A simple, short, and flexible synthesis of viridiofungin derivatives

Article abstract of DOI:10.1021/jo060931e

Described herein is a simple, flexible, and efficient synthesis of the skeleton of the viridiofungins, a family of microbial secondary metabolites. The synthesis utilizes an asymmetric aldol reaction of a chiral oxazolidinone, a diastereoselective alkylat

Full text of DOI:10.1021/jo060931e

A Simple, Short, and Flexible Synthesis of Viridiofungin Derivatives
Stephen M. Goldup,† Christopher J. Pilkington,† Andrew J. P. White,† Andrew Burton,‡ and
Anthony G. M. Barrett*,†
Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, England, and
Chemical DeVelopment, GlaxoSmithKline, Medicines Research Centre, SteVenage SG1 2NY, England
agmb@imperial.ac.uk
ReceiVed May 4, 2006
Described herein is a simple, flexible, and efficient synthesis of the skeleton of the viridiofungins, a
family of microbial secondary metabolites. The synthesis utilizes an asymmetric aldol reaction of a chiral
oxazolidinone, a diastereoselective alkylation of a chiral 1,3-dioxolan-2-one, and a geometrically selective
alkene cross-metathesis reaction as the key C-C bond-forming steps.
Introduction
absolute stereochemistry of viridiofungin A (1) was assigned
to be (3S,4S,2′S) by Hatakeyama and co-workers in 1998
through a 27-step enantioselective total synthesis of the corre-
sponding trimethyl ester in which a Sharpless asymmetric
epoxidation was used to set absolute stereochemistry.5 Subse-
quently in 2004 and 2005, Hiersemann and co-workers reported
diastereoselective 17-step syntheses of triester derivatives of
viridiofungin A, A2, and A4, which showcased an elegant ester
dienolate [2,3] Wittig rearrangement to control the required
relative stereochemistry of the branched citrate unit. Subsequent
elaboration, coupling to (S)-tyrosine, and HPLC separation of
diastereoisomers gave the naturally occurring (3S,4S,2′S) tri-
esters and their (3R,4R,2′S) isomers.6,7 Recently, Hatakeyama
noted that the attempted deprotection of synthetic viridiofungin
A trimethyl ester resulted in its decomposition. He additionally
reported a new 22-step enantioselective total synthesis of
viridiofungin A (1), which successfully used tert-butyl ester
protection.8 Hatakeyama’s second synthesis also relied on
Sharpless asymmetric epoxidation but differed from the first
synthesis in that the lipophilic side chain was added to the vinyl
The viridiofungins, a family of aminoacyl vinyl citrate
antibiotics, which are exemplified by viridiofungins A-C
(1-3) (Scheme 1), were first isolated by Harris et al. in 1993
from a broth of Trichederma Viride Pers.1 These natural products
are composed of a polar, structurally unusual, vinyl citrate
headgroup derivatized as an amide with phenylalanine or another
amino acid and a nonpolar side chain. They were shown to
inhibit serine palmitoyl transferase at the nanomolar level as
well as inhibiting squalene synthase in vitro at the micromolar
level and are thus potent antifungal agents.2,3 In addition these
compounds inhibit Ras-farnesyl transferase and are thus of
potential interest as anticancer agents.4 The viridiofungins,
therefore, represent interesting synthetic targets due to both the
challenging nature of the highly functionalized citrate core and
their application as drug hit structures.
The constitution of viridiofungin A was determined by Harris
and co-workers using NMR and mass spectrum data of the
natural compound and derived degradation products.1 The
* To whom correspondence should be addressed. Phone: 44-207-594-5766.
Fax: 44-207-594-5805.
(4) Huang, L.; Lingham, R. B.; Harris, G. H.; Singh, S. B.; Dufresne,
C.; Nallin-Omstead, M.; Bills, G. F.; Mojena, M.; Sanchez, M.; et al. Can.
J. Bot. 1995, 73, S898.
† Imperial College London.
‡ GlaxoSmithKline.
(1) Harris, G. H.; Jones, E. T. T.; Meinz, M. S.; Nallin-Omstead, M.;
Helms, G. L.; Bills, G. F.; Zink, D.; Wilson, K. E. Tetrahedron Lett. 1993,
34, 5235.
(2) Onishi, J. C.; Milligan, J. A.; Basilio, A.; Bergstrom, J.; Curotto, J.;
Huang, L.; Meinz, M.; Nallin-Omstead, M.; Pelaez, F.; Rew, D.; Salvatore,
M.; Thompson, J.; Vicente, F.; Kurtz, M. B. J. Antibiot. 1997, 50, 334.
(3) Mandala, S. M.; Thornton, R. A.; Frommer, B. R.; Dreikorn, S.; Kurtz,
M. B. J. Antibiot. 1997, 50, 339.
(5) Esumi, T.; Iwabuchi, Y.; Irie, H.; Hatakeyama, S. Tetrahedron Lett.
1998, 39, 877.
(6) Pollex, A.; Abraham, L.; Mu¨ller, J.; Hiersemann, M. Tetrahedron
Lett. 2004, 45, 6915.
(7) Pollex, A.; Millet, A.; Mu¨ller, J.; Hiersemann, M.; Abraham, L. J.
Org. Chem. 2005, 70, 5579.
(8) Morokuma, K.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Chem.
Commun. 2005, 2265.
10.1021/jo060931e CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/30/2006
J. Org. Chem. 2006, 71, 6185-6191
6185

Goldup et al.
SCHEME 1. Proposed Retrosynthesis
SCHEME 2. Model Metathesis Reaction and Precursor
Synthesisa
a Reagents and conditions: (a) Mg, Et2O, reflux; n-C6H13CN, Et2O, 25
°C; 1 M HCl (aq), 0 °C. (b) MeOAc, LiN(i-Pr)2, THF, -78 °C;
MeO2CCO2Me, -78 to 25 °C. (c) 13, In, THF-H2O (1:1), 25 °C. (d) 1 M
HCl (aq), reflux. (e) Grubbs II (17) (20 mol %), PhMe, 80 °C.
citrate headgroup by using alkene cross-metathesis catalyzed
by either the Grubbs’ second generation catalyst or the Hov-
eyda’s catalyst.9,10
In an effort to develop a shorter, more flexible route to these
medicinally interesting compounds, we sought to develop a
concise enantioselective and diastereoselective route to the vinyl
citrate headgroup 5 and to use alkene cross-metathesis to link
the lypophilic side chain 4 (Scheme 1). We considered that the
vinyl citrate unit 5, itself a structurally unusual intermediate
with other possible applications in synthesis, should be available
from the diastereoselective C-3 alkylation of the vinyl malic
acid derivative 7. In turn, we proposed that an asymmetric aldol
reaction between glyoxylic ester 8 and crotonic acid derivative
9 should provide the key intermediate 7.
FIGURE 1. Catalysts for cross-metathesis reactions.
assigned by hydrolysis to the known triacid 15.11 Attempted
cross-metathesis of triester 14 (ds 7:1) with alkene 4 by using
the Grubbs-II catalyst (17) in dichloromethane at reflux was
unsuccessful. However, reaction in toluene at 80 °C gave alkene
16 (62%) as the trans isomer.With this encouraging result, we
embarked on an enantioselective synthesis of the required vinyl
citrate compounds 5 (Scheme 3). Despite a report by Iseki and
co-workers that ethyl glyoxylate participated with poor selectiv-
ity in an Evans’ aldol reaction,12 we decided to examine a
dibutylboron triflate mediated coupling between this com-
mercially available aldehyde and the Evans’ crotonate 21, which
was synthesized according to literature procedures.13 Pleasingly,
the major product (72%) isolated from this reaction was the
syn-aldol 22. The relative stereochemistry of imide 22 was
Results and Discussion
Coupling of the Grignard reagent prepared from bromide 10
with heptanenitrile gave the target ketone 4 (79%). In an effort
to model the key cross-metathesis reaction of alkene 4 with a
vinyl citrate, ester 14 was synthesized in a concise manner
(Scheme 2), using an indium-mediated crotonylation of keto-
diester 12, which proceeded in good yield albeit with a
diastereoselectivity (ds 7:1) that was opposite to that desired
for the viridiofungins. The stereochemistry of adduct 14 was
(9) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S.
P. J. Org. Chem. 2000, 65, 2204. Sanford, M. S.; Ulman, M.; Grubbs, R.
H. J. Am. Chem. Soc. 2001, 123, 749.
(10) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
H. J. Am. Chem. Soc. 1999, 121, 791.
(11) Dolle, R. E.; Novelli, R.; Saxty, B. A.; Wells, T. N. C.; Kruse, L.
I.; Camilleri, P.; Eggleston, D. Tetrahedron Lett. 1991, 32, 4587.
(12) Iseki, K.; Oishi, S.; Kobayashi, Y. Tetrahedron 1996, 52, 71.
(13) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
6186 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Viridiofungin DeriVatiVes
SCHEME 3. Synthesis of (2S,3S) Vinyl Malic Acida
SCHEME 4. Alkylation of Acid 26 and Amide Coupling of
Citrate 27a
a Reagents and conditions: (a) Bu2BOTf, NEt3, CH2Cl2, -78 to 0 °C;
EtO2CCHO (1.3 equiv), -78 to 0 °C. (b) LiOH, H2O2, THF:H2O (3:1), 0
°C. (c) LiOH, MeOH:H2O (1:1), 0 to 25 °C. (d) Me3SiCl or t-BuMe2SiCl,
i-Pr2NEt, THF, 25 °C. (e) t-BuCHO, Me3SiOTf (20 mol %), CH2Cl2,
-35 °C.
a Reagents and conditions: (a) 1 M LiN(SiMe3)2 in THF, DMF,
-70 °C, 50 min; BrCH2CO2t-Bu, -70 °C, 15 min. (b) ArCH2CH-
(CO2t-Bu)NH3Cl, HOBT, HBTU, i-Pr2NEt, DMF, 0 °C. (c) Second yields
refer to overall yields from 26 without purification of the intermediate 27.
assigned on the basis of an X-ray crystallographic structure
determination. Since the oxazolidinone precursor 21 was of
known absolute stereochemistry, this study also established the
absolute stereochemistry of the aldol unit. Subsequent cleavage
of the imide moiety and saponification of the ethyl ester gave
vinyl malic acid 23 in good yield (61%) over three steps.
single diastereoisomer. Amide coupling between citrate 27 and
H-Tyr(t-Bu)-Ot-Bu, H-Phe-Ot-Bu, and H-Try-Ot-Bu mediated
by HBTU and HOBT16 gave the vinyl citrate amides 28 (69%),
29 (86%), and 28 (79%), respectively, all as single diastereo-
isomers. Furthermore, these amide coupling reactions were also
carried out on the crude C-alkylation product 27 thereby
circumventing its purification, which was tedious, and pro-
viding the vinyl citrate amides 28 (41% from 26), 29 (57% from
26), and 28 (47% from 26) in superior overall yields. The
structure and stereochemistry of amide 29 was confirmed by
an X-ray crystallographic structure determination and, by
reference to the known stereochemistry of the amino acid entity,
the absolute stereochemistry was confirmed to be correct for
the viridiofungins.
Attempted cross-metathesis reactions between acid 27 and
alkene 4 in the presence of the Grubbs II catalyst (17) at room
temperature or at 50 °C were unsuccessful. The course of
reaction was conveniently monitored by 1H NMR spectroscopy
and this indicated that, while acid 27 remained unchanged,
complete cross-metathesis of alkene 4 alone giving both alkene
31 and presumably ethylene took place. Unfortunately, unlike
the model synthesis of alkene 16 described earlier, attempted
cross-metathesis of acid 27 and alkene 4 at 80 °C in toluene
proceeded but with very poor conversion. Again the major
product formed was alkene 31. No cross-metathesis of alkene
27 alone was observed. These results indicate that, under
Grubbs’ classification of alkenes for cross-metathesis, alkene
4 is type I (rapid homodimerization) while citrate 27 is type III
(no homodimerization)17 suggesting the major pathway of any
successful reaction will be secondary cross-metathesis between
citrate 27 and alkene 31 and thus alkene 4 was duly homo-
dimerized by using carbene 17 in a separate step to save catalyst
turnover in this crucial reaction. We therefore sought to closely
We considered that C-2 alkylation of diacid 23 with retention
of stereochemistry should be possible via conversion into
dioxolanone 26, using the Seebach “Self-Reproduction of
Stereochemistry” approach (Scheme 3).14 Due to difficulties in
the purification of acid 23, we attempted to prepare dioxolanone
26 using crude diacid 23. Following the Hoye protocol,15 crude
acid 23 was converted into the air and moisture-sensitive silyl
ester 24 and subsequently condensed with pivaldehyde to
stereoselectively provide acetal 26 (79% over 2 steps). In an
effort to improve the reaction, we examined the conversion of
crude diacid 23 into acetal 26 via tert-butyldimethysilyl ester
25. Unfortunately the yield of this modified process was inferior
(57%) and chromatography was required to isolate dioxolanone
26. In contrast, protection via silyl ester 24 was more convenient
in that most of the product dioxolanone 26 was isolated by
recrystallization of the crude material.
Conversion of acetal 26 into the vinyl citrate derivative 27
was carried out by deprotonation with lithium hexamethyl-
silazide in THF at -78 to -30 °C and reaction with tert-butyl
bromoacetate (Scheme 4). These conditions, which were
developed by Seebach for the corresponding malic acid deriva-
tive,14 gave the required acetal 27 but only in poor yield (22%),
albeit as a single diastereoisomer and with no starting material
recovered. When deprotonation was carried out at lower
temperatures in THF no conversion of starting material 26 was
observed. When enolization and alkylation were carried out in
DMF and THF (5:2) as solvent at -70 °C the reaction was
significantly improved and gave acetal 27 (61%) again as a
(16) HOBT ) 1-hydroxy-1,2,3-benzotriazole; HBTU ) 2-(1H-benzo-
triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. See: Dour-
toglou, V.; Ziegler, J. C.; Gross, B. Tetrahedron Lett. 1978, 1269.
(17) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
(14) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313.
(15) Hoye, T. R.; Peterson, B. H.; Miller, J. D. J. Org. Chem. 1987, 52,
1351.
J. Org. Chem, Vol. 71, No. 16, 2006 6187

Goldup et al.
SCHEME 5. Cross-Metathesis of Acid 27 and Amides 28,
29, and 30 and Synthesis of Amides 33, 34, and 35a
SCHEME 6. Synthesis of Ester 38a
a Reagents and conditions: (a) K2CO3, MeOH, 0 to 25 °C. (b) H-Tyr-
(Ot-Bu)-Ot-Bu‚HCl, HOBT, HBTU, i-Pr2NEt, DMF, 0 °C. (c) 31, 20 (20
mol %), CH2Cl2, 65 °C (microwaves). (d) 31, 20 (20 mol %), CH2Cl2, 55
°C (microwaves).
with data reported by Hatakeyama and Hiersemann (Scheme
6).5-7 Unfortunately, direct transesterification of amides 33, 34,
and 35 under either acidic or basic conditions resulted in
extensive decomposition. This is in keeping with the observa-
tions of Hatakeyama that viridiofungin derivatives are highly
sensitive and unstable under standard hydrolysis conditions.8
Since it has been proposed that this instability is due to retro-
aldol processes, we considered that acid 27 would be protected
from such degradation under basic conditions by deprotonation
to give the carboxylate salt. Consistent with this analysis,
transesterification of acid 27 in basic methanol gave rise to the
corresponding methyl ester. Most conveniently, this was directly
converted into the amide 36, which greatly simplified purifica-
tion. Surprisingly dimethyl ester 37 was also isolated from this
sequence presumably through an unusual direct base-mediated
transesterification of the tert-butyl ester. The stereochemistry
of triester 36 was confirmed to have the desired (2S,3S) structure
by an X-ray crystallographic structure determination. Finally
cross-metathesis of triester 36 with alkene 31 gave the virid-
iofungin A derivative 38 (54%). The same derivative 38 was
also prepared directly from dioxolanone 27 and without isolation
of any intermediates by sequential cross-metathesis with alkene
31, base-catalyzed methanolysis, and peptide coupling. Com-
a Reagents and conditions: (a) 17 (10 mol %), CH2Cl2, 25 °C; (b) 27,
20 (20 mol %), CH2Cl2, 55 °C (microwaves), 1 h. (c) Amino acid HCl salt,
HOBT, HBTU, i-Pr2NEt, DMF, 0 °C. (d) 31, 20 (20 mol %), CH2Cl2, 65
°C (microwaves), 4 h. (e) The first yields refer to cross-metathesis of 27
with 31 followed by amide formation; the second yields refer to cross-
metathesis from 28-30 only.
examine the cross-metathesis of alkene 31 and citrate 27 with
variation of temperature, concentration, solvent, and catalyst
(Scheme 5). In particular we focused on the use of the Grubbs
II catalyst (17), the Hoveyda catalyst (18),10 the Blechert catalyst
(19)18 and the Grela catalyst (20).19 In our hands, neither catalyst
17 nor 18 was especially effective with slow and incomplete
conversions. Both catalysts 19 and 20 were superior with the
Grela catalyst 20 the most effective. Although conversion by
1H NMR was high (>95%), extensive chromatography was
required to remove ruthenium residues from the polar acid 32,
which was isolated in 57% yield. Microwave heating was
employed for operational convenience although conventional
heating gave comparable results. The product 32 was isolated
1
parison of H and 13C NMR spectra reported for ester 38 by
Hatakeyama and Hiersemann5-8 for the corresponding trialkyl
esters of viridiofungin A was consistent with the stereochemical
identity of the product.
1
as the pure trans isomer as judged by H and 13C NMR (J )
15.5 Hz). This material was converted without purification to
the viridiofungins A, B, and C derivatives 33, 34, and 35,
respectively (30-46% over 2 steps from 27), and as single
diastereoisomers. Alternatively, amides 28, 29, and 30 could
be converted in high yield (87-92%) into the viridiofungin
derivatives 33, 34, and 35, respectively, by cross-metathesis with
alkene 31.
Further confirmation of the correct stereochemical outcome
of this synthesis was provided by conversion of intermediate
27 to an alternative protected triester species for comparison
Conclusion
During these studies we have developed rapid highly stereo-
selective syntheses of the vinyl malic acid derivative 26 (48%
over 4 steps) and the vinyl citric acid derivative 27 (29% over
5 steps) both as single enantiomers, with fully differentiated
carboxylate functionality. The vinyl citrate 27 was converted
into the viridiofungin derivatives 33, 34, 35, and 38 by using
highly convergent, 3-step sequences. The synthetic brevity and
(19) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos,
G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318.
(18) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 2403.
6188 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Viridiofungin DeriVatiVes
concentrated aqueous HCl, and extracted with CH2Cl2 (2 × 100
mL) and EtOAc (4 × 500 mL). The CH2Cl2 extracts were discarded.
The combined EtOAc extracts were dried (MgSO4) and rotary
evaporated to give crude diacid 23 (7.2 g, ca. 100%) as a colorless
oil. Solid-phase extraction of a small portion of crude material with
CH2Cl2 at reflux left a white powder, which was recrystallized from
MeCN and CHCl3 to give diacid 23 as a white crystalline solid:
overall yields of these syntheses (8 steps from the starting imide
21, 3-26%) compare favorably with the published procedures
of Hatakeyama (2.2% over 27 steps,5 7.5% over 22 steps8) and
Hiersemann (<4% over 18 steps).6,7 Additionally, there is
considerable flexibility in the final three steps with the possibility
of easy variation of electrophile, amide coupling partner, and
cross-metathesis partner from intermediate acid 26. Both
intermediates 26 and 27 should find use in the synthesis of other
unusual citrate natural products.
mp 111-116 °C (MeCN-CHCl3); [R]25 -9.8 (c 1.00, MeOH);
D
IR (film) 3304, 1758, 1690 cm-1; 1H NMR (400 MHz, CD3CN) δ
6.00 (app-dt, J ) 18.0, 9.5 Hz, 1H), 5.16 (m, 2H), 4.68 (d, J ) 3.5
Hz, 1H), 3.47 (dd, J ) 3.5, 9.5 Hz, 1H); 13C NMR (100 MHz,
CD3CN) δ 174.5, 173.5, 133.0, 120.5, 73.1, 54.6; MS (CI, NH3)
m/z 178 (M + NH4)+; HRMS (CI, NH3) m/z calcd for C6H12NO5
(M + NH4)+ 178.0715, found 178.0715. Anal. Calcd for C6H8O5:
C, 45.01; H, 5.04. Found: C, 44.90; H, 4.90.
Experimental Section
(4S)-Benzyl-3-(((2S,3S)-1-ethoxy-2-hydroxy-1-oxo-4-penten-
3-yl)carbonyl)-1,3-oxazolidin-2-one (22). n-Bu2BOTf (1.0 M in
CH2Cl2, 77.0 mL, 77.0 mmol) and NEt3 (12.6 mL, 90.3 mmol)
were added with stirring to imide 21 (17.9 g, 70.0 mmol) in
CH2Cl2 (350 mL) at -78 °C. After 1 h at -78 °C and 15 min at
0 °C, the resultant yellow solution was cooled to -78 °C and freshly
distilled ethyl glyoxalate (2.6 mL, 26 mmol) was added. The
reaction mixture was stirred for a further 1 h at -78 °C and 1 h at
0 °C at which time it was poured onto aqueous HCl (1 M; 400
mL), the phases separated, and the aqueous phase extracted with
CH2Cl2 (2 × 200 mL). The combined organic layers were washed
with H2O (400 mL) and brine (400 mL), dried (MgSO4), and rotary
evaporated. Chromatography (gradient elution 1:2 Et2O:hexane to
1:1 Et2O:hexane to 2:1 Et2O:hexane) gave imide 22 (17.4 g, 72%)
(S)-2-((2S,4S)-2-tert-Butyl-5-oxo-1,3-dioxolan-4-yl)-3-buteno-
ic Acid (26). All manipulations were carried out under Ar.
Me3SiCl (3.8 mL, 30 mmol) followed by i-Pr2NEt (5.2 mL, 30
mmol) were added to acid 23 (1.6 g, 10 mmol) in THF (50 mL).
After 2 h, hexane (50 mL) was added and the mixture was cooled
to -78 °C. This suspension was filtered, the residue was extracted
with hexane (20 mL), and the combined filtrates were rotary
evaporated to give a pale yellow oil. This was treated with hexane
(20 mL) at -14 °C and refiltered to remove residual salts. The
residue was extracted with a further portion of hexane (5 mL) and
the combined filtrates were rotary evaporated to give the crude
trisilyl derivative 24 (3.1 g, 82%) as a pale yellow oil. This material
was dissolved in CH2Cl2 (40 mL) at -35 °C, t-BuCHO (0.93 mL,
8.3 mmol) and Me3SiOTf (0.30 mL, 1.7 mmol) were added
sequentially, and the mixture was stirred for 16 h at -35 °C. From
this point onward manipulations were performed in air. The mixture
was poured into aqueous HCl (1 M; 40 mL), stirred for a further
10 min at room temperature, and extracted with Et2O:hexane (1:1;
100 mL). The combined organic extracts were washed with H2O
(100 mL) and brine (100 mL), dried (MgSO4), and rotary evaporated
to give a pale yellow solid. Recrystallization from Et2O-hexane
gave acid 26 (1.6 g, 69%) as a white crystalline solid. Chroma-
tography of the mother liquors (gradient elution hexane to 1:2 Et2O:
hexane to 1:1 Et2O:hexane) and recrystallization gave a further
portion of acid 26 (0.17 g, 9%; combined yield 1.8 g, 79% over
as a white crystalline solid: mp 84 °C (Et2O); [R]25 + 23.7 (c
D
1
1.00, CDCl3); IR (film) 1784, 1743, 1693, 1636 cm-1; H NMR
(400 MHz, CDCl3) δ 7.28 (m, 3H), 7.18 (d, J ) 7.0 Hz, 2H), 6.05
(app-dt, J ) 17.5, 9.5 Hz, 1H), 5.35 (m, 2H), 4.89 (dd, J ) 9.0,
5.0 Hz, 1H), 4.71 (m, 1H), 4.59 (d, J ) 5.0 Hz, 1H), 4.24 (m, 4H),
3.29 (br s, 1H), 3.25 (dd, J ) 13.5, 3.0 Hz, 1H), 2.76 (dd, J )
13.5, 3.0 Hz, 1H), 1.29 (t, J ) 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.2, 171.1, 152.9, 134.8, 130.6, 129.3, 128.8, 127.2,
121.1, 70.9, 66.0, 62.0, 55.1, 51.4, 37.4, 14.0; MS (CI, NH3) m/z
365 (M + NH4)+, 348 (M + H)+; HRMS (CI, NH3) calcd for
C18H22NO6 (M + H)+ 348.1447, found 348.1444. Anal. Calcd for
C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C, 62.02; H, 5.95;
N, 3.95.
1
(2S,3S)-2-Hydroxy-3-(hydroxycarbonyl)-4-pentenoic Acid (23).11
H2O2 (50 wt %, 9.2 mL, 150 mmol) and LiOH‚H2O (4.2 g, 100
mmol) were added with stirring to the aldol product 22 (17.3 g, 50
mmol) in THF and H2O (3:1; 250 mL) at 0 °C. After 2 h, H2O
(100 mL) was added followed by NaHCO3 (21.0 g, 250 mmol)
and Na2SO3 (25.2 g, 200 mmol) and the THF rotary evaporated.
The aqueous residue was extracted with CH2Cl2 (2 × 250 mL)
and the combined organic extracts were extracted with H2O (60
mL). The combined aqueous extracts were saturated with solid NaCl
and carefully acidified to pH 1 with concentrated aqueous HCl and
the acidified aqueous phase was extracted with EtOAc (4 × 600
mL). The combined EtOAc extracts were dried (MgSO4) and rotary
evaporated to give crude ethyl (2S,3S)-2-hydroxy-3-(hydroxycar-
bonyl)-4-pentenoate (8.0 g, 85%) as a colorless oil: [R]25D -32.0
(c 1.00, CDCl3); IR (film) 3454, 1733, 1644 cm-1; 1H NMR (300
MHz, CDCl3) δ 5.99 (app-dt, J ) 17.5, 10.0 Hz, 1H), 5.32 (d, J )
10.0 Hz, 1H), 5.23 (d, J ) 17.5 Hz, 1H), 4.74 (d, J ) 3.5 Hz, 1H),
4.27 (m, 2H), 3.55 (dd, J ) 9.5, 3.5 Hz, 1H), 1.31 (t, J ) 7.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 175.4, 172.3, 129.6, 121.2,
71.5, 62.4, 53.2, 14.2; MS (CI, NH3) m/z 206 (M + NH4)+; HRMS
(CI, NH3) calcd for C8H16NO5 (M + NH4)+ 206.1028, found
206.1033. The crude ester was used directly without further
purification. LiOH‚H2O (5.4 g, 129 mmol) was added to the crude
ethyl ester (8.0 g, 43 mmol) in MeOH and H2O (1:1; 200 mL) at
0 °C and this mixture was stirred overnight at room temperature.
After rotary evaporation of MeOH, the aqueous residue was
extracted with CH2Cl2 (2 × 100 mL), and the organic phases were
combined and back extracted with H2O (50 mL). The combined
aqueous phases were saturated with NaCl, acidified to pH 1 with
two steps). Only one diastereoisomer was observed by H NMR,
which was assigned to be syn by NOESY spectroscopy: mp 120-
121 °C (Et2O-hexane); [R]25 -19.4 (c 1.00, CDCl3); IR (film)
D
3084, 1794, 1701, 1640 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.97
(app-dt, J ) 17.0, 10.5, 9.0 Hz, 1H), 5.36 (d, J ) 10.0 Hz, 1H),
5.35 (d, J ) 17.0 Hz, 1H), 5.14 (d, J ) 1.0 Hz, 1H), 4.74 (dd, J )
4.0, 1.0 Hz, 1H), 3.62 (dd, J ) 9.0, 4.0 Hz, 1H), 0.97 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 175.6, 171.0, 128.6, 122.3, 109.6, 75.6,
50.4, 34.4, 23.6; MS (CI, NH3) m/z 246 (M + NH4)+, 229 (M +
H)+; HRMS (CI, NH3) m/z calcd for C11H20NO5 246.1341 (M +
NH4)+, found 246.1336. Anal. Calcd for C11H16O5: C, 57.88; H,
7.07. Found: C, 57.77; H, 6.92.
(S)-2-((2S,4S)-4-tert-Butyloxycarbonylmethyl-2-tert-butyl-5-
oxo-1,3-dioxolan-4-yl)-3-butenoic Acid (27). LiN(SiMe3)2 in THF
(1.0 M; 1.00 mL, 1.00 mmol) was added dropwise with stirring
over 1 min to dioxalone 26 (228 mg, 1.00 mmol) in DMF (5.0
mL) at -70 °C. The solution was stirred for 1 min after addition
was completed at which time additional LiN(SiMe3)2 in THF (1.0
M; 1. 0 mL, 1.00 mmol) was added dropwise over 1 min. After 50
min, BrCH2CO2t-Bu (0.16 mL, 1.0 mmol) was added to the
resulting pale orange solution. After a further 15 min, AcOH (1 M
in THF; 1.0 mL) was added and the mixture was partitioned
between Et2O and hexane (1:1; 25 mL) and aqueous HCl (25 mL)
and the phases were separated. The organic phase was washed with
H2O (25 mL) and brine (25 mL). The combined aqueous layers
were extracted with Et2O and hexane (1:1; 25 mL), and the
combined organic extracts were dried (MgSO4) and rotary evapo-
rated. Chromatography (gradient elution hexane to Et2O:hexane 1:2
to Et2O:hexane 1:1) gave a white solid, which was recrystallized
J. Org. Chem, Vol. 71, No. 16, 2006 6189

Goldup et al.
from n-hexane to give acid 27 (209 mg, 61%) as a white solid:
hexane) to give amide 33 (179 mg, 87%) as a pale yellow oil: [R]25
D
mp 111 °C (hexane); [R]25 -67.8 (c 1.00, CDCl3); Rf 0.16 (1:1
-47.8 (c 1.00, CDCl3); Rf 0.38 (1:3 EtOAc:hexane); IR (film) 3412,
3358, 1798, 1730, 1680 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.03
(d, J ) 8.5 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 6.46 (d, J ) 7.5 Hz,
1H), 5.67 (m, 2H), 5.23 (s, 1H), 4.68 (dt, J ) 13.5, 7.5 Hz, 1H),
3.35 (d, J ) 8.5 Hz, 1H), 3.02 (m, 2H), 2.94 (d, J ) 16.0 Hz, 1H),
2.75 (d, J ) 16.0 Hz, 1H), 2.37 (t, J ) 7.5 Hz, 4H), 2.02 (m, 2H),
1.54 (br s, 4H), 1.44 (s, 9H), 1.37 (s, 9H), 1.31 (s, 9H), 1.26 (br s,
14H), 0.95 (s, 9H), 0.87 (t, J ) 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 211.6, 172.1, 170.2, 168.6, 168.4, 154.2, 138.3, 130.9,
130.0, 123.9, 122.6, 109.0, 82.2, 82.1, 80.7, 78.2, 56.8, 53.6, 42.8,
42.7, 39.6, 37.4, 34.2, 32.5, 31.6, 29.2, 29.0, 28.7, 27.9, 23.9, 23.8,
23.7, 22.5, 14.0; MS (FAB) m/z 828 (M + H)+; HRMS (FAB) m/z
calcd for C48H78NO10 (M + H)+ 828.5626, found 828.5637.
tert-Butyl (3S,4S)-4-((1S)-1-tert-Butyloxycarbonyl)-2-(tert-bu-
tyloxycarbonylphenyl)ethylaminocarbonyl)-3-hydroxy-3-(meth-
oxycarbonyl)-5-hexenoate (36). Solid K2CO3 (130 mg, 1.0 mmol)
was added with stirring to dioxolanone 27 (34 mg, 0.10 mmol) in
MeOH (1.0 mL) and the resultant mixture was stirred for 18 h at
room temperature. The mixture was partitioned between EtOAc
(25 mL) and aqueous HCl (1 M; 25 mL) and the phases were
separated. The aqueous phase was saturated with NaCl and extracted
with EtOAc (5 × 25 mL). The combined organic extracts were
dried (MgSO4) and rotary evaporated and the residue was taken
up in DMF (0.5 mL) and cooled to 0 °C, and HOBT (16 mg, 0.12
mmol), H-Tyr(Ot-Bu)-t-Bu‚HCl (38 mg, 0.12 mmol), i-Pr2NEt (45
µL, 0.24 mmol), and HBTU (44 mg, 0.12 mmol) were added. This
mixture was stirred for 90 min at 0 °C and subsequently 30 min at
room temperature after which time it was partitioned between Et2O
and hexane (1:1; 25 mL) and aqueous HCl (1M; 25 mL). The phases
were separated and the organic phase was washed with H2O (25
mL), saturated aqueous NaHCO3 (25 mL), H2O (25 mL), and brine
(25 mL). The combined aqueous washings were extracted with Et2O
and hexane (1:1; 25 mL) and the combined organic extracts dried
(MgSO4) and rotary evaporated. Chromatography (1:2 EtOAc:
hexane) gave diester 36 (16 mg, 28%) as a white crystalline solid
and diester 37 (8.8 mg, 17%) as a colorless oil. Diester 36: mp
117-119 °C (Et2O-hexane); [R]25D -7.9 (c 1.00, CDCl3); Rf 0.20
D
1
Et2O:hexane); IR (film) 3414, 1795, 1723, 1632 cm-1; H NMR
(400 MHz, CDCl3) δ 6.12 (app-dt, J ) 17.0, 10.0 Hz, 1H), 5.42
(m, 2H), 5.26 (s, 1H), 3.70 (d, J ) 9.5 Hz, 1H), 3.00 (d, J ) 16.0
Hz, 1H), 2.78 (d, J ) 16.0 Hz, 1H), 1.46 (s, 9H), 0.96 (s, 9H); 13
C
NMR (CDCl3, 100 MHz) δ 174.2, 172.5, 168.0, 129.4, 123.0, 109.2,
82.3, 79.7, 56.0, 38.8, 34.3, 27.9, 23.7; MS (CI) m/z 360 (M +
NH4)+, 304 (M - t-Bu + H + NH4)+; HRMS (CI) m/z calcd for
C17H30NO7 (M + NH4)+ 360.2025, found 360.2022. Anal. Calcd
for C17H26O7: C, 59.64; H, 7.65. Found: C, 59.38; H, 7.42.
tert-Butyl (S)-3-(4-tert-Butyloxyphenyl)-2-((S)-2-((2S,4S)-2-
tert-butyl-4-tert-butyloxycarbonylmethyl-5-oxo-1,3-dioxolan-4-
yl)but-3-enoylamino)propanoate (28). Method A: HOBT (50 mg,
0.37 mmol), i-Pr2NEt (0.13 mL, 0.73 mmol), H-Tyr(t-Bu)-Ot-Bu‚
HCl (122 mg, 0.37 mmol), and HBTU (140 mg, 0.37 mmol) were
added sequentially to citrate 27 (104 mg, 0.30 mmol) in DMF (3
mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h,
partitioned between Et2O and hexane (1:1; 25 mL) and aqueous
HCl (1 M; 25 mL), the phases separated, and the organic layer
washed sequentially with H2O (25 mL), saturated aqueous NaHCO3
(25 mL), H2O (25 mL), and brine (25 mL). The aqueous extracts
were combined and back extracted with Et2O and hexane (1:1; 100
mL) and the combined organic phases were dried (MgSO4), rotary
evaporated, and chromatographed (gradient elution 5:1 EtOAc:
hexane to 4:1 EtOAc:hexane) to give amide 28 (128 mg, 69%) as
a pale yellow viscous oil: [R]25 -28.2 (c 1.00, CDCl3); Rf 0.37
D
(1:3 EtOAc:hexane); IR (film) 3409, 3365, 1798, 1729, 1663, 1567
1
cm-1; H NMR (CDCl3, 400 MHz) δ 7.03 (d, J ) 8.4 Hz, 2H),
6.87 (d, J ) 8.5 Hz, 2H), 6.45 (d, J ) 7.5 Hz, 1H), 6.06 (ddd, J )
18.0, 13.5, 9.0 Hz, 1H), 5.30 (m, 2H), 5.24 (s, 1H), 4.69 (dt, J )
7.5, 6.0 Hz, 1H), 3.42 (d, J ) 9.5 Hz, 1H), 3.05 (dd, J ) 14.0, 5.5
Hz, 1H), 2.97 (d, J ) 16.0 Hz, 1H), 2.76 (d, J ) 16.0 Hz, 1H),
1.45 (s, 9H), 1.38 (s, 9H), 1.31 (s, 9H), 0.95 (s, 9H); 13C (CDCl3,
100 MHz) δ 172.6, 170.2, 168.3, 167.9, 154.2, 131.2, 130.8, 130.0,
124.0, 121.8, 109.7, 82.3, 82.2, 80.4, 78.3, 57.6, 53.6, 39.4, 37.3,
34.3, 28.7, 27.9, 23.9; MS (CI) m/z 635 (M + NH4)+, 618 (M +
H)+; HRMS (CI) m/z calcd for C34H52NO9 (M + H)+ 618.3642,
found 618.3641. Anal. Calcd for C34H51NO9: C, 66.10; H, 8.32;
N, 2.27. Found: C, 65.97; H, 8.06; N, 2.19.
(1:3 EtOAc:hexane); IR (film) 3473, 3356, 1734, 1659, 1609 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.08 (d, J ) 8.0 Hz, 2H), 6.89 (d,
J ) 8.0 Hz, 2H), 6.78 (d, J ) 7.5 Hz, 1H), 5.90 (app-dt, J ) 17.0,
10.0 Hz, 1H), 5.22 (d, J ) 10.5 Hz, 1H), 5.22 (d, J ) 17.0 Hz,
1H), 4.70 (app-q, J ) 6.0 Hz, 1H), 4.47 (s, 1H), 3.77 (s, 3H), 3.18
(d, J ) 9.5 Hz, 1H), 3.04 (d, J ) 6.0 Hz, 2H), 2.85 (d, J ) 16.0
Hz, 1H), 2.63 (d, J ) 16.0 Hz, 1H), 1.43 (s, 9H), 1.38 (s, 9H),
1.31 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.4, 170.2, 169.4,
169.1, 154.2, 131.4, 130.9, 130.0, 124.1, 120.9, 82.2, 81.6, 78.3,
76.6, 59.0, 53.7, 52.9, 43.0, 37.4, 28.8, 27.9; MS (CI, NH3) m/z
564 (M + H)+, 508 (M - t-Bu + H)+; HRMS (CI) m/z calcd for
C30H46NO9 (M + H)+ 564.3173, found 564.3186. Anal. Calcd for
C30H45NO9: C, 63.92; H, 8.05; N, 2.48. Found: C, 63.87; H, 7.95;
(S)-2-((S)-4-tert-Butyloxycarbonylmethyl-2-tert-butyl-5-oxo-
1,3-dioxolan-4-yl)-11-oxooctadec-3E-enoic Acid (32). Dioxol-
anone 27 (72 mg, 0.20 mmol), dione 31 (45 mg, 0.10 mmol), and
carbene 20 (28 mg, 0.020 mmol, 20 mol %) were dissolved in
freeze-thaw degassed CH2Cl2 (0.20 mL) under Ar and the resultant
mixture microwave heated at 65 °C for 4 h. Rotary evaporation
and chromatography (gradient elution hexane to 1:2 Et2O:hexane
to 1:1 Et2O:hexane) gave alkene 32 (63 mg, 57%) as a pale yellow
oil: [R]25 -42.6 (c 1.00, CDCl3); Rf 0.27 (1:1 Et2O:hexane); IR
D
(film) 3209, 1801, 1724 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.79
(dt, J ) 15.5, 6.5 Hz, 1H), 5.71 (dd, J ) 15.5, 9.0 Hz, 1H), 5.24
(s, 1H), 3.63 (d, J ) 9.0 Hz, 1H), 2.96 (d, J ) 15.8 Hz, 1H), 2.75
(d, J ) 16.0 Hz, 1H), 2.38 (t, J ) 7.5 Hz, 4H), 2.06 (app-dd, J )
13.5, 6.5 Hz, 2H), 1.55 (m, 4H), 1.46 (s, 9H), 1.26 (m, 14H), 0.95
(s, 9H), 0.87 (t, J ) 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
211.9, 174.5, 172.0, 168.1, 139.5, 120.9, 109.0, 82.2, 79.8, 55.2,
42.8, 42.7, 38.9, 34.2, 32.4, 31.6, 29.6, 29.2, 28.9, 28.8, 28.5, 27.9,
23.8, 23.7, 23.5, 22.5, 14.0; MS (CI, NH3) m/z 570 (M + NH4)+;
HRMS (CI) m/z calcd for C31H56NO8 (M + NH4)+ 570.4006, found
570.4015. Anal. Calcd for C31H52O8: C, 67.36; H, 9.48. Found:
C, 67.25; H, 9.35.
N, 2.40. Diester 37: [R]25 -4.0 (c 1.00, CDCl3); Rf 0.10 (1:3
D
1
EtOAc:hexane); H NMR (400 MHz, CDCl3) δ 7.07 (d, J ) 8.5
Hz, 2H), 6.88 (d, J ) 8.5 Hz, 2H), 6.77 (d, J ) 8.0 Hz, 1H), 5.91
(m, 1H), 5.24 (d, J ) 9.8 Hz, 1H), 5.23 (d, J ) 16.4 Hz, 1H), 4.69
(app-dt, J ) 8.0, 6.5 Hz, 1H), 4.54 (s, 1H), 3.77 (s, 3H), 3.68 (s,
3H), 3.21 (d, J ) 9.5 Hz, 1H), 3.07 (dd, J ) 14.0, 6.0 Hz, 1H),
3.01 (dd, J ) 14.0, 6.5 Hz, 1H), 2.89 (d, J ) 16.0 Hz, 1H), 2.66
(d, J ) 16.0 Hz, 1H), 1.39 (s, 9H), 1.31 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 173.2, 170.5; 170.2, 169.5, 154.3, 131.2, 130.9,
129.9, 124.1, 121.2, 82.3, 78.3, 76.5, 58.8, 53.7, 53.1, 51.9, 41.5,
37.2, 28.7, 27.9; MS (CI, NH3) m/z 539 (M + NH4)+, 523 (M +
H)+, 522 (M)+; HRMS (CI) m/z calcd for C27H40NO9 (M + H)+
522.2703, found 522.2720. Anal. Calcd for C27H39NO9: C, 62.17;
H, 7.54; N, 2.69. Found: C, 62.16; H, 7.59; N, 2.67.
tert-Butyl (S)-3-(4-tert-Butyloxyphenyl)-2-((S)-2-((2S,4S)-2-
tert-butyl-4-tert-butyloxycarbonylmethyl-5-oxo-1,3-dioxolan-4-
yl)-11-oxooctadec-3E-enoylamino)propanoate (33). Method A:
Carbene 20 (34 mg, 0.050 mmol, 20 mol %) was added to dione
31 (56 mg, 0.13 mmol) and amide 28 (153 mg, 0.25 mmol) in
freeze-thaw degassed CH2Cl2 (0.25 mL) (Ar). The mixture was
microwave heated at 65 °C for 4 h, rotary evaporated, and
chromatographed (gradient elution 1:5 EtOAc:hexane to 1:4 EtOAc:
tert-Butyl (3S,4S)-4-((1S)-1-tert-Butyloxycarbonyl)-2-(tert-bu-
tyloxycarbonylphenyl)ethylaminocarbonyl)-3-hydroxy-3-(meth-
oxycarbonyl)-13-oxo-5E-eicosenoate (38). Method A: Dioxol-
anone 27 (34 mg, 0.10 mmol), dione 31 (22 mg, 0.050 mmol), and
6190 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Viridiofungin DeriVatiVes
carbene 20 (13 mg, 0.020 mmol, 20 mol %) were dissolved in
freeze-thaw degassed CH2Cl2 (0.10 mL) under Ar and the resultant
mixture microwave heated at 55 °C for 1 h. The solvent was rotary
evaporated, the residue was dissolved in MeOH (1.0 mL), K2CO3
(130 mg, 1.0 mmol) was added, and the resulting mixture was
stirred for 18 h at room temperature. The mixture was partitioned
between EtOAc (25 mL) and aqueous HCl (1 M; 25 mL) and the
phases separated. The aqueous phase was saturated with NaCl and
extracted with EtOAc (5 × 25 mL). The combined organic ex-
tracts were dried (MgSO4) and rotary evaporated and the residue
was dissolved in DMF (0.5 mL) and cooled to 0 °C and HOBT
(16 mg, 0.12 mmol), H-Tyr(Ot-Bu)-t-Bu‚HCl (38 mg, 0.12 mmol),
i-Pr2NEt (45 µL, 0.24 mmol), and HBTU (44 mg, 0.12 mmol) were
added. The mixture was stirred for 90 min at 0 °C and subsequently
at 30 min at room temperature after which time it was partitioned
between Et2O and hexane (1:1; 25 mL) and aqueous HCl (1 M; 25
mL). The phases were separated and the organic phase was washed
with H2O (25 mL), saturated aqueous NaHCO3 (25 mL), H2O (25
mL), and brine (25 mL). The combined aqueous washings were
extracted with Et2O and hexane (1:1; 25 mL) and the combined
organic extracts dried (MgSO4) and rotary evaporated. Chroma-
tography (1:3 EtOAc:cyclohexane) gave amide 38 (8.1 mg, 10%)
as a pale yellow oil. Method B: Ester 36 (15 mg, 0.027 mmol),
dione 31 (5.8 mg, 0.014 mmol), and carbene 20 (1.8 mg, 0.0054
mmol, 20 mol %) were dissolved in freeze-thaw degassed
CH2Cl2 (0.03 mL) under Ar and the resultant mixture was
microwave heated at 65 °C for 4 h. The solvent was rotary
evaporated and the residue chromatographed (1:2 EtOAc:hexane)
) 16.0 Hz, 1H), 2.37 (t, J ) 7.5 Hz, 4H), 1.99 (m, 2H), 1.55 (m,
4H), 1.42 (s, 9H), 1.37 (s, 9H), 1.31 (s, 9H), 1.25 (br s, 14H), 0.87
(t, J ) 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.7, 173.4,
170.2, 170.1, 169.1, 154.2, 137.5, 137.3, 130.0, 127.0, 124.0, 82.1,
81.5, 78.3, 76.3, 58.0, 53.7, 52.8, 43.1, 42.8, 42.6, 37.4, 31.9, 31.6,
29.6, 29.2, 29.0, 28.8, 27.9, 23.8, 22.5, 14.0; MS (CI, NH3) m/z
774 (M + H)+, 718 (M - t-Bu + H)+; HRMS (CI) m/z calcd for
C44H72NO10 (M + H)+ 774.5156, found 774.5164.
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B.), the Royal Society and the
Wolfson Foundation for a Royal Society Wolfson Research
Merit Award (to A.G.M.B.), the Wolfson Foundation for
establishing the Wolfson Centre for Organic Chemistry in
Medical Sciences at Imperial College, the Engineering and
Physical Sciences Research Council, and GlaxoSmithKline for
generous support of our studies. We additionally thank Dr.
Andrew P. White for X-ray crystal structure determinations and
Peter R. Haycock and Richard N. Sheppard for high-resolution
NMR spectroscopy. We also thank Dr. Annett Pollex and
Professor Dr. Martin Hiersemann for kindly providing us with
copies of the 1H, 13C, COSY, HMBC, and HSQC NMR spectra
of their synthetic dimethyl isopropyl esters of viridiofungin A,
A2, and A4 and the corresponding nonnatural diastereoisomers.
Supporting Information Available: Additional experimental
procedures and structural data for all new compounds; crystal-
lographic data (including ORTEPs and CIFs) for compounds 22,
29, and 36 (CCDC 606372, 606373, and 606374, respectively);
copies of 1H NMR and 13C NMR spectra for selected new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
to give amide 38 (11 mg, 54%) as a colorless oil: [R]25 -6.3 (c
D
0.63, CDCl3); Rf 0.25 (1:3 EtOAc:hexane); IR (film) 3426, 3362,
3328, 1733, 1661, 1607 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.08
(d, J ) 8.5 Hz, 2H), 6.88 (d, J ) 8.5 Hz, 2H), 6.82 (d, J ) 7.5 Hz,
1H), 5.56 (m, 2H), 4.68 (dd, J ) 13.5, 6.0 Hz, 1H), 3.75 (s, 3H),
3.13 (d, J ) 9.5 Hz, 1H), 3.06 (dd, J ) 13.5, 6.0 Hz, 1H), 3.01
(dd, J ) 13.5, 6.0 Hz, 1H), 2.84 (d, J ) 16.0 Hz, 1H), 2.62 (d, J
JO060931E
J. Org. Chem, Vol. 71, No. 16, 2006 6191