Total synthesis of (+)-crocacin D

Article abstract of DOI:10.1021/jo047732k

(Chemical Equation Presented) The total synthesis of (+)-crocacin D is described. The convergent asymmetric synthesis relies on the use of a Stille cross-coupling between an (E)-vinyl stannane with an (E)-vinyl iodide to establish the (E,E)-dienamide moie

Full text of DOI:10.1021/jo047732k

Total Synthesis of (+)-Crocacin D†
Luiz C. Dias,*,‡ Luciana G. de Oliveira,‡ Jana´ına D. Vilcachagua,‡ and Florian Nigsch§
Instituto de Quı´mica, Universidade Estadual de Campinas, UNICAMP, C. P. 6154 Campinas, SP, Brazil,
and Ecole Normale Supe´rieure, De´partement de Chimie, 24, rue Lhomond,
F-75231 Paris Cedex 05, France
ldias@iqm.unicamp.br
Received December 28, 2004
The total synthesis of (+)-crocacin D is described. The convergent asymmetric synthesis relies on
the use of a Stille cross-coupling between an (E)-vinyl stannane with an (E)-vinyl iodide to establish
the (E,E)-dienamide moiety followed by a mild and efficient copper-catalyzed coupling between
(+)-crocacin C and a (Z)-vinyl iodide to establish the challenging (Z)-enamide function.
Introduction
The crocacins A (1), B (2), C (3), and D (4) are a group
of compounds that are regularly found in the extracts of
the Chondromyces crocatus and Chondromyces pedicu-
latus strains and represent a second novel group of
modified peptides from C. crocatus (Figure 1).1,2 Crocacin
C (3) is a structure fragment of 1, 2, and 4. The crocacins
moderately inhibit the growth of a few gram-positive
bacteria and are potent inhibitors of animal cell cultures
and several yeasts and fungi. Crocacin D shows higher
biological activity against Saccharomyces cerevisiae as
well as higher toxicity in L929 mouse fibroblast cell
cultures, when compared to crocacins A-C. The relative
configurations of crocacins A-D were proposed by Jansen
and co-workers by means of molecular modeling studies
and NOE experiments2 and were further confirmed by
total synthesis.3-6
FIGURE 1. Crocacins A-D
undertaken the total synthesis of the polyketide (+)-
crocacin D (4), the most active compound in this series.5
Crocacin D (4), a dipeptide of glycine and 6-amino-
hexenoic acid, shows four consecutive stereocenters, three
(E)-double bonds, and a (Z)-enamide moiety, which is
probably responsible for the pharmacological activity of
the crocacins and represents the major synthetic chal-
lenge.7
To provide material for more extensive biological
evaluation, along with access to novel analogues, we have
† Dedicated to Prof. Timothy John Brocksom for his outstanding
contributions to the field of synthetic organic chemistry in Brazil.
* FAX: +55-019-3788-3023.
‡ Universidade Estadual de Campinas.
§ Ecole Normale Supe´rieure.
(1) Kunze, B.; Jansen, R.; Ho¨fle, G.; Reichenbach, H. J. Antibiot.
1994, 47, 881.
(2) (a) Jansen, R.; Washausen, P.; Kunze, B.; Reichenbach, H.; Ho¨fle,
G. Eur. J. Org. Chem. 1999, 1085. (b) Kunze, B.; Jansen, R.; Sasse,
F.; Ho¨fle, G.; Reichenbach, H. J. Antibiot. 1998, 51, 1075.
(3) Total synthesis of crocacin A: (a) Feutrill, J. T.; Rizzacasa, M.
A. Aust. J. Chem. 2003, 56, 783. (b) Chakraborty, T. K.; Laxman, P.
Tetrahedron Lett. 2003, 44, 4989.
(4) Total synthesis of crocacin C: (a) Dias, L. C.; de Oliveira, L. G.
Org. Lett. 2001, 3, 3951. (b) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M.
A. Org. Lett. 2000, 2, 3365. (c) Chakraborty, T. K.; Jayaprakash, S.
Tetrahedron Lett. 2001, 42, 497. (d) Chakraborty, T. K.; Jayaprakash,
S.; Laxman, P. Tetrahedron 2001, 57, 9461.
(5) Total synthesis of crocacin D: (a) Chakraborty, T. K.; Laxman,
P. Tetrahedron Lett. 2002, 43, 2645. (b) Feutrill, J. T.; Lilly, M. J.;
Rizzacasa, M. A. Org. Lett. 2002, 4, 525. (c) Crowley, P. J.; Aspinall, I.
H.; Gillen, K.; Godfrey, C. R. A.; Devillers, I. M.; Munns, G. R.; Sageot,
O. A.; Swanborough, J.; Worthington, P. A.; Williams, J. Chimia 2003,
57, 685.
(6) For fragment synthesis, see: (a) Raghavan, S.; Reddy, S. R.
Tetrahedron Lett. 2004, 45, 5593. (b) Gurjar, M. K.; Khaladkar, T. P.;
Borhade, R. G.; Murugan, A. Tetrahedron Lett. 2003, 44, 5183.
10.1021/jo047732k CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/17/2005
J. Org. Chem. 2005, 70, 2225-2234
2225

Dias et al.
SCHEME 1. First Retrosynthetic Analysis of
Crocacin D
SCHEME 2. Retrosynthetic Analysis of Crocacin
C
Results and Discussion
Our first disconnection, summarized in Scheme 1,8
involved cleavage of the C9-Ν10 bond to give aldehyde
5 (C1-C9 fragment) and crocacin C (3) (C11-C21 frag-
ment). This (Z)-enamide bond is viewed as arising from
an R-amidoalkyl phenyl sulfone followed by enamide
formation, as described by Petrini and co-workers.7h-j
Fragment C1-C9 (aldehyde 5) may be further dissected
in a straightforward manner to give glycine methyl ester
hydrochloride 6 and carboxylic acid 7, available from 1,4-
butanediol 8.
SCHEME 3. Synthesis of Epoxide 12
Our retrosynthetic analysis for crocacin C4a is outlined
in Scheme 2 and employed a Stille coupling to join
fragments C11-C13 ((E)-vinyl stannane 9) and C14-C21
((E)-vinyl iodide 10).4a We anticipated that vinyl stannane
9 would be derived from ethyl 2-butynoate 11 and vinyl
iodide 10 from allylic alcohol 13.
Synthesis of (E)-vinyl iodide 10 began with asymmetric
aldol addition of the boron enolate derived from N-
propionyloxazolidinone 14 with cinnamaldehyde to give
aldol adduct 15 in 82% yield (ds > 95:5) (Scheme 3).9
Silylation of aldol 15 with TBSOTf and 2,6-lutidine was
followed by treatment with LiBH4 in MeOH to provide
alcohol 16 (75% yield, two steps).9 Allylic alcohol 13 was
obtained in a high overall yield following Swern10 oxida-
tion of alcohol 16 to the aldehyde, conversion to the R,â-
unsaturated ester 17, and treatment of 17 with excess
DIBAL-H at 0 °C (82%, three steps). We were pleased to
find that epoxidation of allylic alcohol 13 with m-CPBA
gave the anti-epoxy alcohol 12 in 94% yield and 92:8
diastereoselectivity.4a,12
Treatment of epoxy alcohol 12 with Me2CuCNLi2 gave
diol 18 in 90% yield (Scheme 4).13,14 Cleavage of the
secondary TBS ether in the presence of TBAF followed
by selective monoprotection gave diol 19 (89% yield, two
steps).14 Methylation of the OH-functions at C17 and C19
(KH, MeI, THF) followed by removal of the TBDPS group
provided alcohol 20 (96% yield, two steps). Dess-Martin15
oxidation, followed by treatment of the aldehyde with
CrCl2 and CHI3, gave (E)-vinyl iodide 10 (E:Z > 95:05)
(7) Enamide synthesis: (a) Jiang, L.; Job, G. E.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2003, 5, 3667. (b) Pan, X.; Cai, Q.; Ma, D.
Org. Lett. 2004, 6, 1809. (c) Shen, R.; Lin, C. T.; Bowman, E. J.;
Bowman, B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 7889.
(d) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org. Lett. 2004, 6, 27. (e)
Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577. (f) Wang, Y.; Porco,
J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040. (g) Bayer, A.; Maier, M.
E. Tetrahedron. 2004, 60, 6665. (h) Mecozzi, T.; Petrini, M. J. Org.
Chem. 1999, 64, 8970. (i) Ballini, R.; Petrini, M. Tetrahedron Lett. 1999,
40, 4449. (j) Mecozzi, T.; Petrini, M. Synlett 2000, 73. (k) Fu¨rstner, A.;
Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3, 3955. (l) Bhatta-
charjee, A.; Seguil, O. R.; De Brabander, J. K. Tetrahedron Lett. 2001,
42, 1217. (m) Stefanuti, I.; Smith, S. A.; Taylor, R. J. K. Tetrahedron
Lett. 2000, 41, 3735. (n) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2,
1333. (o) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407. (p) Kuramochi,
K.; Watanabe, H.; Kitahara, T. Synlett 2000, 397. (q) Brettle, R.;
Mosedale, A. J. J. Chem. Soc., Perkin Trans. 1 1988, 2185. (r) Hudrlik,
P. F.; Hudrlik, A. M.; Rona, R. J.; Misra, R. N.; Withers, G. P. J. Am.
Chem. Soc. 1977, 99, 1993. (s) Trost, B. M.; Surivet, J.-P. Angew.
Chem., Int. Ed. 2001, 40, 1468.
(11) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(12) (a) Isobe, M.; Kitamura, M.; Mio, S.; Goto, T. Tetrahedron Lett.
1982, 23, 221. (b) Maruyama, K.; Ueda, M.; Sasaki, S.; Iwata, Y.;
Miyazawa, M.; Miyashita, M. Tetrahedron Lett. 1998, 39, 4517.
(13) Johnson, M. R.; Kishi, Y. Tetrahedron Lett. 1979, 20, 4347.
(14) Diols 18 and 19 showed spectral data and physical properties
identical in all respects to published data. See ref 3.
(15) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (c) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(8) Numbering of 4 follows that suggested in ref 2a.
(9) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83. (b) Evans,
D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. (c)
Evans, D. A.; Taber, T. R. Tetrahedron Lett. 1980, 21, 4675. (d) Evans,
D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127.
(10) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
2226 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of (+)-Crocacin D
SCHEME 4. Synthesis of (E)-Vinyl Iodide 10
SCHEME 6. Synthesis of (E)-Vinylstannane 9
SCHEME 7. Synthesis of Crocacin C: Stille
Coupling
SCHEME 8. Preparation of Aldehyde 5
SCHEME 5. Determination of the Relative
Stereochemistry for Diols 18 and 19
Since our first publication, we were able to further
improve the synthesis of crocacin C, especially regarding
the Stille20 coupling reaction between the C11-C13 and
C14-C21 fragments (Scheme 7).4a Treatment of a solu-
tion of (E)-vinylstannane 9 and (E)-vinyl iodide 10 in THF
with a catalytic amount of Pd2(dba)3 in the presence of
AsPh3 and CuCl(I) at 50 °C gave (+)-crocacin C in 84%
yield, after purification by silica gel column chro-
matography (EtOAc/hexane 40%).4a The total synthesis
of crocacin C was accomplished in 15 steps from N-
propionyl-oxazolidinone 14 and produced the desired
product in 21% overall yield.
Our approach for preparation of fragment C1-C9,
corresponding to aldehyde 5, is described in Scheme 8.
Treatment of 1,4-butanediol 8 with NaH and PMBCl in
DMF gave primary alcohol 24 (87%), which was submit-
ted to oxidation under the standard Swern10 conditions.
The unpurified aldehyde was directly subjected to a
Horner-Emmons11 homologation with the requisite sta-
bilized reagent, producing R,â-unsaturated ester 25 in
87% overall yield for the two-step sequence. This ester
was smoothly hydrogenated (Pd-C 5%, 10% m/m) to give
the corresponding saturated ester (95%), which was
submitted to basic hydrolysis, providing carboxylic acid
7 (90% yield). Compound 26 is readily prepared from
carboxylic acid 7 and glycine methyl ester hydrochloride
in 67% overall yield for the two-step sequence.16 Overall
this route required 14 steps starting from 14 and resulted
in 25% overall yield of 10.
The relative stereochemistry for 1,3-diols 18 and 19
was determined after conversion to their corresponding
acetonides 21 and 22 (Scheme 5).17 Coupling constants
between Ha-Hc (11.7 Hz), Hc-Hd (11.5 Hz), and Hb-
Hc (4.4 Hz) confirmed the relative stereochemistry for
C16-C17 bond in 21.14 The stereochemistry at C17 and
C19 was determined after analysis of acetonide 22, which
showed 13C NMR resonances at 23.7, 25.9, and 100.5,
characteristic of an anti acetonide.17
Conjugate organostannyl cuprate addition to ethyl
2-butynoate 11 (-100 °C to -78 °C) gave (E)-vinyl-
stannane 23 (E:Z, > 95:5) (Scheme 6).18,19 Treatment of
vinylstannane 23 with Me3Al and NH4Cl in toluene at
50 °C gave (E)-vinylstannane 9 in 50% yield for the two-
step sequence. The (E)-geometry for vinylstannane 9 was
confirmed by NOESY interactions between the vinylic
hydrogen at C12 and the hydrogens of the tributyltin
group.
(16) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408. (b) Paterson, I.; Lombart, H.; Allerton, C. Org. Lett. 1999,
1, 19.
(17) (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. (c) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I.
Acc. Chem. Res. 1998, 31, 9.
(18) Piers, E.; Morton, H. E. J. Org. Chem. 1980, 45, 4263.
(19) Brabander, J. D.; Vandewalle, M. Synthesis 1994, 855.
(20) (a) Recent review: Espinet, P.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2004, 43, 4704. (b) Stille, J. K. Angew. Chem., Int. Ed.
Engl. 1986, 25, 508. (c) Duncton, M. A. J.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1999, 1235. (d) Stille, J. K.; Groh, B. L. J. Am.
Chem. Soc. 1987, 109, 813.
J. Org. Chem, Vol. 70, No. 6, 2005 2227

Dias et al.
SCHEME 9. Attempted Coupling of Crocacin C (3)
with Aldehyde 5
SCHEME 10. Revised retrosynthetic Analysis of
Crocacin D
ing R,â-unsaturated ester 31 in 89% overall yield for the
two-step sequence. This ester was smoothly hydrogenated
to give the corresponding saturated ester (97%), which
was submitted to basic hydrolysis, providing carboxylic
acid 29 (89% yield).
6 by a simple peptide21 coupling reaction (DCC, HOBt,
NaHCO3 in CH2Cl2, 84%). Removal of the PMB protecting
group (60%) was accomplished by treatment of 26 with
DDQ/H2O. Oxidation of the primary OH-function with
TPAP22 led to aldehyde 5 (92%). The 10-step sequence
from 8 to 5 proceeded in an overall yield of 30%.
With fragments 3 (crocacin C) and 5 in hand, we
attempted their coupling (Scheme 9). Treatment of (+)-
crocacin C (3) with sodium benzenesulfinate in THF/H2O
followed by the addition of aldehyde 5 and formic acid
at 25 °C did not furnish the desired R-amidoalkyl phenyl
sulfone 27.7h-j We expected to isolate the corresponding
R-amidoalkyl phenyl sulfone intermediate 27, which,
after treatment with DBU in THF, should lead to the
(Z)-enamide. After several attempts, we isolated only
starting material or a complex mixture of products. In a
few cases, we isolated small amounts of what appears to
be a mixture of crocacin D with the corresponding (E)-
enamide isomer, although in very low yields.
Due to the difficulties in forming the R-amidoalkyl
phenyl sulfone, we abandoned this strategy and altered
our synthetic route. At this point, we were attracted to a
study by Buchwald et al.,7a who reported the copper-
catalysis-promoted substitution of vinyl iodides with
amides to give enamides in good yields. On the basis of
this precedent and related Cu(I)-catalyzed C-N cross-
coupling reactions, we focused our attention on this
synthetic strategy.7
Scheme 10 illustrates our revised retrosynthetic analy-
sis of crocacin D. Our revised disconnection involved
cleavage of the C9-Ν10 bond to give (Z)-vinyl iodide 28
(C1-C9 fragment) and crocacin C (3) (C11-C21 frag-
ment).8 Fragment C1-C9 ((Z)-vinyl iodide 28) may be
further dissected in a straightforward manner to give
glycine methyl ester hydrochloride 6 and carboxylic acid
29, available from primary alcohol 30.
Our approach for the preparation of fragment C1-C9
is described in Scheme 11. Primary alcohol 3023 was
submitted to oxidation under the standard Swern10
conditions, and the unpurified aldehyde was directly
subjected to a Horner-Emmons11 homologation, produc-
Compound 32 is readily prepared from carboxylic acid
29 and glycine methyl ester hydrochloride 6 by a simple
peptide-coupling reaction21 (81%), followed by Boc protec-
tion under standard conditions (90% yield). At this stage,
only four synthetic operations remained to arrive at (Z)-
vinyl iodide 28, an intermediate suitable for coupling with
crocacin C. Removal of the TIPS protecting group (83%)
was accomplished by treatment of 32 with a solution of
HF-pyr in a solution of THF/pyridine. Oxidation of the
primary OH-function with Dess-Martin periodinane15
led to aldehyde 33 (90%), which was directly reacted with
the phosphorane prepared from treatment of iodomethyl
triphenylphosphonium iodide24 (34) with NaHMDS in
THF at -78 °C to give the corresponding N-Boc-(Z)-vinyl
iodide in 90% yield and >95:5 selectivity. The last step
involved removal of the Boc protecting group, easily
accomplished by treatment of the N-Boc-(Z)-vinyl iodide
with CF3CO2H to give (Z)-vinyl iodide 28 in 85% yield
(Z:E > 95:05). The 10-step sequence from 30 to 28
proceeded in an overall yield of 32% and is easily
amenable to a gram scale-up.
With synthesis of crocacin C (3) and the requisite (Z)-
vinyl iodide 28 in hand, their coupling was undertaken
(Scheme 12). This was done by using the copper-catalyzed
cross-coupling of amides with vinyl halides, recently
described independently by Buchwald and co-workers as
well as by Ma and co-workers.7a,b Treatment of crocacin
C (3) and (Z)-vinyl iodide 28 in THF, using a combination
of 5 mol % copper(I) iodide, 20 mol % N,N′-dimethyl-
ethylenediamine, and Cs2CO3 as a base, at 70 °C, gave
crocacin D in 67% yield after purification by flash column
chromatography using Et3N-deactivated silica gel.5,7a The
use of 20 mol % N,N-dimethylglycine in dioxane as a
solvent, as described by Ma and co-workers, led to similar
results.7b
The spectroscopic and physical data [1H and 13C NMR,
IR, [R]D, Rf] were identical in all respects with published
data.2a,25
(21) (a) Dias, L. C.; Diaz, G.; Ferreira, A. A.; Meira, P. R. R.;
Ferreira, E. Synthesis 2003, 603. (b) Na´jera, C. Synlett 2002, 1388.
(22) (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639. (b) Bloch, R.; Brillet, C. Synlett 1991, 829.
(23) Primary alcohol 30 is most conveniently prepared by mono-
protection of 1,3-propanediol: McDougal, P. G.; Rico, J. G.; Oh, Y.-I.;
Condon, B. D. J. Org. Chem. 1986, 51, 3388. See Experimental Section.
(24) (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (b)
Seyferth, D.; Heeren, J. K.; Singh, G.; Grim, S. O. Hughes, W. B. J.
Organomet. Chem. 1966, 5, 267.
2228 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of (+)-Crocacin D
SCHEME 11. Synthesis of (Z)-Vinyl Iodide 28
resulting yellow solution was then cooled to -78 °C, and
cinnamaldehyde (1.73 mL, 13.75 mmol) was added slowly
(internal temperature below -70 °C). After 20 min, the
solution was warmed to 0 °C and stirred at that temperature
for 1 h. The reaction was quenched by the addition of 18 mL
of pH 7.0 aqueous phosphate buffer solution and 60 mL of
MeOH (internal temperature below +10 °C, bath temperature
) -10 °C). A solution of 40 mL of MeOH and 20 mL of 30%
aqueous H2O2 was added carefully (internal temperature below
+10 °C), and the resulting yellow solution was stirred at 0 °C
for 1 h. The volatiles were removed at aspirator pressure, and
the residue was extracted with three 30 mL portions of Et2O.
The combined organic extracts were washed with 50 mL of
saturated aqueous NaHCO3 and 50 mL of brine. The organic
solution was dried over anhydrous MgSO4 and purified by flash
column chromatography (EtOAc/hexane 25%) to give 3.74 g
of the syn-aldol adduct 15 as a white solid (82% yield, >99:1
diastereoselectivity): Rf 0.3 (EtOAc/hexanes, 30:70); mp 116.0
SCHEME 12. Total Synthesis of Crocacin D
The total synthesis of crocacin D has been completed.
Notable features of this approach include convergence,
a Stille cross-coupling between a vinyl stannane and a
vinyl iodide, as well as a mild and efficient copper-
catalyzed coupling between crocacin C and a (Z)-vinyl
iodide to establish the challenging (Z)-enamide function.
The synthesis required 16-steps from N-propionyl-
oxazolidinone 144a (longest linear sequence) and produced
the desired product in 14.0% overall yield. As a result,
the route to crocacin D presented here is, in principle,
readily applicable for the preparation of other crocacins.
Further optimization of the synthesis and application to
the preparation of novel structural analogues of crocacin
D are underway.25
20
°C; [R]D -83.3 (c 1.08, CH2Cl2); IR νmax (film) 3466, 3084,
3027, 2928, 1769, 1664, 1391, 1346, 1200 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.40 (d, J 7.3 Hz, 2H), 7.35-7.23 (m, 6H), 7.21
(d, J 7.0 Hz, 2H), 6.68 (d, J 15.9 Hz, 1H), 6.22 (dd, J 15.9, 6.0
Hz, 1H), 4.70 (m, 1H), 4.68 (ap q, J 4.3 Hz, 1H), 4.18 (s, 1H),
4.17 (d, J 2.4 Hz, 1H), 3.99 (qd, J 7.1, 4.0 Hz, 1H), 3.26 (dd, J
13.4, 3.4 Hz, 1H), 2.80 (dd, J 13.4, 9.5 Hz, 1H), 1.31 (d, J 7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 176.5, 153.1, 136.5,
135.0, 131.4, 129.4, 129.0, 128.6, 128.5, 127.7, 127.4, 126.5,
72.7, 66.2, 55.1, 42.9, 37.8, 11.4; HRMS calcd for C22H23NO4
[M+] 365.1627, found 365.1624. Anal. Calcd for C22H23NO4: C,
72.31; H, 6.34; N, 3.83. Found: C, 72.31; H, 6.55; N, 4.20.
(R)-4-Benzyl-3-((2R,3S,E)-3-(tert-butyldimethylsilyloxy)-
2-methyl-5-phenylpent-4-enoyl)oxazolidin-2-one. To a so-
lution of aldol 15 (708 mg, 1.94 mmol) and 2,6-lutidine (0.26
mL, 2.23 mmol) in CH2Cl2 (4 mL) at 0 °C was added TBSOTf
(0.47 mL, 2.04 mmol) dropwise. The reaction mixture was
stirred for 30 min at 0 °C before it was diluted with CH2Cl2
(20 mL) and 15 mL of saturated aqueous NaHCO3 solution.
The organic layer was separated, and the aqueous layer was
further extracted with CH2Cl2 (2 × 15 mL). All the organic
layers were combined and dried with MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (EtOAc/hexanes, 25:75) to give
the desired product (737 mg, 87%) as a white solid: Rf 0.68
(EtOAc/hexanes, 25:75); mp 82.9-85.7 °C; [R]D 20 -59.1 (c 1.01,
CH2Cl2); IR νmax (film) 3084, 3027, 2957, 2928, 1763, 1693,
Experimental Section
(R)-4-Benzyl-3-((2R,3S,E)-3-hydroxy-2-methyl-5-phenyl-
pent-4-enoyl)oxazolidin-2-one (-)-15. Di-n-butylboryltri-
fluoromethanesulfonate (3.78 mL, 15 mmol) was added to a
solution of (R)-4-benzyl-3-propionyloxazolidin-2-one 14 (2.91
g, 12.5 mmol) in 28 mL of CH2Cl2 at such a rate as to maintain
the internal temperature below +3 °C (type K thermocouple
thermometer). Triethylamine (2.26 mL, 16.25 mmol) was then
added dropwise (internal temperature below +4 °C). The
(25) New compounds and the additional isolated intermediates gave
satisfactory 1H and 13C NMR, IR, HRMS, and analytical data. Yields
refer to chromatographically and spectroscopically homogeneous ma-
terials.
1467, 1387, 1259, 1200 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.40-7.20 (m, 10H), 6.52 (d, J 16.1 Hz, 1H), 6.25 (dd, J 16.1,
7.0 Hz, 1H), 4.55 (m, 1H), 4.49 (td, J 6.2, 0.7 Hz, 1H), 4.13 (t,
J. Org. Chem, Vol. 70, No. 6, 2005 2229

Dias et al.
J 6.8 Hz, 1H), 4.09 (dd, J 9.0, 2.0 Hz, 1H), 3.92 (dd, J 8.2, 7.7
Hz, 1H), 3.27 (dd, J 13.3, 2.9 Hz, 1H), 2.78 (dd, J 13.3, 9.5 Hz,
1H), 1.30 (d, J 7.0 Hz, 3H), 0.93 (s, 9H), 0.09 (s, 3H), 0.05 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 174.5, 153.0, 136.4, 135.2,
130.6, 129.3, 128.8, 128.5, 127.5, 127.2, 126.3, 75.4, 65.9, 55.6,
44.6, 37.8, 25.8, 18.2, 13.0, -4.0, -4.9; HRMS calcd for C28H37-
NO4Si [M+] 479.2492, found 479.2498. Anal. Calcd for C28H37-
NO4Si: C, 70.11; H, 7.77; N, 2.92. Found: C, 69.77; H, 7.53;
N, 2.97.
2.53 (m, 1H), 1.08 (d, J 7.0 Hz, 3H), 0.91 (s, 9H), 0.06 (s, 3H),
0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.9, 151.3, 136.7,
130.8, 130.4, 128.5, 127.5, 126.4, 120.8, 76.6, 51.4, 43.6, 25.9,
18.3, 14.4, -4.0, -4.7; HRMS calcd for C21H32O3Si [M+]
360.2120, found 360.2101. Anal. Calcd for C21H32O3Si: C,
69.95; H, 8.95. Found: C, 69.68; H, 8.51.
(2E,4S,5S,6E)-5-(tert-Butyldimethylsilyloxy)-4-methyl-
7-phenylhepta-2,6-dien-1-ol (+)-(13). To a stirred solution
of R,â-unsaturated ester 17 (652 mg, 1.70 mmol) in CH2Cl2
(10 mL) at -15 °C was added DIBALH (0.82 mL, 4.55 mmol).
After 2 h at -15 °C, aqueous sodium tartrate (0.5 M, 10 mL)
was added and the solution was warmed to ambient temper-
ature and stirred for 30 min. Additional sodium tartrate (0.5
M, 10 mL) was added, and the organic layer was diluted with
CH2Cl2 (10 mL). The aqueous layer was further extracted with
CH2Cl2, and the combined organic layers were washed with
H2O and brine, dried over MgSO4, filtered, and concentrated
in vacuo. The crude product was purified by flash chromatog-
raphy with EtOAc/hexanes (20:80) as the eluant to give allylic
alcohol 13 (565 mg, 94%) as a colorless oil (82% over three
(2S,3S,E)-3-(tert-Butyldimethylsilyloxy)-2-methyl-5-
phenylpent-4-en-1-ol (+)-16. To a solution of 207 mg (0.433
mmol) of the previously prepared imide and 44 µL (1.08 mmol)
of MeOH in 1.8 mL of THF at 0 °C was slowly added 0.54 mL
(1.08 mmol) of a 1.0 M solution of LiBH4 in THF (gas
evolution). After the reaction mixture was stirred for 2 h at 0
°C, the reaction was quenched by the addition of 1.5 mL of
1.0 M aqueous sodium potassium tartrate solution and the
mixture stirred for an additional 10 min. The mixture was then
diluted with 5 mL of CH2Cl2 and 1.5 mL of 1.0 M aqueous
sodium potassium tartrate solution. The layers were sepa-
rated, and the aqueous layer was extracted with two 5 mL
portions of CH2Cl2. The combined organic extracts were
washed with 5 mL of brine, dried over anhydrous MgSO4, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (EtOAc/hexanes, 25%) to give the
desired product 16 (114 mg, 86%) as a viscous oil: Rf 0.24
20
steps): Rf 0.50 (EtOAc/hexanes, 20:80); [R]D +22.4 (c 1.18,
CH2Cl2); IR νmax (film) 3370, 3033, 2954, 2931, 2858, 1690,
1601, 1470, 1360, 1260 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.37-7.20 (m, 5H), 6.47 (dd, J 16.2, 0.7 Hz, 1H), 6.14 (dd, J
16.2, 6.8 Hz, 1H), 5.74 (dd, J 15.0, 6.8 Hz, 1H), 5.64 (dt, J
15.0, 5.4 Hz, 1H), 4.12 (m, 3H), 2.38 (sext, J 6.5 Hz, 1H), 1.49
(brs, 1H), 1.04 (d, J 7.0 Hz, 3H), 0.92 (s, 9H), 0.069 (s, 3H),
0.030 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.1, 135.3, 131.4,
130.2, 129.0, 128.5, 127.3, 126.3, 77.2, 63.9, 43.3, 25.9, 18.3,
15.1, -4.14, -4.80; HRMS calcd for C20H32O2Si [M+] 332.2171,
found 332.2166. Anal. Calcd for C20H32O2Si: C, 72.23; H, 9.70.
Found: C, 71.15; H, 9.72.
(EtOAc/hexane, 10:90); [R]20 +56.5 (c 1.15, CH2Cl2); IR νmax
D
(film) 3383, 3085, 3059, 3032, 2959, 2853, 1475, 1359, 1253,
1122, 1033 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40-7.18 (m,
5H), 6.54 (d, J 16.0 Hz, 1H), 6.24 (dd, J 16.0, 6.4 Hz, 1H), 4.43
(dd, J 6.4, 3.8 Hz, 1H), 3.71 (dd, J 10.6, 8.8 Hz, 1H), 3.53 (dd,
J 10.6, 4.4 Hz, 1H), 2.07 (m, 1H), 0.93 (s, 9H), 0.86 (d, J 6.6
Hz, 3H), 0.11 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 136.7, 131.0, 129.3, 128.5, 127.5, 126.3, 77.2, 65.8, 41.4, 25.9,
18.2, 12.5, -4.1, -4.9; HRMS calcd for C18H30O2Si [M+]
306.2015, found 306.2019. Anal. Calcd for C18H30O2Si: C,
70.53; H, 9.87. Found: C, 70.13; H, 9.91.
((2R,3R)-3-((2S,3S,E)-3-(tert-Butyldimethylsilyloxy)-5-
phenylpent-4-en-2-yl)oxiran-2-yl)methanol (+)-(12). To a
stirred solution of allylic alcohol 13 (252 mg, 0.76 mmol) in
CH2Cl2 (8 mL) at 0 °C was added m-CPBA (261 mg, 1.51 mmol,
77% pure), and the resulting white suspension was stirred for
1 h. The reaction mixture was quenched by addition of
saturated aqueous Na2S2O3 (2 mL) and stirred for 15 min at
ambient temperature. After addition of 5% NaHCO3 aqueous
solution (15 mL), the mixture was extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were washed with H2O
and brine and then dried over MgSO4, filtered, and concen-
trated in vacuo. The crude product was purified by flash
chromatography with EtOAc/hexanes (20:80) as the eluant to
give epoxide 12 (248 mg, 94%, dr 92:8) as a colorless oil: Rf
0.38 (EtOAc/hexanes, 20:80); [R]D20 +34.3 (c 1.20, CH2Cl2); IR
νmax (film) 3435, 3028, 2922, 2859, 2652, 1704, 1475, 1256, 1073
(2E,4S,5S,6E)-Methyl 5-(tert-Butyldimethylsilyloxy)-4-
methyl-7-phenylhepta-2,6-dienoate (+)-17. To a solution
of 0.45 mL (6.41 mmol) of DMSO in 15 mL of CH2Cl2 at -78
°C was added 0.43 mL (4.97 mmol) of oxalyl chloride (gas
evolution). After 10 min, a solution of 633 mg (2.07 mmol) of
alcohol (+)-16 in 10 mL of CH2Cl2 was added, forming a cloudy
white mixture. This was stirred for 15 min at -78 °C, and
then 1.44 mL (10.35 mmol) of triethylamine was added. The
reaction mixture was stirred at -78 °C for 40 min, and then
the reaction was quenched by the addition of 10 mL of
saturated aqueous NH4Cl. The mixture was allowed to warm
to ambient temperature then diluted with 30 mL of CH2Cl2.
The layers were separated, and the aqueous phase was
extracted with two 20 mL portions of CH2Cl2. The combined
organic extracts were washed with 30 mL of brine, dried over
anhydrous MgSO4, and concentrated in vacuo. 1H NMR
spectroscopy of the unpurified aldehyde was very clean. To a
stirred suspension of NaH (198 mg, 8.28 mmol) in THF (10
mL) at 0 °C under argon was added methyl diethylphosphono-
acetate (1.7 mL, 9.31 mmol). The reaction mixture was allowed
to warm to ambient temperature, and then a solution of the
previously prepared aldehyde (304 mg, 2.07 mmol) in 5 mL of
THF was added dropwise. After stirring for 12 h, the reaction
was diluted with 15 mL of Et2O and quenched by the slow
addition of 6 mL of H2O. The layers were separated, and the
aqueous phase was extracted with two 15 mL portions of Et2O.
The combined organic extracts were washed with 30 mL of
brine, dried over anhydrous MgSO4, and concentrated in vacuo
to give unsaturated ester 17 as a viscous oil that was used in
the next step without further purification: Rf 0.53 (EtOAc/
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.38-7.21 (m, 5H), 6.55
(d, J 15.9 Hz, 1H), 6.18 (dd, J 15.9, 6.4 Hz, 1H), 4.50 (m, 1H),
3.92 (dd, J 12.4, 2.2 Hz, 1H), 3.63 (dd, J 12.4, 4.4 Hz, 1H),
3.02 (dd, J 7.7, 2.2 Hz, 1H), 2.98 (m, 1H), 1.76 (brs, 1H), 1.54
(quint d, J 7.3, 3.3 Hz, 1H), 0.96 (d, J 7.0 Hz, 3H), 0.95 (s,
9H), 0.12 (s, 3H), 0.064 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
136.9, 131.2, 130.0, 128.6, 127.4, 126.3, 74.1, 61.8, 58.0, 57.8,
42.7, 25.9, 18.2, 9.9, -4.2, -5.0; HRMS calcd for C20H32O3Si
[M+] 348.2120, found 348.2118. Anal. Calcd for C20H32O3Si:
C, 68.92; H, 9.25. Found: C, 69.27; H, 9.29.
(2S,3S,4S,5S,E)-5-(tert-Butyldimethylsilyloxy)-2,4-di-
methyl-7-phenylhept-6-ene-1,3-diol (+)-(18). To a suspen-
sion of copper(I) cyanide (500 mg, 5.58 mmol) in THF (2.3 mL)
at -78 °C was added a solution of MeLi in Et2O (7.7 mL, 10.6
mmol) dropwise. After the solution was stirred at -78 °C for
30 min, a solution of epoxide 12 (216 mg, 0.62 mmol) in THF
(3 mL) was added. The reaction mixture was stirred at -20
°C for 20 h, and a 2:1 (3 mL) mixture of saturated aqueous
NH4Cl and 28% aqueous NH3 was added. The resulting
mixture was stirred at room temperature for 1.5 h, and the
organic layer was separated. The aqueous layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with H2O and brine (5 mL of each), dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The
20
hexane, 10:90); [R]D +28.2 (c 1.24, CH2Cl2); IR νmax (film)
3022, 2954, 2931, 2863, 1726, 1658, 1437 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.37-7.20 (m, 5H), 7.03 (dd, J 15.7, 7.3 Hz,
1H), 6.49 (d, J 15.8 Hz, 1H), 6.10 (dd, J 15.8, 6.5 Hz, 1H), 5.82
(dd, J 15.7, 1.0 Hz, 1H), 4.22 (apt, J 6.5 Hz, 1H), 3.72 (s, 3H),
2230 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of (+)-Crocacin D
crude product was purified by flash chromatography with
1469, 1426, 1260 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.66 (m,
4H), 7.40-7.29 (m, 10H), 7.23 (t, J 7.0 Hz, 1H), 6.53 (d, J 16.0
Hz, 1H), 6.12 (dd, J 16.0, 7.1 Hz, 1H), 4.01 (dd, J 7.1, 2.6 Hz,
1H), 3.76 (dd, J 10.0, 5.3 Hz, 1H), 3.56 (dd, J 10.2, 8.1 Hz,
1H), 3.46 (s, 3H), 3.31 (s, 3H), 3.19 (dd, J 9.1, 2.6 Hz, 1H),
2.02 (m, 1H), 1.75 (m, 1H), 1.12 (d, J 7.0 Hz, 3H), 1.03 (s, 9H),
0.81 (d, J 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 136.8,
135.5, 133.9, 131.6, 129.6, 129.4, 129.3, 128.4, 127.5, 127.3,
126.2, 85.4, 81.4, 64.8, 61.1, 56.5, 41.7, 38.0, 26.9, 19.3, 16.0,
10.5; HRMS calcd for C33H44O3Si [M+] 516.3060, found 516.3090.
EtOAc/hexanes (20:80) as the eluant to give diol 18 (203 mg,
20
90%) as a colorless oil: Rf 0.38 (EtOAc/hexanes, 20:80); [R]D
+17.1 (c 1.19, CH2Cl2); IR νmax (film) 3400, 2962, 2931, 2860,
1640, 1456, 1257 cm-1; H NMR (300 MHz, CDCl3) δ 7.40-
1
7.23 (m, 5H), 6.54 (d, J 15.9 Hz, 1H), 6.27 (dd, J 15.9, 7.0 Hz,
1H), 4.57 (dd, J 7.0, 3.3 Hz, 1H), 3.94 (dd, J 10.8, 2.7 Hz, 1H),
3.68 (dd, J 8.4, 4.0 Hz, 1H), 3.61 (dd, J 10.8, 5.0 Hz, 1H), 2.11
(quint d, J 8.0, 3.3 Hz, 1H), 1.78 (m, 1H), 1.11 (d, J 7.0 Hz,
3H), 0.93 (s, 9H), 0.91 (d, J 8.0 Hz, 3H), 0.15 (s, 3H), 0.09 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 136.3, 131.5, 128.5, 128.1,
127.7, 126.4, 80.2, 78.4, 65.4, 41.5, 36.2, 25.8, 18.1, 15.1, 13.1,
-4.0, -4.9; HRMS calcd for C21H36O3Si [M+] 364.2433, found
364.2296.
(2S,3S,4R,5S,E)-3,5-Dimethoxy-2,4-dimethyl-7-phenyl-
hept-6-en-1-ol (-)-(20). To a solution of the previously
prepared dimethyl ether (0.202 g, 0.393 mmol) in 2 mL of THF,
at ambient temperature, was added 0.79 mL (0.79 mmol) of a
1.0 M solution of TBAF in THF. The reaction mixture was
stirred at ambient temperature for 16 h and then concentrated
in vacuo. The crude product was purified by flash chromatog-
raphy (EtOAc/hexanes 25%) as the eluant to give primary
alcohol 20 (108 mg, 99%) as a colorless oil: Rf 0.35 (EtOAc/
(2S,3S,4R,5S,E)-2,4-Dimethyl-7-phenylhept-6-ene-1,3,5-
triol. To a solution of diol 18 (0.253 g, 0.696 mmol) in 5 mL of
THF, at ambient temperature, was added 1.39 mL (1.39 mmol)
of a 1.0 M solution of TBAF in THF. The reaction mixture was
stirred at ambient temperature for 16 h and then concentrated
in vacuo. The crude product was purified by flash chromatog-
raphy (EtOAc/hexanes 80%) as the eluant to give the desired
triol (172 mg, 99%) as a colorless oil: Rf 0.42 (EtOAc/hexane,
20
20
hexane, 30:70); [R]D -3.6 (c 1.80, CH2Cl2); lit. [R]D -4.1 (c
1.87, CH2Cl2); IR νmax (film) 3456, 3052, 2971, 2933, 2833, 1613,
1526, 1460, 1378, 1250 cm-1 1H NMR (300 MHz, CDCl3) δ
;
20
7.41 (dd, J 7.3, 1.5 Hz, 2H), 7.32 (t, J 7.3 Hz, 2H), 7.24 (tt, J
7.3, 1.5 Hz, 1H), 6.58 (d, J 15.9 Hz, 1H), 6.18 (dd, J 15.9, 7.3
Hz, 1H), 4.06 (dd, J 7.3, 1.8 Hz, 1H), 3.82 (dd, J 10.8, 3.7 Hz,
1H), 3.54 (dd, J 10.8, 4.8 Hz, 1H), 3.53 (s, 3H), 3.32 (s, 3H),
3.28 (dd, J 9.1, 2.6 Hz, 1H), 2.78 (brs, 1H), 1.87 (m, 2H), 1.20
(d, J 7.3 Hz, 3H), 0.91 (d, J 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 136.5, 131.9, 129.1, 128.4, 127.4, 126.2, 88.2, 81.1,
64.4, 61.5, 56.3, 42.2, 35.9, 16.2, 10.4; HRMS calcd for C17H26O3
[M+ (278.1882) - H2CO] 248.1776, found [M+ - H2CO]
248.1410. Anal. Calcd for C17H26O3: C, 73.34; H, 9.41. Found:
C, 72.49; H, 9.41.
80:20); [R]D +9.6 (c 0.98, CH2Cl2); IR νmax (film) 3294, 3055,
2924, 1755, 1670, 1406 cm-1 1H NMR (500 MHz, CDCl3) δ
;
7.39 (d, J 7.5 Hz, 2H) 7.31 (t, J 7.5 Hz, 2H), 7.24 (apt, J 7.5
Hz, 1H), 6.62 (d, J 15.9 Hz, 1H), 6.26 (dd, J 15.9, 5.8 Hz, 1H),
4.76 (brs, 1H), 4.71 (d, J 5.5 Hz, 1H), 4.08 (brs, 1H), 3.88 (dd,
J 10.7, 3.0 Hz, 1H), 3.66 (m, 3H), 1.99 (m, 2H), 1.04 (d, J 7.1
Hz, 3H), 0.93 (d, J 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
136.6, 130.2, 130.0, 128.4, 127.4, 126.3, 82.2, 73.4, 67.8, 39.3,
36.9, 14.1, 11.7; HRMS calcd for C15H22O3 [M+] 250.1568, found
250.1562. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found:
C, 71.27; H, 8.36.
tert-Butyldimethyl((3S,4S,E)-1-phenyl-4-((4S,5S)-2,2,5-
trimethyl-1,3-dioxan-4-yl)pent-1-en-3-yloxy)silane (21).
To a solution of diol 18 (15 mg, 0.041 mmol) in 2,2-dimethoxy-
propane (3 mL) at ambient temperature were added a few
crystals of PPTS. The reaction mixture was stirred at ambient
temperature for 2 h before it was concentrated in vacuo. The
remaining organic residue was purified by flash chromatog-
raphy on silica gel using EtOAc/hexanes (5:95) as the eluant
to provide the desired product 21 (14.4 mg, 87%) as a colorless
oil: Rf 0.58 (EtOAc/hexanes, 30:70); 1H NMR (300 MHz,
CDCl3) δ 7.17-7.39 (m, 5H), 6.43 (d, J 15.7, 1H), 6.30 (dd, J
15.9, 7.1 Hz, 1H), 4.40 (dd, J 7.0, 5.1 Hz, 1H), 3.69 (dd, J 11.5,
4.9 Hz, 1H), 3.46 (dd, J 9.9, 4.4 Hz, 1H), 3.39 (dd, J 11.7, 9.5
Hz, 1H), 2.04 (m, 1H), 1.89 (m, 1H), 1.38 (s, 6H), 1.01 (d, J 7.0
Hz, 3H), 0.91 (s, 9H), 0.82 (d, J 6.6 Hz, 3H), 0.07 (s, 3H), 0.02
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.4, 133.3, 129.4, 128.5,
127.2, 126.3, 98.3, 74.7, 66.2, 43.4, 32.4, 29.7, 29.2, 26.0, 19.7,
18.2, 14.3, 13.2, -3.7, -4.7.
(3S,4R,5S,6S,E)-7-(tert-Butyldiphenylsilyloxy)-4,6-di-
methyl-1-phenylhept-1-ene-3,5-diol (+)-(19). To a stirred
solution of the corresponding triol prepared before (172 mg,
0.69 mmol) in CH2Cl2 (4 mL) at -5 °C were added imidazole
(59.3 mg, 0.904 mmol) and tert-butyldiphenylsilyl chloride (199
mg, 0.765 mmol), and stirring was continued for 1 h. The
reaction mixture was partitioned between EtOAc and H2O, and
then the organic layer was washed with brine, dried over
anhydrous MgSO4, filtered, and evaporated. Purification of the
crude product on silica gel with EtOAc/hexanes (15:85) as the
eluant gave the silyl ether 19 (301.5 mg, 90%) as a colorless
20
oil: Rf 0.62 (EtOAc/hexanes, 50:50); [R]D +9.6 (c 1.10,
CH2Cl2); lit.4 [R]D20 +10.1 (c 1.35, CH2Cl2); IR νmax (film) 3420,
3054, 2962, 2927, 2859 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.69 (m, 3H), 7.51-7.38 (m, 8H), 7.32 (tt, J 7.3, 1.5 Hz, 2H),
7.22 (tt, J 7.3, 1.5 Hz, 2H), 6.67 (dd, J 15.8, 1.5 Hz, 1H), 6.27
(dd, J 15.9, 5.3 Hz, 1H), 4.77 (d, J 2.9 Hz, 1H), 4.72 (m, 1H),
4.29 (d, J 2.9 Hz, 1H), 3.88 (dd, J 10.2, 3.7 Hz, 1H), 3.72 (m,
1H), 3.69 (dd, J 10.2, 7.3 Hz, 1H), 2.10 (quint d, J 7.3, 3.7 Hz,
1H), 1.95 (m, 1H), 1.08 (s, 9H), 1.06 (d, J 7.3 Hz, 3H), 0.88 (d,
J 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 137.2, 135.6, 132.3,
132.2, 131.0, 130.1, 130.0, 129.7, 128.5, 127.9, 127.8, 127.2,
126.4, 82.1, 72.8, 69.4, 39.7, 36.7, 26.8, 19.0, 13.7, 11.7; HRMS
calcd for C31H40O3Si [M+] 488.2747, found 488.2739.
tert-Butyldiphenyl((S)-2-((4S,5R,6S)-2,2,5-trimethyl-6-
((E)-styryl)-1,3-dioxan-4-yl)propoxy)silane (22). To a solu-
tion of diol 19 (14.9 mg, 0.03 mmol) in 2,2-dimethoxypropane
(3 mL) at ambient temperature were added a few crystals of
PPTS. The reaction mixture was stirred at ambient temper-
ature for 2 h before it was concentrated in vacuo. The
remaining organic residue was purified by flash chromatog-
raphy on silica gel using EtOAc/hexanes (5:95) as the eluant
to provide the desired product 22 (12.9 mg, 80%) as a colorless
oil: Rf 0.52 (EtOAc/hexanes, 5:95); 1H NMR (500 MHz, CDCl3)
δ 7.72 (d, J 7.2 Hz, 4H), 7.39-7.47 (m, 8H), 7.33 (t, J 7.3 Hz,
2H), 7.24 (t, J 7.1 Hz, 1H), 6.57 (d, J 15.9, 1H), 6.18 (dd, J
16.2, 6.1 Hz, 1H), 4.54 (ap t, J 5.5 Hz, 1H), 3.75 (dd, J 10.1,
5.2 Hz, 1H), 3.69 (dd, J 10.1, 5.8 Hz, 1H), 3.45 (dd, J 7.2, 5.8
Hz, 1H), 2.0 (m, 1H), 1.90 (m, 1H), 1.40 (s, 3H), 1.37 (s, 3H),
tert-Butyl((2S,3S,4R,5S,E)-3,5-dimethoxy-2,4-dimethyl-
7-phenylhept-6-enyloxy)diphenylsilane. To a stirred sus-
pension of KH (170 mg, 4.24 mmol) in THF (10 mL) at 0 °C
under argon was added a solution of diol 19 (346 mg, 0.708
mmol) in THF (12 mL) via cannula; then, MeI (264 µL, 4.24
mmol) was added dropwise, and the reaction mixture was
warmed to ambient temperature and stirred for 2 h. The
mixture was cooled to 0 °C, and H2O (5 mL) was cautiously
added followed by Et2O (10 mL); the combined organic layers
were washed with brine, dried (MgSO4), filtered, and evapo-
rated. The crude product was purified on silica gel using
EtOAc/hexanes (5:95) as the eluant to give the dimethyl ether
(356 mg, 97%) as a colorless oil: Rf 0.67 (EtOAc/hexanes, 10:
1.08 (s, 9H), 1.04 (d, J 6.7 Hz, 3H), 0.93 (d, J 6.7 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 137.1, 135.7, 135.6, 133.9, 130.2,
129.5, 128.4, 127.8, 127.6, 127.3, 126.3, 100.5, 75.8, 70.5, 65.1,
39.9, 38.1, 26.9, 25.9, 23.7, 19.3, 13.8, 13.5.
20
20
90); [R]D -17.6 (c 1.36, CH2Cl2); lit.4 [R]D -17.6 (c 1.14,
CH2Cl2); IR νmax (film) 3050, 2965, 2930, 2890, 2859, 2827,
1-((1E,3S,4R,5S,6S,7E)-8-Iodo-3,5-dimethoxy-4,6-di-
methylocta-1,7-dienyl)benzene (-)-(10). To a stirred solu-
J. Org. Chem, Vol. 70, No. 6, 2005 2231

Dias et al.
tion of the alcohol 20 (41 mg, 0.147 mmol) in CH2Cl2 (3 mL)
at ambient temperature under argon was added Dess-Martin
periodinane (125 mg, 0.294 mmol), and stirring was continued
for 15 min. Saturated aqueous NaHCO3 (2 mL), aqueous
Na2S2O3 (1.5 M, 2 mL), and Et2O (5 mL) were added, and
stirring was continued for 15 min at ambient temperature. The
aqueous layer was further extracted with Et2O, and the
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. To a stirred solution of
anhydrous chromium(II) chloride (299 mg, 2.44 mmol, gently
flame-dried under vacuum: 0.1 mmHg) in dry THF (1 mL) at
ambient temperature was added dropwise via cannula a
solution of the corresponding aldehyde (40.6 mg, 0.147 mmol)
and iodoform (319 mg, 0.814 mmol) in THF (3 mL). The
reaction mixture was stirred in the dark at ambient temper-
ature for 1 h, during which time it turned brown. The reaction
was quenched by the addition of H2O (5 mL), and the phases
were separated. The aqueous layer was extracted with Et2O
(3 × 10 mL), and the combined organic layers were washed
with Na2S2O3 solution (6 mL, 0.5 N aq) and brine (10 mL),
dried with MgSO4, and concentrated in vacuo to give a yellow
solid. The crude product was purified by flash column chro-
matography (EtOAc/hexanes, 5:95) to give the vinyl iodide 10
(39.6 mg, E:Z > 95:5, 67% for the two steps) as a pale yellow
375.1584, found 375.1453. Anal. Calcd for C16H33NOSn: C,
51.36; H, 8.89. Found: C, 51.86; H, 9.01.
(2E,4E,6S,7S,8R,9S,10E)-7,9-Dimethoxy-3,6,8-trimeth-
yl-11-phenylundeca-2,4,10-trienamide (3) [(+)-Crocacin
C]. To a stirred suspension of CuI(I) (64 mg, 0.65 mmol) and
triphenylarsine (4.5 mg, 0.015 mmol) in THF (5 mL) under
argon was added tris(dibenzylideneacetone)dipalladium(0) (6
mg, 0.006 mmol). After 5 min, (E)-vinyl iodide 10 (44 mg, 0.11
mmol) in THF (1 mL) was added, and the resulting suspension
was stirred for an additional 30 min. A solution of stannane 9
(45 mg, 0.12 mmol) in THF (1 mL) was added, and the
resultant brown solution was stirred at 25 °C for 1 h and then
warmed to 55 °C and stirred for 15 h. The reaction mixture
was partitioned between EtOAc and H2O, and the organic
layer was washed with H2O and then brine and dried. The
crude product was purified on silica gel with EtOAc/hexane
(40%) as the eluant to give crocacin C (3) (35 mg, 84%) as a
white powder: Rf 0.50 (petrol/EtOAc, 1:1); [R]D20 + 53.6 (c 0.21,
MeOH); lit.1 [R]D +52.2 (c 0.3, MeOH); IR νmax (film) 3478,
22
3349, 3207, 3055, 2976, 2931, 1660, 1448, 1088 cm-1; 1H NMR
(500 MHz, acetone-d6) δ 7.46 (dd, J 8.0, 1.8 Hz, 2H), 7.31 (dd,
J 8.0, 7.5 Hz, 2H), 7.22 (dd, J 7.5, 7.5 Hz, 1H), 6.65 (br s, 1H),
6.59 (d, J 16.2 Hz, 1H), 6.25 (dd, J 7.1, 16.2 Hz, 1H), 6.10 (br
s, 1H), 6.02-6.12 (m, 2H), 5.80 (d, J 1.1 Hz, 1H), 4.08 (ddd, J
7.3, 2.6, 1.1 Hz, 1H), 3.29 (s, 3H), 3.52 (s, 3H), 3.19 (dd, J 2.2,
9.5 Hz, 1H), 2.62 (m, 1H), 2.21 (d, J 1.1 Hz, 3H), 1.58 (m, 1H),
1.20 (d, J 6.8 Hz, 3H), 0.88 (d, J 7.0 Hz, 3H); 13C NMR (125
MHz, acetone-d6) δ 169.1, 148.1, 137.9, 137.1, 135.0, 132.5,
130.5, 129.4, 128.3, 127.2, 121.9, 87.1, 81.8, 61.4, 56.5, 43.6,
40.8, 19.3, 13.5, 10.2; HRMS (ESI) calcd for C22H31NO3 [M+]
357.2304, found 357.2304.
20
oil: Rf 0.64 (EtOAc/hexanes, 25:75); [R]D -6.1 (c 1.20,
CH2Cl2); 1H NMR (300 MHz, C6D6) δ 7.27-7.07 (m, 5H), 6.80
(dd, J 14.4, 9.1 Hz, 1H), 6.48 (d, J 16.1 Hz, 1H), 6.08 (dd, J
16.1, 7.0 Hz, 1H), 5.78 (d, J 14.4 Hz, 1H), 4.12 (ddd, J 7.0, 2.2,
1.1 Hz, 1H), 3.35 (s, 3H), 3.20 (s, 3H), 3.06 (dd, J 9.7, 2.0 Hz,
1H), 2.23 (m, 1H), 1.70 (m, 1H), 0.98 (d, J 7.0 Hz, 3H), 0.87
(d, J 7.0 Hz, 3H); 13C NMR (75 MHz, C6D6) δ 148.0, 137.2,
132.1, 129.6, 128.3, 127.7, 126.8, 86.1, 81.1, 75.4, 61.4, 56.2,
43.7, 43.0, 18.5, 10.1.
3-(Triisopropylsilyloxy)propan-1-ol (30). To a stirred
suspension of NaH (444 mg, 11.1 mmol) in THF (20 mL) at 0
°C under argon was added dropwise a solution of 1,3-pro-
panediol (0.80 mL, 11.1 mmol). After the mixture was stirred
for 30 min at room temperature, triisopropylsilyl chloride (1.19
mL, 11.1 mmol) was added in one portion. The reaction
mixture was stirred for 18 h at room temperature and diluted
with Et2O (20 mL) followed by addition of H2O (20 mL). The
organic phase was separated; the aqueous layer was further
extracted with Et2O, and the combined organic layers were
washed with brine, dried (MgSO4), filtered, and evaporated.
The crude product was purified on silica gel using EtOAc/
hexanes (10:90) as the eluant to give the desired alcohol 30
(2.20 g, 86%): Rf 0.37 (EtOAc/hexane 20%); IR νmax (film) 3400,
2942, 2863, 1465, 1386, 1267 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.93 (t, J 5.5 Hz, 2H), 3.84 (t, J 5.5 Hz, 2H), 1.80 (quint, J
5.5 Hz, 2H); 1.09 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 63.5,
62.6, 34.3, 18.0, 11.9; HRMS calcd for C12H28O2Si [M+ (232.1859)
- (CH3)2CH+] 189.1317, found 189.1375.
(E)-Methyl 5-(Triisopropylsilyloxy)pent-2-enoate (31).
To a solution of 0.60 mL (6.66 mmol) of oxalyl chloride in 50
mL of CH2Cl2 at -78 °C was added 1.0 mL (5.55 mmol) of
DMSO (gas evolution). After 10 min, a solution of 1.29 g (5.55
mmol) of the alcohol 30 in 20 mL of CH2Cl2 was added. The
cloudy white mixture was stirred for 15 min at -78 °C, after
which 3.8 mL (27.7 mmol) of triethylamine was added. The
reaction mixture was stirred at -78 °C for 40 min, and then
the reaction was quenched by the addition of 30 mL of
saturated aqueous NH4Cl. The mixture was allowed to warm
to room temperature and then diluted with 30 mL of CH2Cl2
and 30 mL of saturated aqueous NH4Cl. The layers were
separated, and the aqueous phase was extracted with two 30
mL portions of CH2Cl2. The combined organic extracts were
washed with 30 mL of brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. A 1H NMR spectrum of the
unpurified aldehyde proved to be very clean. To a stirred
suspension of NaH (160 mg, 6.66 mmol) in THF (12 mL) at 0
°C under argon was added methyldiethylphosphonoacetate (1.3
mL, 7.21 mmol). After stirring for 30 min at room temperature,
the previously prepared aldehyde in THF (5 mL) was added.
The reaction mixture was stirred for 1 h at room temperature
(E)-Ethyl 3-(Tributylstannyl)but-2-enoate (23). To a
solution of LDA (9.36 mmol) was added dropwise tributyltin
hydride (2.6 mL, 8.92 mmol) at 0 °C. After cooling to -50 °C,
the solution was added to CuBr‚Me2S complex (1.84 g, 8.92
mmol). After 30 min of stirring, a precooled solution of ethyl-
2-butynoate 11 (500 mg, 4.46 mmol) and dry MeOH (0.31 mL,
7.58 mmol) in dry THF (30 mL) was added to the cuprate at
-95 °C. After stirring for 30 min at -95 °C and 2 h at -78
°C, the mixture was poured into 5% aqueous NH4OH (3 mL).
Extraction with Et2O (3 × 15 mL), drying, solvent evaporation,
and column chromatography (hexanes) gave 23 (1.26 g, 70%)
as a colorless oil: Rf 0.69 (hexanes 100%); IR νmax (film) 2930,
1
1713, 1596, 1170 cm-1; H NMR (300 MHz, CDCl3) δ 5.96 (q,
J 1.8 Hz, 1H), 4.16 (q, J 7.0 Hz, 2H), 2.40 (d, J 1.8 Hz, 3H),
1.50 (m, 6H), 1.31 (m, 9H), 0.96 (m, 6H), 0.90 (t, J 7.3 Hz,
9H); 13C NMR (75 MHz, CDCl3) δ 171.1, 164.4, 128.1, 60.3,
28.9, 27.3, 22.3, 14.1, 13.6, 9.4. Anal. Calcd for C18H36O2Sn:
C, 53.62; H, 9.00. Found: C, 53.56; H, 9.17.
(E)-3-(Tributylstannyl)but-2-enamide (9). To a suspen-
sion of NH4Cl (490 mg, 9.2 mmol) in toluene (5.0 mL) under
argon at 0 °C was added dropwise a solution of AlMe3 in
toluene (2 M, 4.6 mL, 9.2 mmol). The resulting solution was
allowed to warm to ambient temperature and then recooled
to 0 °C; a solution of R,â-unsaturated ester 23 (1 g, 2.50 mmol)
in toluene (40 mL) was added, and the mixture was heated to
50 °C for 16 h. The reaction mixture was then cooled to 0 °C
and treated with EtOAc (75 mL) followed by 10% HCl (25 mL)
in saturated NaCl, and the organic layer was washed with
saturated aqueous NaHCO3 and brine; the dried solvent was
removed. The crude product was purified by flash chromatog-
raphy on silica gel (EtOAc/hexanes, 80:20) as the eluant to
give (E)-vinylstannane 9 (590 mg, 72%) as a white solid: Rf
0.60 (EtOAc 100%); mp 39.5 °C; IR νmax (film) 3339, 3187, 2960,
2926, 2853, 1656, 1549, 1377 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.92 (q, J 1.8 Hz, 1H), 5.46 (brs, 1H), 5.36 (brs, 1H), 2.35 (d,
J 1.8 Hz, 3H), 1.49 (m, 6H), 1.31 (m, 6H), 0.96 (m, 6H), 0.89
(t, J 7.3 Hz, 9H); 13C NMR (75 MHz) δ 167.3, 162.9, 130.2,
29.0, 27.3, 22.1, 13.6, 9.3; HRMS calcd for C16H33NOSn
2232 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of (+)-Crocacin D
and diluted with Et2O (20 mL) followed by addition of H2O (6
mL). The organic phase was separated; the aqueous layer was
further extracted with Et2O, and the combined organic layers
were washed with brine, dried (MgSO4), filtered, and evapo-
rated. The crude product was purified on silica gel using
EtOAc/hexanes (10:90) as the eluant to give ester 31 (1.42 g,
89% for the two-step sequence): Rf 0.65 (EtOAc/hexane 20%);
IR νmax (film) 3051, 2946, 2867, 1730, 1651, 1259 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.00 (dt, J 15.7, 7.0 Hz, 1H); 5.88 (d, J
15.7 Hz, 1H); 3.80 (t, J 6.6 Hz, 2H), 3.72 (s, 3H), 2.44 (dt, J
7.0, 6.6 Hz, 2H); 1.06 (m, 21H); 13C NMR (75 MHz, CDCl3) δ
166.7, 146.2, 122.3, 61.8, 51.4, 36.0, 18.0, 12.0; HRMS calcd
for C15H30O3Si [M+ (286.1964) - (CH3)2CH+] 243.1422, found
243.1243.
and the combined organic layers were washed with brine, dried
(MgSO4), filtered, and evaporated. Purification by flash chro-
matography (10% EtOAc in hexane) gave 0.70 g (90%) of
dipeptide 32: Rf 0.34 (EtOAc/hexane 10%); IR νmax (film) 3055,
2940, 2870, 1747, 1688, 1459, 1365, 1263 cm-1; 1H NMR (300
MHz, CDCl3) δ 4.45 (s, 2H), 3.73 (s, 3H), 3.70 (t, J 6.2 Hz,
2H), 2.96 (t, J 7.0 Hz, 2H), 1.72 (m, 2H), 1.60 (m, 2H), 1.50 (s,
9H), 1.06 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 175.4, 169.4,
152.0, 83.7, 63.2, 52.1, 45.2, 37.9, 32.5, 28.0, 21.6, 18.1, 12.1;
HRMS calcd for C22H43NO6Si [M+ (445.2860) - (CH3)2CH+]
402.2318, found 402.1926.
Methyl 2-(N-(tert-Butoxycarbonyl)-5-hydroxypentan-
amido)acetate. To a solution of carbamate 32 (200 mg, 0.45
mmol) in 6.2 mL of THF at 0 °C was added 6.2 mL of a solution
of HF-pyridine/pyridine/THF (1:4:5). The reaction mixture was
stirred at ambient temperature for 18 h, diluted with 5 mL of
EtOAc, and quenched by the slow addition of powder NaHCO3
(100 mg). The resulting mixture was stirred for 15 min at room
temperature, filtered, and concentrated in vacuo. Purification
by flash chromatography (10% EtOAc in hexane) gave 0.107
g (83%) of the desired primary alcohol: Rf 0.34 (EtOAc/hexane
10%); IR νmax (film) 3423, 2958, 2876, 1747, 1691, 1347, 1341,
Methyl 5-(Triisopropylsilyloxy)pentanoate. After two
vacuum/H2 cycles to remove air from the reaction flask, a
stirred solution of 1.85 g (6.46 mmol) of the R,â-unsaturated
ester 31 and 10% Pd/C (185 mg, 10% m/m) in 10 mL of MeOH
was hydrogenated at 1 atm and room temperature for 24 h.
The reaction mixture was filtered (Celite) and the filtrate
concentrated. Purification by flash chromatography (10%
EtOAc in hexane) gave 1.80 g (97%) of the desired saturated
ester: Rf 0.65 (EtOAc/hexane 20%); IR νmax (film) 2945, 2860,
1
1220, 1154 cm-1; H NMR (500 MHz, CDCl3) δ 4.44 (s, 2H),
1743, 1460, 1383, 1245 cm-1
;
1H NMR (300 MHz, CDCl3) δ
3.72 (s, 3H), 3.64 (t, J 6.2 Hz, 2H), 2.96 (t, J 7.3 Hz, 2H), 1.79
(brs, 1H), 1.74 (quint, J 7.3 Hz, 2H), 1.61 (ap quint, J 6.2 Hz,
2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 175.5, 169.3,
152.0, 83.9, 62.2, 52.2, 45.2, 37.5, 32.0, 28.0, 21.1.
3.69 (t, J 6.6 Hz, 2H), 3.67 (s, 3H), 2.35 (t, J 7.0 Hz, 2H), 1.72
(m, 2H), 1.58 (m, 2H), 1.08 (m, 21H); 13C NMR (75 MHz,
CDCl3) δ 173.9, 62.8, 51.4, 33.9, 32.4, 21.5, 18.0, 12.0; HRMS
calcd for C15H32O3Si [M+ (288.2121) - (CH3)2CH+] 245.1579,
found 245.1436.
Methyl 2-(N-(tert-Butoxycarbonyl)-5-oxopentanamido)-
acetate (33). To a stirred solution of the previously prepared
primary alcohol (150 mg, 0.52 mmol) in CH2Cl2 (5 mL) at 0 °C
under argon was added pyridine (0.42 mL, 5.2 mmol), followed
by Dess-Martin periodinane (440 mg, 1.04 mmol), and stirring
was continued for 1 h at room temperature. Saturated aqueous
NaHCO3 (2 mL), aqueous Na2S2O3 (1.5 M, 2 mL), and Et2O (5
mL) were added, and stirring was continued for 15 min at rt.
The aqueous layer was further extracted with Et2O, and the
combined organic layers were dried, filtered, and concentrated
to give aldehyde 33: Rf 0.33 (EtOAc/hexane 20%); IR νmax (film)
3419, 2985, 1739, 1150 cm-1; 1H NMR (300 MHz, C6D6) δ 9.75
(apt, J 1.1 Hz, 1H), 4.43 (s, 2H), 3.72 (s, 3H), 2.99 (t, J 7.1 Hz,
2H), 2.51 (td, J 7.3 e 1.1 Hz, 2H), 1.97 (quint, J 7.3 Hz, 2H),
1.47 (s, 9H); 13C NMR (75 MHz, C6D6) δ 201.7, 174.6, 169.2,
151.9, 83.9, 52.1, 45.1, 43.0, 37.0, 27.9, 17.5.
5-(Triisopropylsilyloxy)pentanoic Acid (29). To a stirred
solution of the previously prepared saturated ester (1.80 g, 6.25
mmol) in MeOH (3 mL) was added a 3.0 M solution of KOH
in MeOH (10 mL). The reaction was stirred for 24 h at room
temperature, and citric acid was added in order to neutralize
the solution. The solvent was removed, and to the residue was
added 10 mL of a saturated aqueous solution of NaCl. The
aqueous phase was further extracted with Et2O (3 × 10 mL),
and the combined organic layers were washed with brine, dried
(MgSO4), filtered, and evaporated. Purification by flash chro-
matography (10% EtOAc in hexane) gave 1.52 g (89%) of
carboxylic acid 29: Rf 0.28 (EtOAc/hexane 20%); IR νmax (film)
3539, 2940, 2869, 2718, 1711, 1460, 1379, 1263, 1166, 1112,
1010, 882 cm-1 1H NMR (500 MHz, CDCl3) δ 3.71 (t, J 6.0
;
Hz, 2H), 2.40 (t, J 7.3 Hz, 2H); 1.73 (m, 2H), 1.60 (m, 2H),
1.07 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 177.7, 62.9, 33.5,
32.1, 21.3, 18.0, 11.9; HRMS calcd for C14H30O3Si [M+]
274.1964, found 274.2668.
(Z)-Methyl 2-(N-(tert-Butoxycarbonyl)-6-iodohex-5-
enamido)acetate. To a suspension of iodomethyl triphenyl-
phosphonium iodide 34 (834 mg, 1.57 mmol) in THF (5.0 mL)
at room temperature was added a solution of NaHMDS (2.08
mL, 1.24 mmol, 0.6 M in toluene) dropwise. After stirring for
6 min, the reaction mixture was cooled to -78 °C by the time
aldehyde 33 (0.52 mmol) in 3 mL of THF was added slowly.
After the reaction mixture was stirred for 1 h at -78 °C, the
reaction was quenched by the addition of saturaded aqueous
NH4Cl (5 mL), and the phases were separated. The aqueous
layer was extracted with CH2Cl2 (3 × 10 mL), and the
combined organic layers were dried with MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
column chromatography (EtOAc/hexanes, 10:90) to give the
N-Boc-protected (Z)-vinyl iodide (>95:5 Z:E) in 81% yield for
the two-step sequence: Rf 0.34 (EtOAc/hexane 10%); IR νmax
(film) 2981, 1742, 1685, 1646, 1213, 1150 cm-1; 1H NMR (300
MHz, C6D6) δ 5.88 (d, J 7.1 Hz, 1H), 5.71 (q, J 7.1 Hz, 1H),
4.48 (s, 2H), 3.29 (s, 3H), 2.08 (t, J 7.3 Hz, 2H), 2.08 (q, J 7.2
Hz, 2H), 1.74 (quint, J 7.3 Hz, 2H), 1.33 (s, 9H); 13C NMR (75
MHz, C6D6) δ 174.6, 169.3, 152.4, 140.8, 83.0, 82.9, 51.7, 45.4,
37.6, 34.4, 27.9, 23.7.
Methyl 2-(5-(Triisopropylsilyloxy)pentanamido)acetate.
To a solution of carboxylic acid 29 (1.67 g, 6.09 mmol) in
CH2Cl2 (30 mL) at room temperature were added glycine
methyl ester 6 (1.15 g, 9.13 mmol), NaHCO3 (0.75 g, 8.89
mmol), HOBt (1.64 g, 12.2 mmol), and DCC (2.51 mg, 12.2
mmol). The resulting mixture was stirred for 18 h at room
temperature and concentrated in vacuo to give a residue that
was diluted with benzene (10 mL), filtered, and evaporated.
Purification by flash chromatography (50% EtOAc in hexane)
gave 1.70 g (81%) of the desired peptide: Rf 0.28 (EtOAc/
hexane 50%); IR νmax (film) 3302, 2939, 2869, 1751, 1653, 1545,
1460, 1207, 1104 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.03 (brs,
1H), 4.05 (d, J 5.1 Hz, 2H), 3.76 (s, 3H), 3.70 (t, J 6.2 Hz, 2H),
2.29 (t, J 7.3 Hz, 2H), 1.74 (m, 2H), 1.59 (m, 2H), 1.08 (m,
21H); 13C NMR (75 MHz, CDCl3) δ 173.0, 170.3, 62.9, 52.2,
41.1, 36.0, 32.3, 22.1, 18.0, 12.0; HRMS calcd for C17H35NO4Si
[M+ (345.2335) - (CH3)2CH+] 302.1793, found 302.1768.
Methyl 2-(N-(tert-Butoxycarbonyl)-5-(triisopropylsilyl-
oxy)pentanamido)acetate (32). To a solution of the previ-
ously prepared peptide (600 mg, 1.73 mmol) in THF (7.5 mL)
at 0 °C were added DIPEA (0.7 mL, 3.48 mmol), DMAP (21
mg, 0.0173 mmol), and Boc2O (756 mg, 3.48 mmol). The
resulting mixture was stirred for 1 h at room temperature (gas
evolution) and quenched by addition of brine (10 mL). The
aqueous phase was further extracted with Et2O (3 × 10 mL),
(Z)-Methyl 2-(6-iodohex-5-enamido)acetate (28). To a
solution of the previously prepared N-Boc-protected (Z)-vinyl
iodide (15 mg, 0.036 mmol) in 0.2 mL of CH2Cl2 was added 1
mL of trifluoroacetic acid. The resulting solution was stirred
at room temperature for 18 h before it was concentrated in
vacuo. The crude product was purified by flash column
chromatography (EtOAc/hexanes, 50%) to give (Z)-vinyl iodide
J. Org. Chem, Vol. 70, No. 6, 2005 2233

Dias et al.
28 (9.5 mg, >95:5 Z:E) in 85% yield: Rf 0.25 (EtOAc/hexane
50%); IR νmax (film) 3300, 3067, 2932, 2850, 1753, 1653, 1541,
Hz, 2H), 7.32 (ap t, J 7.2 Hz, 2H), 7.21 (ap t, J 7.2 Hz, 1H),
6.79 (dd, J 10.5, 9.0 Hz, 1H), 6.60 (d, J 16.0 Hz, 1H), 6.25 (dd,
J 16.0, 7.3 Hz, 1H), 6.12 (m, 2H), 5.92 (d, J 1.3 Hz, 1H), 4.65
(dt, J 9.0, 7.1 Hz, 1H), 4.09 (dd, J 7.1, 1.7 Hz, 1H), 3.96 (d, J
6.1 Hz, 2H), 3.65 (s, 3H), 3.50 (s, 3H), 3.30 (s, 3H), 3.16 (dd, J
9.6, 2.3 Hz, 1H), 2.58 (m, 1H), 2.26 (br s, 3H), 2.26 (t, J 7.1
Hz, 2H), 2.11 (dt, J 7.1, 6.9 Hz, 2H), 1.68 (tt, J 7.1, 6.9 Hz,
2H), 1.55 (ddq, J 9.5, 7.0, 2.3 Hz, 1H), 1.18 (d, J 6.7 Hz, 3H),
0.83 (d, J 7.1 Hz, 3H); 13C NMR (125 MHz, acetone-d6) δ 174.4,
171.3, 164.5, 149.5, 137.7, 135.1, 132.5, 130.3, 129.3, 128.3,
127.1, 123.9, 121.7, 109.7, 87.1, 81.6, 61.5, 56.3, 52.2, 43.5, 41.5,
40.7, 34.4, 26.2, 25.3, 19.2, 13.8, 10.1; HRMS calcd for
C31H44N2O6Na [M + Na+] 563.3097, found 563.3110.
1435, 1367 cm-1 1H NMR (300 MHz, C6D6) δ 5.90 (d, J 7.1
;
Hz, 1H), 5.68 (q, J 7.1 Hz, 1H), 5.26 (brs, 1H), 3.75 (d, J 5.1
Hz, 2H), 3.26 (s, 3H), 2.01 (q, J 7.0 Hz, 2H), 1.76 (t, J 7.3 Hz,
2H), 1.61 (q, J 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 172.2,
170.3, 140.7, 83.1, 51.7, 41.3, 35.2, 34.5, 24.1; HRMS calcd for
C9H14INO3 [M+] 311.0018, found 311.0015.
Methyl 2-((Z)-6-((2E,4E,6S,7S,8R,9S,10E)-7,9-Dimethoxy-
3,6,8-trimethyl-11-phenylundeca-2,4,10-trienamido)hex-
5-enamido)acetate [(+)-Crocacin D] (4). A resealable
Schlenk tube was charged with CuI (1.0 mg, 0.0052 mmol),
crocacin C (3) (44.7 mg, 0.125 mmol), and Cs2CO3 (52.0 mg,
0.16 mmol). The tube was evacuated and backfilled with argon,
and N,N′-dimethylethylenediamine (1.15 µL, 0.01 mmol, 10
mol %), (Z)-vinyl iodide 28 (31 mg, 0.10 mmol), and THF (1.0
mL) were added under argon. The Schlenk tube was sealed
with a Teflon valve, and the reaction was stirred at 70 °C for
15 h. After the resulting pale blue suspension was allowed to
reach room temperature, ethyl acetate (2 mL) was added. The
reaction mixture was filtered through a silica plug eluting with
ethyl acetate (15 mL). The filtrate was concentrated, and the
residue was purified by column chromatography using Et3N-
deactivated silica gel to provide crocacin D (4) (44.9 mg, 67%)
Acknowledgment. We are grateful to FAPESP and
CNPq for financial support. We thank also Prof. Carol
H. Collins for helpful suggestions about English gram-
mar and style, Prof. Mark A. Rizzacasa for providing
us with an authentic sample of crocacin D, and Prof.
Carlos R. D. Correia for useful discussions.
Supporting Information Available: Experimental pro-
cedures and product characterization for compounds 5, 7, and
1
24 and selected IR, HRMS, and H and 13C NMR spectra for
20
20
as a colorless gum; [R]D +104.9 (c 0.35, MeOH); lit.2a [R]D
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
+109.6 (c 0.56, MeOH); IR νmax (film) 3301, 2929, 1749, 1654,
1608, 1510, 1263, 1090, 972 cm-1; 1H NMR (500 MHz, acetone-
d6) δ 9.14 (br d, J 10.4 Hz, 1H), 7.60 (br m, 1H), 7.48 (d, J 7.2
JO047732K
2234 J. Org. Chem., Vol. 70, No. 6, 2005