A catalytic enantioselective hetero Diels-Alder approach to the C20-C32 segment of the phorboxazoles

Article abstract of DOI:10.1021/jo050034v

(Chemical Equation Presented) An efficient synthesis of the C20-C32 segment of the phorboxazoles has been achieved using an enantioselective hetero Diels-Alder reaction catalyzed by Jacobsen's Cr(III) amino indanol Schiff base catalyst.

Full text of DOI:10.1021/jo050034v

A Catalytic Enantioselective Hetero
Diels-Alder Approach to the C20-C32
Segment of the Phorboxazoles
Brian S. Lucas, Laura M. Luther, and Steven D. Burke*
Department of Chemistry, University of Wisconsin,
1101 University Avenue, Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
Received January 6, 2005
FIGURE 1. Phorboxazoles.
phorboxazoles are believed to operate by a unique mode
of action: phorboxazole A induces S-phase arrest in
Burkitt lymphoma cells yet shows no inhibition of tubulin
polymerization or interference with microtubular stabil-
ity.9 From a synthetic standpoint, the phorboxazoles
present an attractive challenge. They contain a number
of interesting structural features, including 15 asym-
metric centers, a 21-membered macrolactone, four di-
versely substituted tetrahydropyran rings, two oxazoles,
and a vinyl bromide.
An efficient synthesis of the C20-C32 segment of the
phorboxazoles has been achieved using an enantioselective
hetero Diels-Alder reaction catalyzed by Jacobsen’s Cr(III)
amino indanol Schiff base catalyst.
The most widely studied region of the phorboxazoles
is the C22-C26 tetrahydropyran ring system. This
highly-functionalized polypropionate segment features
five contiguous asymmetric centers and has been a
showcase for various methods of polypropionate and
tetrahydropyan synthesis. Thus far, all approaches have
been dependent on stoichiometric amounts of a chiral
source which may be chiral starting materials, auxilia-
ries, or reagents. Our retrosynthetic analysis for a
catalytic enantioselective approach to this region is
shown in Scheme 1. Disconnection at the C27-C28 olefin
in 1 is a strategy first used by Pattenden5b and most
recently employed by Zhou.7a We noted that the stereo-
chemistry at C26 in 2 could be ignored initially because
the acidity of the C26 proton should allow for base-
catalyzed epimerization to the more stable desired equa-
torial methyl ketone.10 Therefore, it was hoped that
Since the discovery of the cytotoxic macrolide phor-
boxazoles (Figure 1) by Molinski in 1995,1 considerable
effort has been directed toward their synthesis. In 1998,
the first total synthesis of phorboxazole A was completed
by Forsyth;2 the subsequent total syntheses were per-
formed by Evans (phorboxazole B),3 Smith,4 Pattenden,5
and Williams.6 The phorboxazoles have been the focus
of numerous other efforts,7 including our own recent
approach to the C1-C17 segment of phorboxazole B.8
Phorboxazole A and its C13 epimer, phorboxazole B,
exhibit exceptional cytostatic activity; they have shown
a mean GI50 value of <1.6 × 10-9 M in vitro against the
NCI panel of 60 tumor cell lines.9 In addition, the
(1) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(2) (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem.
Soc. 1998, 120, 5597. (b) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997,
62, 5672. (c) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37, 6449.
(d) Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183.
(3) (a) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am.
Chem. Soc. 2000, 122, 10033. (b) Evans, D. A.; Cee, V. J.; Smith, T.
E.; Fitch, D. M.; Cho, P. S. Angew. Chem., Int. Ed. 2000, 39, 2533. (c)
Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. 2000, 39, 2536. (d)
Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett. 1999,
1, 87.
(4) (a) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas,
M. J. Am. Chem. Soc. 2001, 123, 10942. (b) Smith, A. B., III; Verhoest,
P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123,
4834. (c) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J.
Org. Lett. 1999, 1, 909. (d) Smith, A. B., III; Minbiole, K. P.; Verhoest,
P. R.; Beauchamp, T. J. Org. Lett. 1999, 1, 913.
(5) (a) Pattenden, G.; Gonza´lez, M. A.; Little, P. B.; Millan, D. S.;
Plowright, A. T.; Tornos, J. A.; Ye, T. Org. Biomol. Chem. 2003, 1, 4173.
(b) Gonza´lez, M. A.; Pattenden, G. Angew. Chem., Int. Ed. 2003, 42,
1255. (c) Ye, T.; Pattenden, G. Tetrahedron Lett. 1998, 39, 319. (d)
Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T. Tetrahedron Lett.
1998, 39, 6099. (e) Plowright, A. T.; Pattenden, G. Tetrahedron Lett.
2000, 41, 983.
(6) (a) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.;
Berliner, M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258.
(b) Williams, D. R.; Clark, M. P.; Emde, U.; Berliner, M. A. Org. Lett.
2000, 2, 3023. (c) Williams, D. R.; Clark, M. P.; Berliner, M. A.
Tetrahedron Lett. 1999, 40, 2287.
(7) (a) Li, D. R.; Sun, C. Y.; Su, C.; Lin, G.-Q.; Zhou, W.-S. Org. Lett.
2004, 6, 4261. (b) Li, D. R.; Tu, Y.-Q.; Lin, G.-Q.; Zhou, W.-S.
Tetrahedron Lett. 2003, 44, 8729. (c) Liu, B.; Zhou, W.-S. Tetrahedron
Lett. 2003, 44, 4933. (d) Paterson, I.; Arnott, E. A. Tetrahedron Lett.
1998, 39, 7185. (e) Paterson, I.; Luckhurst, C. A. Tetrahedron Lett.
2003, 44, 3749. (f) Paterson, I.; Steven, A.; Luckhurst, C. A. Org.
Biomol. Chem. 2004, 2, 3026. (g) Greer, P. B.; Donaldson, W. A.
Tetrahedron 2002, 58, 6009. (h) Huang, H.; Panek, J. S. Org. Lett. 2001,
3, 1693. (i) Greer, P. B.; Donaldson, W. A. Tetrahedron Lett. 2000, 41,
3801. (j) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217.
(k) Rychnovsky, S. D.; Hu, Y.; Ellsworth, B. Tetrahedron Lett. 1998,
39, 7271. (l) Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469. (m)
Wolbers, P.; Hoffmann, H. M. R.; Sasse, F. Synlett 1999, 1808. (n)
Wolbers, P.; Misske, A. M.; Hoffmann, H. M. R. Tetrahedron Lett. 1999,
40, 4527. (o) Wolbers, P.; Hoffmann, H. M. R. Synthesis 1999, 797. (p)
Misske, A. M.; Hoffmann, H. M. R. Tetrahedron 1999, 55, 4315. (q)
Wolbers, P.; Martin, H.; Hoffmann, H. M. R. Tetrahedron 1999, 55,
1905. (r) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001,
3, 4003. (s) Brinkmann, Y.; Carren˜o, M. C.; Urbano, A.; Colbert, F.;
Solladie´, G. Org. Lett. 2004, 6, 4335. (t) Yadav, J. S.; Rajaiah, G. Synlett
2004, 9, 1537. (u) Chakraborty, T. K.; Reddy, R. V.; Reddy, J. T.
Tetrahedron 2003, 59, 8613.
(8) (a) Lucas, B. S.; Burke, S. D. Org. Lett. 2003, 5, 3915. (b) Lucas,
B. S.; Luther, L. M.; Burke, S. D. Org. Lett. 2004, 6, 2965.
(9) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879.
10.1021/jo050034v CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005
J. Org. Chem. 2005, 70, 3757-3760
3757

SCHEME 1. C20-C32 Retrosynthesis
FIGURE 2. Jacobsen hetero Diels-Alder catalysts.
SCHEME 2. Synthesis of the C20-C27 Subunit
trapping of a C26 oxonium ion 3 with an acyl anion
equivalent would give the desired tetrahydropyran 2. The
oxonium ion 3 would arise from the methyl glycoside 4,
available from a catalytic enantioselective hetero Diels-
Alder reaction between aldehyde 511 and Danishefsky
diene 6.12
Our forward synthesis of the C20-C27 subunit of the
phorboxazoles is shown in Scheme 2. The combination
of the high enantioselectivity of Jacobsen’s chromium-
(III) Schiff base catalyst 7a13 (Figure 2) with the reactiv-
ity of Danishefsky’s siloxy diene 6 produced the inter-
mediate cyclic silyl enol ether 8 in less than 3 h using 5
mol % 7a; normal catalyst loadings of 2 mol % 7a were
typically allowed to stir overnight to ensure complete
reaction. Although the tenuously stable vinylogous ortho
ester 8 can be isolated and purified by silica gel chro-
matography, we found it advantageous to directly affect
axial protonation of the enol ether12,14 setting the C25
methyl group equatorial and producing ketone 4 in a 77%
yield. Chiral HPLC analysis indicated that ketone 4
obtained with catalyst 7a had an enantiomeric excess of
91%.15 Our attempts at improving the enantiomeric
excess at this stage met with no success: lowering the
temperature to 0 °C produced an identical ee, as did the
treatment of methyl glycoside 10 with TMS-CN/TMS-OTf
at 0 °C in MeCN to produce axial nitrile 11. We were
encouraged at this stage because the two steps needed
to complete our synthesis of 2, namely, conversion of
nitrile 11 to axial methyl ketone 12 and epimerization
to 2, have precedents, set by Hoffmann,10 in a closely
related system. Unfortunately, both of these steps proved
to be problematic in our case. Hoffman’s conditions for
the methylation of the nitrile (MeMgBr/sonication/15 h)
did produce 12 but in a low yield (∼30%) with significant
decomposition and unreacted starting material. AlMe3
-
use of catalyst 7b which contains the SbF6 counterion.
However, after the ketone was reduced to equatorial
alcohol 9 using sodium borohydride, the product could
be recrystallized from boiling hexanes to produce crystal-
line 9 in a 98.5% ee.15 This material was protected as
the PMB ether 10 and carried on to the key C26 carbon-
carbon bond-forming event. After considerable experi-
mentation, we were able to install a C26 nitrile by
16
and catalytic Ni(acac)2 proved to be superior for our
substrate, providing a 65% yield of 12 after 48 h.
Although the reaction was difficult to force to completion,
these conditions provided a near-quantitative recovery
of the unreacted 11 to give a 99% yield of 12; the yield
was based on recovered starting material (BORSM). The
axial methyl ketone 12 proved surprisingly resistant to
epimerization under mildly basic conditions, including
Hoffmann’s method (DBU/CH2Cl2/reflux/48 h), triethyl-
(10) Misske, A. M.; Hoffmann, H. M. R. Chem.sEur. J. 2000, 6,
3313.
(11) Matsuda, F.; Kito, M.; Sakai, T.; Okada, N.; Miyashita, M.;
Shirahama, H. Tetrahedron 1999, 55, 14369.
(12) Danishefsky, S.; Harvey, D. F. J. Am. Chem. Soc. 1985, 107,
6647.
(13) Dossetter, A.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398.
(14) Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263.
(15) The enantiomeric excess of 4 and 9 was determined by synthesis
of ent-4 and ent-9 from catalyst ent-7a and injection against a
standardized mixture of the enantiomers on a Chiralcel OD HPLC
column.
(16) Bagnell, L.; Jeffery, E. A.; Meisters, A.; Mole, T. Aust. J. Chem.
1974, 27, 2577.
3758 J. Org. Chem., Vol. 70, No. 9, 2005

over K2CO3, filtered, and concentrated in vacuo to produce crude
ketone 4. Purification by column chromatography (10/1 hexanes/
ether) gave 1.70 g (77.3% yield, 91% ee) of ketone 4 as a clear
colorless oil. Data for 4: HPLC (Chiracel OD-H, 0.3% 2-propanol
in hexanes, flow rate 1 mL/min, observation taken at 230 nm)
tR ) 7.4 min, tR enantiomer ) 8.8 min; Rf ) 0.28 (9/1 hexanes/
SCHEME 3. Synthesis of the C20-C32 Subunit
ethyl acetate); IR (thin film) 2933, 1717 cm-1 1H NMR (500
;
MHz, CDCl3) δ 1.05 (s, 9H), 1.06 (d, J ) 6.8 Hz, 3H), 1.13 (d, J
) 7.1 Hz, 3H), 1.70 (dddd, J ) 14.1, 9.2, 5.9, 3.6 Hz, 1H), 1.92
(app ddt, J ) 13.7, 9.0, 4.7 Hz, 1H), 2.36 (qd, J ) 7.3, 2.7 Hz,
1H), 2.57 (dq, J ) 8.6, 6.5 Hz, 1H), 3.75-3.87 (series of m, 3H),
4.01 (d, J ) 8.5 Hz, 1H), 7.35-7.42 (series of m, 6H), 7.65-7.63
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 8.4 (CH3), 11.2 (CH3),
19.2 (C), 26.8 (CH3), 34.3 (CH2), 47.5 (CH), 48.5 (CH), 56.9 (CH3),
60.0 (CH2), 69.7 (CH), 106.6 (CH), 127.7 (CH), 129.7 (CH), 133.6
(C), 133.7 (C), 135.5 (CH), 211.3 (C); HRMS (MNa+) calcd
amine (EtOH/rt/48 h), and LDA (THF/0 °C/4 h), none of
which produced any epimerization that could be detected
by 1H NMR analysis. Epimerization to 2 was ultimately
accomplished in a 91% yield using LiCl and substoichio-
metric amounts of KHMDS in toluene at 55 °C. With
equatorial methyl ketone 2 in hand, we intersected a
known intermediate in Zhou’s efforts toward the synthe-
sis of the phorboxazoles.7a Installation of the oxazole
moiety (Scheme 3) according to the method of
Pattenden,5a,b as applied by Zhou,7a produced the fully
elaborated C20-C32 subunit 1 in a 68% yield (78%
BORSM) as expected. A comparison of the published 1H
and 13C NMR spectra for 1 and 2 confirmed our structure
assignments, and the identical signs of the optical
rotation indicated that we had made the same enanti-
omers of these products, although the magnitudes of the
specific rotations differed slightly (+31.4 vs +387a for 1,
+72.3 vs +53.67a for 2).17
In summary, the synthesis of the C20-C32 phorbox-
azole subunit 1 was completed in 7 steps with a 20%
overall yield (36% BORSM) from readily available start-
ing materials which compares favorably to Zhou’s syn-
thesis of 1 [15 steps, 3.8% overall yield (4.8% BORSM)].7a,c
Efficient introduction of the five contiguous asymmetric
centers and requisite functionality of the C20-C32
subunit via a catalytic enantioselective hetero Diels-
Alder reaction13 was demonstrated, adding to the growing
application of Jacobsen’s catalyst to construct the
phorboxazoles7e,f and other tetrahydropyran-containing
natural products.
463.2281, obsd 463.2283; optical rotation [R]21 ) -6.0 (c 1.0,
D
CHCl3).
Equatorial Alcohol 9. Ketone 4 (970 mg, 2.2 mmol) was
dissolved in anhydrous EtOH (22 mL) and cooled to -10 °C.
Solid NaBH4 (168 mg, 4.4 mmol, 2 equiv) was added in a single
portion. The mixture was stirred for 15 min, and then saturated
NH4Cl (22 mL) was added which was followed by the addition
of saturated NaHCO3 (44 mL) and CH2Cl2 (200 mL). The
aqueous layer was extracted with CH2Cl2 (4 × 100 mL), and
the combined organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo to produce crude 9. Purification by
column chromatography (8/2 hexanes/ethyl acetate) gave 890 mg
(92% yield, 91% ee) of 9 as a white solid. Recrystallization of
170 mg of 9 from 10 mL of boiling hexanes gave, after the
mixture was allowed to stand at room temperature for 1 day
and -15 °C for 6 h, 152 mg (89% recovery) of white crystalline
9 (ee 98.5%). Data for 9: mp 122-124 °C; HPLC (Chiracel OD-
H, 1% 2-propanol in hexanes, flow rate 1 mL/min, observation
taken at 230 nm) tR ) 11.7 min, tR enantiomer ) 13.7 min; Rf )
1
0.30 (7/3 hexanes/ethyl acetate); IR (ATR) 3580, 2945 cm-1; H
NMR (500 MHz, CDCl3) δ 0.90 (d, J ) 6.8 Hz, 3H), 1.03 (d, J )
6.5 Hz, 3H), 1.05 (s, 9H), 1.45 (br s, 1H), 1.55 (ddq, J ) 10.7,
8.3, 6.5 Hz, 1H), 1.70 (dddd, J ) 14.5, 10.0, 5.9, 4.1 Hz, 1H),
1.78 (qdd, J ) 6.7, 5.2, 2.1 Hz, 1H), 1.90 (app ddt, J ) 13.9, 9.2,
4.7 Hz, 1H), 3.41 (s, 3H), 3.40-3.45 (m, 1H), 3.66 (ddd, J ) 8.9,
3.9, 1.8 Hz, 1H), 3.74-3.85 (m, 2H), 3.81 (d, J ) 8.7 Hz, 1H),
7.35-7.45 (series of m, 6H), 7.65 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 5.7 (CH3), 12.3 (CH3), 19.2 (C), 26.9 (CH3), 35.4 (CH2),
38.4 (CH), 56.8 (CH3), 60.4 (CH2), 70.8 (CH), 105.5 (CH), 127.6
(CH), 129.6 (CH), 133.9 (C), 13.3.9 (C), 135.6 (CH); HRMS
(MNa+) calcd 465.2437, obsd 463.2416; optical rotation [R]21
+3.5 (c 1.0, CHCl3).
)
D
PMB-ether 10. KH (480 mg of 25 wt % suspension in mineral
oil, 3 mmol, 3 equiv) was added to a solution of equatorial alcohol
9 (442 mg, 1 mmol) in dry THF (4 mL) at room temperature.
The resulting slurry was allowed to stir for 30 min at room
temperature, after which 4-methoxybenzyl chloride (420 µL, 3
mmol, 3 equiv) was added. The reaction was quenched after 1 h
with a saturated NH4Cl solution (5 mL) which was followed by
the addition of a saturated NaHCO3 solution (10 mL). The layers
were separated, and the aqueous layer was extracted with ether
(5 × 25 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated to an oil. Purification by
column chromatography (10/0.3 hexanes/acetone) produced 497
mg (88%) of pure 10 as a clear, colorless oil. Data for 10: Rf )
0.23 (9/1 hexanes/ethyl acetate); IR (thin film) 2956, 1513, 1248
Experimental Section
Ketone 4. Jacobsen catalyst 7a13 (72 mg, 0.16 mmol, 0.025
equiv) and oven-dried 4 Å molecular sieves [powdered, 1.0 g
(∼150 mg of sieves/mmol of aldehyde)] were added with stirring
to a round-bottom flask containing Danishefsky diene 612 (1.70
g, 7 mmol, 1.1 equiv) and aldehyde 511 (2.0 g, 6.4 mmol, 1.0
equiv). The reaction mixture was allowed to stir overnight under
N2. The intermediate silyl enol ether 8 was then diluted with
dry methanol (40 mL) and transferred via cannula to a plastic
reaction vessel containing 50% aq HF (2.5 mL), pyridine (38 mL),
and dry MeOH (38 mL) at -15 °C. The mixture was stirred for
15 min, and then saturated NaHCO3 (40 mL) was added
(caution: gas evolution!) which was followed by the addition of
solid CaCO3 (2 g) (caution: additional gas evolution!). The
mixture was filtered through Celite, and the filter cake was
rinsed thoroughly with ether. H2O (100 mL) and ether (200 mL)
were added to the filtrate. The layers were separated, and the
aqueous layer was extracted with ether (3 × 200 mL). The
combined organic layers were washed with brine (50 mL), dried
cm-1 1H NMR (500 MHz, CDCl3) δ 0.94 (d, J ) 6.8 Hz, 3H),
;
1.01 (d, J ) 6.5 Hz, 3H), 1.10 (s, 9H), 1.70 (ddq, J ) 10.8, 8.4,
6.3 Hz, 1H), 1.75 (m, 1H), 1.94 (app ddt, J ) 13.8, 9.4, 4.7 Hz,
1H), 2.05 (m, 1H), 3.15 (dd, J ) 10.8, 5 Hz, 1H), 3.42 (s, 3H),
3.62 (ddd, J ) 9.0, 3.8, 1.9 Hz, 1H), 3.79-3.90 (series of m, 3H),
3.82 (s, 3H), 4.20 (1/2 ABq, JAB ) 11.3 Hz, 1H), 4.72 (1/2 ABq,
JAB ) 11.3 Hz, 1H), 6.90 (m, 2H), 7.30 (m, 2H), 7.42 (m, 6H),
7.69 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 5.9 (CH3), 12.7 (CH3),
19.3 (C), 26.9 (CH3), 34.1 (CH), 35.5 (CH2), 36.9 (CH), 55.3 (CH3),
56.7 (CH3), 60.6 (CH2), 69.8 (CH2), 70.9 (CH), 82.2 (CH), 106.7
(CH), 113.8 (C), 127.6 (CH), 129.3 (CH), 129.6 (CH), 130.5 (C),
(17) We suggest that the chiral HPLC assay (see Supporting
Information) of intermediate 9 (98.5% ee) provides the most reliable
data supporting the optical purity of 1 and 2 prepared by the route
described herein.
J. Org. Chem, Vol. 70, No. 9, 2005 3759

133.8 (C), 133.9 (C), 153.5 (CH), 159.2 (C); HRMS (MNa+) calcd
hexanes/ethyl ether) yielded 27.2 mg of 2 (91%) as a clear oil.
Data for 2: Rf ) 0.23 (9/1 hexanes/ethyl acetate); IR (thin film)
585.3012, obsd 585.2994; optical rotation [R]21 ) +31.0 (c 1.0,
D
1
CHCl3).
1720, 1513 cm-1; H NMR (500 MHz, CDCl3) δ 0.90 (d, J ) 6.5
Axial Nitrile 11. TMS-CN (0.34 mL, 2.56 mmol, 10 equiv)
was added to a solution of methyl glycoside 10 (144 mg, 0.256
mmol) in dry acetonitrile (3.5 mL) at 0 °C. The mixture was
stirred for 10 min; then TMS-OTf (23 µL, 0.128 mmol, 0.5 equiv)
was added, and the reaction mixture was allowed to stir at 0-5
°C for 2 h. The reaction was quenched with a 15% Na2CO3
solution (10 mL), and the mixture was allowed to stir for an
additional 1 h at 0-5 °C. Dichloromethane (30 mL) was added;
the layers were separated, and the aqueous layer was extracted
with dichloromethane (3 × 30 mL). The combined organic layers
were washed with a 15% Na2CO3 solution (10 mL), dried over
MgSO4, filtered, and concentrated. Purification by column
chromatography (10/0.075 benzene/ethyl acetate) produced 117
mg (82%) of 11. Trituration with pentane produced a white solid.
Data for 11: mp 95 °C; Rf ) 0.25 (10/0.2 benzene/ethyl acetate);
Hz, 3H), 0.94 (d, J ) 7.2 Hz, 3H), 1.06 (s, 9H), 1.70 (dddd, J )
14.1, 8.7, 6.1, 3.9 Hz, 1H), 1.75 (tq, J ) 10.9, 6.6 Hz, 1H), 1.85
(ddt, J ) 13.8, 9.3, 4.8 Hz, 1H), 2.09 (m, 1H), 2.12 (s, 3H), 3.17
(dd, J ) 10.3, 4.7 Hz, 1H), 3.32 (d, J ) 10.6 Hz, 1H), 3.64 (ddd,
J ) 8.9, 4.0, 1.8 Hz, 1H), 3.76 (m, 2H), 3.81 (s, 3H), 4.29 (1/2
ABq, JAB ) 11.0 Hz, 1H), 4.57 (1/2 ABq, JAB ) 11.0 Hz, 1H),
6.88 (m, 2H), 7.22 (m, 2H), 7.40 (m, 6H), 7.65 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 6.0 (CH3), 12.9 (CH3), 19.2 (C), 25.3 (CH3),
26.8 (CH3), 32.4 (CH), 34.3 (CH), 35.8 (CH2), 55.3 (CH3), 60.5
(CH2), 69.7 (CH2), 74.8 (CH), 83.0 (CH), 87.7 (CH), 113.8 (CH),
127.7 (CH), 129.3 (CH), 129.6 (CH), 130.4 (C), 133.7 (C), 133.8
(C), 135.5 (CH), 135.5 (CH), 159.2 (C), 207.4 (C); HRMS (MNa+)
calcd 597.3012, obsd 597.2991; optical rotation [R]21 ) +72.3
D
(c 0.5, CHCl3).
C20-C32 Subunit 1. Oxazole phosphonate 135a (145 mg, 0.7
mmol, 4 equiv) was dissolved in anyhydrous THF (3 mL) and
cooled to -78 °C. LDA (1.0 M in THF, 0.7 mL, 0.7 mmol, 4 equiv)
was added to the solution which resulted in a bright yellow
solution after stirring for 30 min at -78 °C. Equatorial methyl
ketone 2 (98 mg, 0.17 mmol) as a solution in THF (3 mL) was
added dropwise. The resulting reaction mixture was allowed to
slowly warm to room temperature overnight (∼16 h). The
reaction mixture was diluted with EtOAc (100 mL) and washed
with a 1/1 solution of saturated NH4Cl and water (20 mL),
followed by brine (2 × 5 mL). The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. Purification by
column chromatography (9/1 hexanes/ethyl acetate) produced 1
(75.8 mg, 68% yield) and recovered 2 (13 mg, 13%, 78% BORSM
yield of 1). Data for 1: Rf ) 0.08 (9/1 hexanes/ethyl acetate); IR
IR (ATR) 2988, 2905, 2838, 1518 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 0.89 (d, J ) 6.9 Hz, 3H), 1.07 (s, 9H), 1.09 (d, J ) 6.6
Hz), 1.70 (m, 1H), 1.83 (ddt, J ) 13.7, 8.2, 5.3 Hz), 2.10-2.20
(series of m, 2H), 3.47 (dd, J ) 10.9, 4.4 Hz, 1H), 3.75 (m, 2H),
3.81 (s, 3H), 4.12 (ddd, J ) 7.5, 4.8, 1.9 Hz, 1H), 4.31 (1/2 ABq,
JAB ) 10.9 Hz, 1H), 4.53 (1/2 ABq, JAB ) 10.9 Hz, 1H), 4.67 (d,
J ) 5.9 Hz, 1H), 6.89 (m, 2H), 7.25 (m, 2H), 7.41 (m, 6H), 7.69
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 5.5 (CH3), 13.1 (CH3),
19.2 (C), 28.8 (CH3), 32.5 (CH), 34.3 (CH), 35.4 (CH2), 55.3 (CH3),
60.3 (CH2), 69.9 (CH2), 70.5 (CH), 73.8 (CH), 79.8 (CH), 113.9
(CH), 116.3 (C), 127.7 (CH), 129.3 (CH), 129.6 (CH), 130.2 (C),
133.6 (C), 133.8 (C), 135.5 (CH), 135.6 (CH), 159.3 (C); HRMS
(MNa+) calcd 580.2859, obsd 580.2843; optical rotation [R]21
+75.6 (c 1.0, CHCl3).
)
D
Axial Methyl Ketone 12. Nitrile 11 (30 mg, 0.054 mmol)
was dissolved in dry toluene (2 mL) and cooled to 0 °C.
Trimethylaluminum (2.0 M solution in hexanes, 108 µL, 0.216
mmol, 4 equiv) was added and then followed by the addition of
Ni(acac)2 (10 mg/mL solution in benzene, 70 µL, 0.7 mg, 0.0027
mmol, 0.05 equiv). The brown reaction mixture was allowed to
stir at 0 °C for 42 h, after which 1 M HCl (2 mL) was added.
The biphasic mixture was stirred at room temperature for 15
min and subsequently extracted with ether (3 × 15 mL). The
combined organic extracts were dried with MgSO4, filtered, and
concentrated. Purification by column chromatography (10/0.15
benzene/ethyl acetate) afforded 20 mg of 12 (64.5%) as a white
solid and 10.6 mg of recovered 11 (35%). Data for 12: mp 124-
126 °C; Rf ) 0.16 (10/0.2 benzene/ethyl acetate); IR (ATR) 2921,
(thin film) 2929, 2855, 1247, 1111, 1035 cm-1 1H NMR (500
;
MHz, CDCl3) δ 0.83 (d, J ) 6.5 Hz, 3H), 0.95 (d, J ) 7.0 Hz,
3H), 1.07 (s, 9H), 1.70 (ddt, J ) 13.6, 8.0, 5.6 Hz, 1H), 1.78-
1.88 (series of m, 2H), 1.90 (s, 3H), 2.11 (qdd, J ) 6.5, 4.7, 1.9
Hz, 1H), 3.20 (dd, J ) 10.5, 4.7 Hz, 1H), 3.42 (d, J ) 10.2 Hz,
1H), 3.66 (ddd, J ) 7.1, 5.0, 1.6 Hz, 1H), 3.71-3.82 (series of m,
2H), 3.81 (s, 3H), 4.30 (1/2 ABq, JAB ) 11.0 Hz, 1H), 4.58 (1/2
ABq, JAB ) 11.1 Hz, 1H), 6.19 (br s, 1H), 7.00 (m, 2H), 7.28 (m,
2H), 7.34-7.44 (series of m, 6H), 7.49 (s, 1H), 7.68 (m, 4H); 13
C
NMR (125 MHz, CDCl3) δ 6.0 (CH3), 13.76 (CH3), 13.82 (CH3),
14.2 (CH3), 19.2 (C), 26.9 (CH3), 33.3 (CH), 34.2 (CH), 35.8 (CH2),
55.3 (CH3), 60.8 (CH2), 69.6 (CH2), 74.8 (CH), 83.5 (CH), 88.9
(CH), 113.8 (CH), 118.5 (CH), 127.6 (CH), 129.3 (CH), 129.5 (CH),
130.7 (C), 133.9 (C), 134.0 (C), 135.5 (CH), 137.9 (C), 138.2 (C),
159.1 (C), 160.5 (C); HRMS (MNa+) calcd 676.3434, obsd
1
2858, 1710, 1506 cm-1; H NMR (500 MHz, CDCl3) δ 0.88 (d, J
) 7.0 Hz, 3H), 0.92 (d, J ) 7.1 Hz, 3H), 1.05 (s, 9H), 1.65 (dtd,
J ) 15.2, 8.3, 3.1 Hz, 1H), 2.04 (s, 3H), 2.10-2.20 (series of m,
2H), 2.25 (m, 1H), 3.40 (br t, J ) 4 Hz, 1H), 3.65-3.77 (series of
m, 2H), 3.80 (s, 3H), 3.96 (ddd, J ) 7.8, 4.3, 2.9 Hz, 1H), 4.09 (d,
J ) 3.4 Hz, 1H), 4.36 (1/2 ABq, JAB ) 11.2 Hz, 1H), 4.54 (1/2
ABq, JAB ) 11.2 Hz, 1H), 6.86 (m, 2H), 7.25 (m, 2H), 7.36 (m,
6H), 7.65 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 11.6 (CH3),
19.2 (C), 26.9 (CH3), 27.8 (CH3), 32.3 (CH), 32.9 (CH), 55.3 (CH3),
61.0 (CH2), 70.9 (CH2), 73.7 (CH), 80.7 (CH), 113.7 (CH), 127.6
(CH), 128.8 (CH), 129.5 (CH), 129.6 (CH), 131.0 (C), 133.9 (C),
133.9 (C), 135.5 (CH), 159.1 (CH), 210.5 (C); HRMS (MNa+) calcd
597.3012, obsd 597.3007; optical rotation [R]21D ) + 19.9 (c 1.0,
CHCl3).
676.3463; optical rotation [R]24 ) +31.4 (c 1.0, CHCl3).
D
Acknowledgment. We thank Dr. David E. Chavez
for advice on the synthesis of the Jacobsen hetero Diels-
Alder catalysts, Gregory Hanson for assistance in the
conversion of 10 to 11, and the NIH (Grants CA074394
and CA108488) for generous support. L.M.L. gratefully
acknowledges the 2004-2005 Wisconsin/Hilldale Un-
dergraduate/Faculty Research Award for assistance.
Note Added after ASAP Publication. Reference 14
was omitted in the version published ASAP April 2, 2005;
the corrected version was published April 6, 2005.
Equatorial Methyl Ketone 2. LiCl (2 mg, 0.052 mmol, 1
equiv) and KHMDS (0.5 M solution in toluene, 52 µL, 0.026
mmol, 0.5 equiv) were added to a solution of 12 (30 mg, 0.052
mmol) in toluene. The resulting orange solution was heated to
55 °C for 2 h, cooled to room temperature, and diluted with 30
mL of ethyl ether. The ether layer was washed with 1 M HCl (2
× 1.5 mL) and brine (1 × 1.5 mL), dried over MgSO4, filtered,
and concentrated. Purification by column chromatography (10/1
Supporting Information Available: 1H and 13C spectra
for compounds 2, 4, and 8-12 and chiral HPLC traces for
compounds 4 and 9. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO050034V
3760 J. Org. Chem., Vol. 70, No. 9, 2005