Total synthesis of clathculins A and B

Article abstract of DOI:10.1021/jo100971j

Clathculins A and B represent a new class of vic-diamine alkaloids containing a PA2 unit as the basic structure. We report the first total syntheses of 1 and 2, which confirm the assigned structure of each. Dependence of their NMR spectroscopic behavior a

Full text of DOI:10.1021/jo100971j

pubs.acs.org/joc
natural product to have a terminal CH2dCH(CH2)2CHd
Total Synthesis of Clathculins A and B
CHCtCCH2- subunit.
Given these unique structural features as well as their
inherent inseparability, we decided to prepare each of the
natural products by chemical synthesis. Our retrosynthetic
approach is shown above. It was anticipated that palladium-
catalyzed coupling of alkyne B with the appropriate vinyl
iodide A or A0 would create a precursor for C-N bond
formation with commercially available N,N0-dimethylethy-
lenediamine (C).
Rebecca C. Hoye,* Gretchen L. Anderson,
Susan G. Brown, and Erica E. Schultz
Department of Chemistry, Macalester College, 1600
Grand Avenue, Saint Paul, Minnesota 55105, United States
hoye@macalester.edu
Received May 30, 2010
The R,ω-alkynyl alcohol (B) was prepared as shown in
Scheme 1. The dianion of propargyl alcohol was generated in
THF and treated with 1-bromooctane in DMPU3 to yield
3-undecyn-1-ol (3) in 60% yield. Zipper isomerization to the
terminal alkyne B was effected in 87% yield in THF with 5.0
equiv of diaminopropane in the presence of 4.0 equiv of
n-BuLi and 4.0 equiv of t-BuOK. These conditions are
operationally simpler than the standard zipper isomerization
conditions4 and also avoid the use of noxious 1,3-diamino-
propane as the reaction solvent.
SCHEME 1. Preparation of Compound B
Clathculins A and B represent a new class of vic-diamine
alkaloids containing a PA2 unit as the basic structure. We
report the first total syntheses of 1 and 2, which confirm
the assigned structure of each. Dependence of their NMR
spectroscopic behavior as a function of protonation state
has been observed.
Vinyl iodides A and A0 were prepared as shown in Scheme 2.
Following a strategy first reported by Kluge, Untch, and
Fried,5 1-iodohexyne,6 4, was reduced with diimide7 to give
(Z)-1-iodohexene, A, in 55% yield. Similarly, 5-hexyn-1-ol
was converted to iodide 58 and reduced with diimide to give
6. Formation of the tosylate9 7 and conversion to the selenide
8 followed by oxidation and elimination10 afforded A0.
Clathculins A and B were obtained as shown in Scheme 3.
Sonogashira coupling11 of iodide A or A0 with B afforded the
enynes 9 and 10, respectively. Formation of the correspond-
ing tosylates 11 and 12 and reaction of each with N,N0-
dimethylethylenediamine afforded clathculins A (1) and B
(2), respectively.
Clathculins A and B were isolated from the Indo-Pacific
sponge Clathrina aff. reticulum collected in Sodwana Bay,
South Africa.1 They were described as an unstable (and, not
surprisingly, inseparable) mixture of compounds 1 and 2.1
Structures were assigned on the basis of NMR spectroscopy
(COSY, TOCSY, and HMBC correlations) of the mixture as
well as by acetylation and reduction to the common satu-
rated analog. Clathculins A and B are the first reported
examples of acyclic long-chain marine metabolites contain-
ing a >NCH2CH2N< (PA2) moiety.2 Additionally, there
appear to be no known examples of natural substances
containing the array of substituents R1R2NCH2CH2NHR3
where R1, R2, and R3 are any combination of Me and
-CH2R substituents. This contrasts with the 1,3-diamino-
propane (PA3) and 1,4-diaminobutane (PA4) elements com-
mon to the spermidine and spermine classes of polyamines.
Other key structural features are the presence of an internal
enyne moiety in a C-17 chain and the differentiating alkene
vs alkane chain termini. Clathculin A is the only known
(3) Kaiser, A.; Marazano, C.; Maier, M. J. Org. Chem. 1999, 64, 3778–
3782.
(4) Abrams, S. R.; Shaw, A. C. Organic Syntheses; Wiley & Sons: New
York, 1993; Collect. Vol. No. 8, pp 146-148.
(5) Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc. 1972, 94,
9256–9258.
(6) Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083–1090.
(7) Paquette, L. A.; Browne, A. R.; Chamot, E.; Blount, J. F. J. Am. Chem.
Soc. 1980, 102, 643–651. Pasto, D. J.; Taylor, R. L. In Organic Syntheses;
Paquette, L. A., Ed.; Wiley & Sons: New York, 1991; Vol. 40, pp 91-155.
(8) Denmark, S. E.; Yang, S. M. Tetrahedron 2004, 60, 9695–9708.
(9) Kabalka, G. W.; Varma, M.; Varma, R. S. J. Org. Chem. 1986, 51,
2386–2388.
(1) Rudi, A.; Schleyer, M.; Kashman, Y. J. Nat. Prod. 2000, 63, 1434–
(10) Chakraborty, T. K.; Mohan, B. K. Tetrahedron Lett. 2006, 47, 4999–
5002.
(11) Chackalamannil, S.; Davies, R.; McPhail, A. T. Org. Lett. 2001, 3,
1427–1429.
1436.
(2) Bienz, S.; Bisegger, P.; Guggisberg, A.; Hesse, M. Nat. Prod. Rep.
2005, 22, 647–658.
7400 J. Org. Chem. 2010, 75, 7400–7403
Published on Web 10/11/2010
DOI: 10.1021/jo100971j
r
2010 American Chemical Society

Hoye et al.
JOCNote
TABLE 1. 1H NMR Data (300 MHz) of Clathculins A and B (1 and 2) in CDCl3
SCHEME 2. Preparation of Vinyl Iodides A and A0
SCHEME 3. Convergent Couplings Leading to 1 and 2
1H NMR chemical shifts data for selected protons of 1 and
2 in CDCl3 (synthetic vs natural1) and in 2% TFA in CDCl3
(synthetic) are shown in Table 1. Our initial concern over
differences in chemical shifts between those reported for
natural vs those we observed for the synthetic samples led
us to probe the question of protonation. It has been shown
that chemical shifts of protons12 and carbons13 in close
proximity to amines are dependent on degree of protonation.
To give confidence that we were observing the free-base
forms of the synthetic materials, the crude reaction pro-
ducts were chromatographed on silica gel using CMA
[chloroform/methanol/ammonia (83: 17: 0.5)] as eluent,
(12) Rabenstein, D. L.; Sayer, T. L. Anal. Chem. 1976, 48, 1141–1146.
(13) Hague, D. N.; Moreton, A. D. J. Chem. Soc., Perkin Trans. 2 1994,
265–270.
J. Org. Chem. Vol. 75, No. 21, 2010 7401

Hoye et al.
JOCNote
and the NMR spectra were recorded in CDCl3 that had been
stored over K2CO3. We have investigated the 1H NMR
spectral behavior of clathculins A and B in CDCl3 in the
presence of 2% trifluoroacetic and 2% acetic acid-d4. Upon
addition of trifluoroacetic acid (2% TFA in CDCl3), full (i.e.,
double) protonation of clathculins was observed, as judged
by the diastereotopic nature of the methylene protons at C1
and at C10 adjacent to the stereogenic nitrogen of the tertiary
ammonium ion. The salient differences are highlighted in
gray boxes. In contrast, in the presence of the weaker acetic
acid, less than full protonation was observed (see the Sup-
porting Information). The chemical shifts reported for the
natural sample1 fall between those we observed for the free-
base versus in the presence of either TFA or AcOH. The most
reasonable explanation is that the spectral data for the
natural material were recorded for a sample that was slightly
protonated.
Although the natural material was described as a mixture
of two unstable compounds,1 we have not observed instabil-
ity with either crude or purified synthetic samples in either
the free-base or protonated forms. We do not have a good
explanation for the original observations; our samples of
clathculins A and B, each in 2% TFA in CDCl3, were allowed
to stand at room temperature for 3 weeks, during which time
they showed no evidence of change by 1H NMR analysis.
We have achieved a convergent synthesis of the natural
enyne diamines clathculins A (1) and B (2). We have also
shown the value of recording and reporting NMR data of
basic amine-containing compounds both as the free-base as
well as in the presence of excess acid (here 2% TFA in
CDCl3).
2.10 (ddt, J = 1.1, 7.0, 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ
144.6, 140.2 133.0, 129.8, 127.8, 83.1, 70.1, 33.7, 28.0, 23.6, 21.5;
HRMS (ESI) calcd for C13H17IO3S [M þ Na]þ 402.9835, found
402.9858.
(Z)-(6-Iodohex-5-en-1-yl)(phenyl)selane (8). With modifica-
tion of a literature procedure,15 diphenyl diselenide (4.92 g,
15.8 mmol, 0.6 equiv) in 200 mL of absolute ethanol was treated
with NaBH4 (1.45 g, 38.2 mmol) in portions until the solution
became colorless. The solution was cooled in an ice bath, and a
solution of 7 (10.03 g, 26.3 mmol, 1 equiv) in 30 mL of THF was
added. The reaction was gradually warmed to room tempera-
ture and stirred overnight. The reaction mixture was poured into
500 mL of 5% Na2CO3 and 100 mL of brine and extracted with
Et2O. The combined organic extracts were washed with brine,
dried (MgSO4), filtered, and evaporated in vacuo. Purification
by flash chromatography (hexanes) afforded a light yellow oil
(7.27 g, 20.0 mmol, 76%): IR (neat) 3069, 3014, 2929, 2853,
1
1609, 1578 cm-1; H NMR (CDCl3, 300 MHz) δ 7.58 - 7.45
(m), 7.29 - 7.23 (m), 6.19 (dt, J = 7.3, 11.1 Hz), 6.13 (dt, J = 7.2,
6.3 Hz), 2.93 (t, J = 7.6 Hz), 2.15 (q, J = 7.1 Hz), 1.75 (quintet,
J = 7.2 Hz) 1.56 (quintet, J = 7.3 Hz); 13C NMR (CDCl3, 75
MHz) δ 140.7, 132.5, 130.3, 128.9, 126.7, 82.8, 34.0, 29.4, 27.9,
27.6; GC-MS 366 (Mþ), 239 (base, Mþ - I).
(Z)-1-Iodohexa-1,5-diene (A0). m-CPBA (478 mg, 2.31 mmol,
1.2 equiv) was added portionwise to a solution of 8 (839 mg, 2.31
mmol, 1 equiv) in 5 mL of CH2Cl2 at 0 °C. The solution was
stirred for 15 min, diluted with 10 mL of CH2Cl2, and extracted
with satd NaHCO3. The organic solution was washed with
brine, dried (MgSO4), filtered, and evaporated in vacuo to give
a light yellow oil that was dissolved in 3 mL of CH2Cl2 and
added to a refluxing solution of 10 mL CCl4 and diisopropyla-
mine (270 mg, 0.390 mL, 2.77 mmol, 1.2 equiv). After being
refluxed for 30 min, the reaction mixture was poured into 30 mL
of water and the aqueous layer extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried
(MgSO4), filtered, and evaporated in vacuo to give a bright
orange oil that was purified by flash chromatography (pentane)
to yield A0 as a colorless liquid (235.0 mg, 1.13 mmol, 49%): IR
(neat) 3076, 2979, 2924, 2847, 1641, 2609, 1440 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 6.23-6.14 (m, 2H), 5.82 (ddt, J = 17.1,
10.2, 6.4 Hz), 5.04 (ddt, J = 17.2, 1.8, 1.6 Hz), 5.00 (ddt, 10.2,
1.9, 1.1 Hz), 2.28-2.13 (m, 4H); 13C NMR (CDCl3, 75 MHz)
δ 140.5, 137.4, 115.3, 82.7, 33.9, 32.0; GC-MS 208 (Mþ), 126
(M - C3H5)þ, 81 (M - I)þ.
Experimental Section
Undec-10-yn-1-ol (B). To a solution of 1,3-diaminopropane
(2.40 g, 2.7 mL, 32.3 mmol, 5.0 equiv) in 10 mL of THF at 0 °C
was added dropwise n-BuLi (2.48 M in hexanes, 10.5 mL,
26.0 mmol, 4.0 equiv). The resulting mixture was stirred for
20 min, and t-BuOK (1.0 M in THF, 26.0 mL, 26.0 mmol, 4.0
equiv) was added dropwise. The resulting yellow solution was
warmed to room temperature, and 3 (1.08 g, 6.51 mmol, 1 equiv)
in 2.0 mL of THF was added dropwise via cannula. The solution
was stirred for 3 h (red-brown color), poured into 100 mL of satd aq
NH4Cl, and extracted with ether. The combined organic extracts
were washed with 5% HCl, satd aq NaHCO3, and brine, dried
(MgSO4), filtered, and evaporated in vacuo. Flash chromatography
[hexanes/ethyl acetate (8:2)] afforded B14 as a colorless liquid
(0.94 g, 5.66 mmol, 87%).
(Z)-6-Iodohex-5-en-1-yl 4-methylbenzenesulfonate (7). Com-
pound 6 (13.85 g, 61.3 mmol, 1 equiv), Et3N (17.00 mL, 122.6
mmol, 2.0 equiv), and DMAP (375 mg, 3.1 mmol, 0.5 equiv) were
combined in 150 mL of CH2Cl2 and cooled to 0 °C. p-Toluene-
sulfonyl chloride (17.46 g, 91.9 mmol, 1.5 equiv) was added in one
portion. The solution was allowed to warm to room temperature
and stirred overnight. Saturated aq NaHCO3 was added, and
the mixture was extracted with EtOAc. The combined extracts
were washed with brine, dried (MgSO4), filtered, and evaporated in
vacuo. Purification by flash chromatography [hexanes/ethyl ace-
tate (8:2)] provided 7 as a yellow oil (20.48 g, 53.0 mmol, 88%): IR
(neat) 3294, 3066, 2945, 2865, 1598 cm-1; 1H NMR (CDCl3, 300
MHz) δ7.81 (d, J = 8.4 Hz), 7.36 (d, J= 8.1 Hz), 6.26 (dt, J =7.3,
1.4 Hz), 6.08 (dt, J = 7.1, 7.0 Hz), 4.04 (t, J = 6.3 Hz,), 2.45 (s),
(Z)-Heptadeca-12,16-dien-10-yn-1-ol (9). PdCl2(PhCN)2
(52.0 mg, 0.136 mmol, 0.05 equiv) and CuI (52 mg, 0.272 mmol,
0.10 equiv) were combined and purged with argon. Pyrrolidine
(2 mL) was added, and after the mixture was stirred for 5 min,
the iodide A0 (680.0 mg, 3.27 mmol, 1.2 equiv) in 1 mL of
pyrrolidine was added followed by the addition of alkyne
B (451.5 mg, 2.72 mmol, 1.0 equiv) in 1 mL of pyrrolidine.
The solution was stirred overnight in the dark and then poured
into 50 mL of satd aq NH4Cl. The mixture was extracted
(EtOAc), and the combined extracts were washed with water
and brine, dried (MgSO4), filtered, and evaporated in vacuo.
Purification by flash chromatography [hexanes/ethyl acetate
(8:2)] gave a colorless oil (541.1 mg, 2.18 mmol, 80%): IR (neat)
1
3332, 3077, 3021, 2931, 2855, 2212, 1641, 1617, 1465 cm-1; H
NMR (CDCl3, 300 MHz) δ 5.83 (ddt, J = 17.3, 10.2, 6.5 Hz), 5.82
(dt, J = 10.6, 7.2 Hz), 5.46 (dtt, J = 10.6, 2.2, 1.5 Hz), 5.04 (ddt,
J = 17.1, 1.9, 1.6 Hz), 4.98 (ddt, J = 10.2, 2.0, 1.3 Hz), 3.64 (t, J =
6.5 Hz), 2.39 (ddt, J = 7.3, 1.5, 7.3 Hz), 2.34 (dt, J = 6.9, 2.2 Hz),
2.16 (br dt, J = 6.5, 7.5 Hz), 1.60-1.28 (m, 14H); 13C NMR
(CDCl3, 75 MHz) δ 141.4, 138.0, 114.8, 109.8, 94.8, 77.2, 63.0, 32.9,
32.8, 29.5, 29.3, 29.2, 29.0, 28.8, 25.7, 19.5; HRMS (ESI) calcd for
C17H28O [M þ Na]þ 271.2032, found 271.2004.
(14) Poleschner, H.; Heydenreich, M. Magn. Reson. Chem. 1995, 33, 917–
921.
(15) Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1976, 41, 1396–1403.
7402 J. Org. Chem. Vol. 75, No. 21, 2010

Hoye et al.
JOCNote
(Z)-Heptadeca-12-en-10-yn-1ol (10). According to the proce-
dure for 9, iodide A (1.87 g, 8.9 mmol, 1.5 equiv) and alkyne
B (986 mg, 5.94 mmol, 1.0 equiv) were added to a solution of
PdCl2(PhCN)2 and CuI (113 mg, 0.594 mmol, 0.1 equiv) in
10.0 mL of pyrrolidine. Flash chromatography of the crude
reaction mixture gave the product (1.095 g, 4.41 mmol, 74%) as
a colorless oil: IR (neat) 3333, 3020, 2928, 2856, 2215, 1617, 1465
cm-1; 1H NMR (300 MHz, CDCl3) δ 5.82 (dt, J = 10.7, 7.4 Hz),
5.44 (dtt, J = 10.7, 2.2, 1.4 Hz), 3.63 (dt, J = 3.3, 6.4 Hz, CH2OH),
2.33 (dt, J=2.2, 7.0Hz), 2.29(ddt,J= 7.4, 1.5, 7.3), 1.60-1.46 (m,
4H), 1.44-1.25 (m, 12H), 0.90 (t, J = 7.1 Hz); 13C NMR (75 MHz,
CDCl3) δ 142.6, 109.3, 94.4, 77.4, 63.0, 32.8, 31.0, 29.7, 29.5, 29.4,
29.1, 28.84, 28.82, 25.7, 22.3, 19.5, 13.9; HRMS (ESI) Calcd for
C17H30O [M þ Na]þ 273.2189, found 273.2187.
of satd aq NaHCO3. The aqueous solution was extracted with
ethyl acetate. The combined organic layers were washed with
brine, dried (Na2SO4), filtered, and evaporated in vacuo.
Purification by flash chromatography [CMA: chloroform/
methanol/ammonia (83:17:0.5)] gave two components, the less
polar dialkylated diamine 13 (81.0 mg, see the Supporting Informa-
tion for complete characterization) and clathculin A (374.6 mg, 1.18
mmol, 77%). These two compounds had Rf values of 0.40 and
0.05 in CMA: IR (neat) 3328, 3077, 3020, 2929, 2854, 2797, 2212,
1641, 1470 cm-1 1HNMR (CDCl3, 300 MHz) δ 5.84 (ddt,
;
J = 17.1, 10.3, 6.5 Hz, H2CdCH), 5.83 (dt, J = 10.7, 7.2 Hz,
CHdCHCtC), CH2CHdCHCtC), 5.47 (dtt, J = 10.7, 2.2, 1.4
Hz, CHdCHCtC), 5.05 (ddt, J = 17.1, 1.9, 1.6 Hz, HCHdCH),
4.97 (ddt, J = 10.2, 2.1, 1.2 Hz, HCHdCH), 2.68 (t, J = 6.2,
NCH2CH2N), 2.49 (t, J = 6.2, NCH2CH2N), 2.47 (s, NCH3), 2.39
(ddt, J = 7.3, 1.5, 7.5, CH2CHdCHCtC), 2.34 (∼t with some
evidence of nonfirst order character, J = 7.0 Hz, CH2CH2CH2N),
2.33 (dt, J = 2.2, 7.0, CtCCH2), 2.16 (dddt, J = 6.5, 1.6, 1.2, 7.5,
CH2dCHCH2), 1.58-1.22 (m, 7 CH2); 13C NMR (75 MHz,
CDCl3) δ 141.3, 137.9, 114.7, 109.8, 94.8, 77.2, 58.1, 56.7, 49.2,
42.2, 36.2, 29.46, 29.44, 29.21, 29.20, 29.03, 28.78, 28.76, 27.4, 27.3,
19.4; HRMS (ESI) calcd for C21H38N2 [M þ H]þ 319.3108, found
319.3111.
(Z)-Heptadeca-12,16-dien-10-yn-1-yl 4-Methylbenzenesulfo-
nate (11). According to the procedure for 7, p-toluenesulfonyl
chloride (564.2 mg, 2.97 mmol, 1.5 equiv), alcohol 9 (491.1 mg,
1.98 mmol, 1.0 equiv), Et3N (400 mg, 0.55 mL, 3.96 mmol,
2.0 equiv), and DMAP (12.2 mg, 0.10 mmol, 0.05 equiv) were
reacted in 5 mL of CH2Cl2. Purification of the crude reaction
mixture by flash chromatography [hexanes/ethyl acetate (8:2)]
gave 11 as a colorless oil (693.0 mg, 1.72 mmol, 87%): IR (neat)
3075, 3021, 2929, 2856, 2211, 1640, 1599, 1465 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.79 (d, J = 8.3 Hz), 7.34 (d, J = 8.3 Hz),
5.83 (ddt, J = 17.0, 10.2, 6.5), 5.82 (dt, J = 10.6, 7.2 Hz), 5.46
(dtt, J = 10.7, 2.1, 1.4 Hz), 5.04 (ddt, J = 17.1, 1.9, 1.7 Hz), 4.98
(ddt, J = 10.2, 1.9, 1.3 Hz), 4.02 (t, J = 7.3 Hz), 2.45 (s), 2.39
(ddt, J = 7.3, 1.5, 7.3 Hz), 2.33 (dt, J = 7.0, 2.2 Hz), 2.16 (dddt,
J = 6.5, 1.5, 1.5, 2.5 Hz), 1.68-1.46 (m, 4H), 1.43-1.29 (m,
12H); 13C NMR (CDCl3, 75 MHz) δ 144.6, 141.4, 138.0, 133.2,
129.7, 127.8, 114.8, 109.8, 94.7, 77.2, 70.6, 32.9, 29.3, 29.2, 28.8,
28.76, 28.75, 28.73, 25.3, 21.6, 19.5; HRMS (EI) calcd for
C24H34O3S [M þ Na]þ 425.2121, found 425.2120.
Clathculin B (2). Following the procedure for 1, tosylate
10 (536.6.mg, 1.33 mmol, 1 equiv), and N,N0-dimethylethyl-
enediamine (469.9 mg, 0.57 mL, 4.0 equiv) in 5.0 mL of CH3CN
afforded two components upon flash chromatography
[chloroform/methanol/ammonia (83:17:0.5), the less polar dialky-
lated diamine 14 (50.7 mg, see the Supporting Information for full
characterization) and clathculin B (328.1 mg, 1.03 mmol, 78%).
These two compounds had Rf values of 0.40 and 0.05 in CMA: IR
1
(neat) 3329, 3019, 2928, 2854, 2787, 2215, 1466 cm-1; H NMR
(CDCl3, 300 MHz) δ 5.80 (dt, J = 10.7, 7.4 Hz, CH2CHd), 5.43
(dtt, J = 10.7, 2.2, 1.3 Hz, CHdCHCtC), 2.66 (t, J = 6.2 Hz,
NCH2CH2N), 2.50 (t, J = 6.1 Hz, NCH2CH2N), 2.46 (s, NCH3),
2.37-2.25 (m. 6H, 3CH2), 2.20 (s, NCH3), 1.97 (brs, 1H, NH)
1.60-1.23 (m, 9 CH2), 0.91 (t, J = 6.9 Hz, CH3); 13C NMR
(CDCl3, 75 MHz) δ 142.5, 109.3, 94.3, 77.3, 58.1, 56.9, 49.4, 42.3,
36.4, 31.0, 29.7, 29.50, 29.49, 29.1 28.83, 28.82, 27.4, 27.3, 22.2, 19.5,
13.9; HRMS (ESI) calcd for C21H40N2 [M þ H]þ 321.3264, found
321.3270.
(Z)-Heptadeca-12-en-10-yn-1-yl 4-Methylbenzenesulfonate (12).
According to the procedure for 7, p-toluenesulfonyl chloride
(912 mg, 4.80 mmol, 1.5 equiv), alcohol 10 (794.7 mg, 3.20 mmol,
1 equiv), Et3N (646 mg, 0.87 mL, 6.4 mmol, 2.0 equiv), and DMAP
(19.5 mg, 0.16 mmol, 0.05 equiv) were reacted in 10 mL of CH2Cl2.
Purification by flash chromatography [hexanes/ethyl acetate (8:2)]
gave 12 as a light yellow oil (1.0885 g, 2.50 mmol, 84%): IR (neat)
1
3019, 2028, 2857, 2213, 1653, 1599, 1495, 1465 cm-1; H NMR
(CDCl3, 300 MHz) δ7.78 (d, J=8.4Hz), 7.33(d, J= 8.5 Hz), 5.80
(dt, J = 10.7, 8.4 Hz), 5.41 (dtt, J = 10.7, 2.2, 1.4 Hz), 4.01 (t, J =
6.5Hz), 2.44(s), 2.32(dt,J= 6.8, 2.2 Hz), 2.28 (dt, J= 7.3, 1.4 Hz),
1.68 - 1.29 (m, 18H), 0.91 (t, J = 7.1 Hz); 13C NMR (CDCl3, 75
MHz) δ 144.6, 142.6, 133.2, 129.8, 127.8, 109.3, 94.3, 77.4, 70.6,
31.1, 29.7, 29.2, 28.9, 28.85, 28.79, 28.78, 28.75, 25.3, 22.2, 21.6,
19.5, 14.0; HRMS (ESI) calcd for C24H36O3S [M þ Na]þ 427.2277,
found 427.2297.
Clathculin A (1). To a solution of tosylate 11 (625.0 mg, 1.55
mmol, 1 equiv) in 5.0 mL of CH3CN was added N,N0-dimethy-
lethylenediamine (687 mg, 0.84 mL, 7.77 mmol, 5 equiv). The
solution was stirred overnight, concentrated in vacuo, and
transferred (EtOAc) to a separatory funnel containing 30 mL
Acknowledgment. S.G.B. thanks Macalester College for a
summer stipend from the Violet Olson Beltmann Fund. E.E.S.
thanks the Arnold and Mabel Beckman Foundation for sup-
port in the form of a Beckman Scholarship.
Supporting Information Available: General experimental
1
conditions, H NMR and 13C NMR spectra for all new com-
pounds, experimental procedures for preparation and zipper
isomerization of 3, and our interpretative assignments for
selected 1H NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.”
J. Org. Chem. Vol. 75, No. 21, 2010 7403