol) was treated with 49% aqueous HF in CH3CN (1:9, 0.71
mL) in one portion. After 3 min, the reaction mixture was diluted
with ether (5 mL), and the reaction was quenched with saturated
aqueous NaHCO3 (2 mL). Additional ether (10 mL) was then added,
and the organic phase was washed with saturated aqueous NaHCO3 (5
mL) and brine (5 mL), dried over MgSO4, filtered, and concentrated.
Flash chromatography (hexanes/ethyl acetate, 5:1) gave (+)-39a (6.0
mg, 88% yield) as a colorless amorphous solid: mp 138-139 °C;
[R]2D5 +131° (c 0.55, CHCl3); IR (CHCl3) 3440 (w, br), 3005 (m),
1
2955 (s), 2930 (s), 1700 (s), 1455 (m), 1105 (s) cm-1; H NMR (500
MHz, CDCl3) δ 7.67-7.65 (m, 4 H), 7.43-7.35 (m, 6 H), 5.25 (d, J
) 9.5 Hz, 1 H), 5.17 (dd, J ) 11.0, 1.2 Hz, 1 H), 5.13 (d, J ) 2.5 Hz,
1 H), 4.96-4.90 (m, 1 H), 4.60 (s, 1 H), 4.33-4.26 (m, 1 H), 4.12
(dd, J ) 11.8, 2.2 Hz, 1 H), 3.92-3.86 (m, 1 H), 2.53 (ABq, JAB
)
14.6 Hz, ∆υAB ) 47.5 Hz, 2 H), 2.39 (ddd, J ) 15.2, 10.6, 2.0 Hz, 1
H), 2.08 (apparent t, J ) 12.8 Hz, 1 H), 1.98 (ddt, J ) 12.1, 4.6, 1.4
Hz, 1 H), 1.74 (d, J ) 1.2 Hz, 3 H), 1.72-1.65 (m, 1 H), 1.64 (s, 3 H),
1.64-1.51 (m, 5 H), 1.35 (td, J ) 12.7, 2.5 Hz, 1 H), 1.30-1.18 (m,
5 H), 1.09 (s, 3 H), 1.06 (s, 9 H), 1.01 (d, J ) 6.6 Hz, 3 H), 0.87 (t,
J ) 7.0 Hz, 3 H), 0.83 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ
215.4, 172.4, 135.7, 135.1, 134.7, 134.3, 130.6, 129.7, 127.6, 126.4,
96.6, 79.7, 75.8, 74.1, 66.1, 52.6, 44.6, 44.1, 43.1, 38.3, 35.3, 32.6,
31.5, 27.0, 25.5, 24.9, 22.5, 19.2, 19.1, 16.0, 13.9, 12.9, 11.1; high-
resolution mass spectrum (FAB, NBA matrix) m/z 741.4175 [(M +
Na)+; calcd for C46H62O7SiNa 741.4163].
Alcohol (+)-39b. TES ether (+)-38b (8.5 mg, 10.0 µmol) was
desilylated via the same procedure described above for the preparation
of (+)-39a; in this case, the reaction time was 2 min. Workup and
flash chromatography as before afforded (+)-39b (6.4 mg, 89% yield)
as a colorless amorphous solid: mp 136-137 °C; [R]2D5 +136.4° (c
0.55, CHCl3); IR (CHCl3) 3450 (w, br), 2930 (s), 1700 (s), 1445 (m),
1
1110 (s), 1000 (s) cm-1; H NMR (500 MHz, CDCl3) δ 7.71-7.65
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through grant GM-33833. In addition, we
thank Drs. George T. Furst and Patrick J. Carroll and Mr. John
Dykins of the University of Pennsylvania Spectroscopic Service
Center for assistance in securing and interpreting high-field
NMR spectra, X-ray crystal structures, and mass spectra,
respectively.
(m, 4 H), 7.44-7.35 (m, 6 H), 5.44-5.32 (m, 2 H), 5.24 (apparent d,
J ) 9.3 Hz, 1 H), 5.17 (dd, J ) 11.0, 1.1 Hz, 1 H), 5.11 (d, J ) 2.5
Hz, 1 H), 4.96-4.91 (m, 1 H), 4.59 (d, J ) 2.9 Hz, 1 H), 4.32-4.26
(m, 1 H), 4.11 (dd, J ) 11.8, 2.2 Hz, 1 H), 3.92-3.86 (m, 1 H), 2.52
(ABq, JAB ) 14.6 Hz, ∆υAB ) 52.9 Hz, 2 H), 2.39 (ddd, J ) 13.1,
10.6, 2.1 Hz, 1 H), 2.08 (apparent t, J ) 12.7 Hz, 1 H), 2.01-1.93 (m,
3 H), 1.74 (d, J ) 1.2 Hz, 3 H), 1.72-1.69 (m, 1 H), 1.67-1.63 (m,
1 H), 1.63 (s, 3 H), 1.62 (d, J ) 6.4 Hz, 3 H), 1.62-1.56 (m, 2 H),
1.38-1.33 (m, 2 H), 1.26 (s, 1 H), 1.09 (s, 3 H), 1.06 (s, 9 H), 1.01 (d,
J ) 6.5 Hz, 3 H), 0.83 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ
215.4, 172.3, 135.7, 135.1, 134.8, 134.3, 130.6, 129.8, 129.7, 127.6,
126.2, 125.8, 96.6, 79.7, 75.7, 73.6, 66.1, 52.6, 44.6, 44.0, 43.1, 38.3,
35.1, 32.6, 28.4, 27.0, 25.5, 19.15, 19.13, 17.9, 16.0, 12.9, 11.1; high-
resolution mass spectrum (FAB, 1-thioglycerol matrix) m/z 739.4015
[(M + Na)+; calcd for C46H60O7SiNa 739.4006].
Supporting Information Available: Characterization data
for i, 3a, 3b, 5, 6, 8, 11, 12, 14, 15, 17, 18, 23, 25-31, 32a-
34a, and 32b-34b (12 pages). See any current masthead page
for ordering and Internet access instructions.
JA972497R