Total synthesis of (+)-crocacin C

Article abstract of DOI:10.1016/j.bmc.2010.03.003

Two approaches toward the total synthesis of cytotoxic polyketide natural product (+)-crocacin C (1) are described. The first approach, which was ultimately unsuccessful, was replaced altogether with a second that afforded target 1 in 10 linear steps from commercially available Evans' chiral propionimide (5% overall yield). No protecting groups were utilized in the total synthesis of 1.

Full text of DOI:10.1016/j.bmc.2010.03.003

Bioorganic & Medicinal Chemistry 18 (2010) 3648–3655
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Total synthesis of (+)-crocacin C
*
Gopal Sirasani, Tapas Paul, Rodrigo B. Andrade
Temple University, Department of Chemistry, Philadelphia, PA 19122, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Two approaches toward the total synthesis of cytotoxic polyketide natural product (+)-crocacin C (1) are
described. The first approach, which was ultimately unsuccessful, was replaced altogether with a second
that afforded target 1 in 10 linear steps from commercially available Evans’ chiral propionimide (5% over-
all yield). No protecting groups were utilized in the total synthesis of 1.
Received 14 January 2010
Accepted 4 March 2010
Available online 15 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Crocacin
Polyketide
1. Introduction
inhibition of Gram-positive bacterial growth, in addition to anti-
fungal and cytotoxic activity.1 In 1999, the relative stereochemistry
Jansen and co-workers in 1944 reported the isolation and struc-
ture determination of a group of electron transport inhibitors from
the myxobacterium Chondromyces crocatus possessing moderate
of crocacin C (1) and its congeners crocacins A (2), B (3) and D (4)
was established (Fig. 1).2
MeO MeO
Me
O
21
18
15
NH2
11
Me
Me
(+)-Crocacin C (1)
MeO MeO
18
Me
O
1
21
21
15
H
N
O
CO2R
NH
11
4
Me
Me
9
6
(+)-Crocacin A (2); R = Me
(+)-Crocacin B (3); R = H
MeO MeO
18
Me
O
1
15
H
N
O
6
CO2Me
NH
11
4
Me
Me
9
(+)-Crocacin D (4)
Figure 1. Structures of crocacins A–D (1–4).
* Corresponding author. Tel.: +1 215 204 7155; fax: +1 215 204 9851.
E-mail address: randrade@temple.edu (R.B. Andrade).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.03.003

G. Sirasani et al. / Bioorg. Med. Chem. 18 (2010) 3648–3655
3649
The crocacins have recently been identified as novel agricultural
2.2. Attempted synthesis of crocacin C (1)
pesticide leads, which have led to a renewed interest in these
natural products.3 By inspection, crocacin C (1) is composed of a
polyketide fragment possessing the challenging anti–anti–syn ste-
reotetrad (C16–C19) in addition to a conjugated (E,E)-dienamide
system (C11–C15). Crocacins A (2), B (3) and D (4) are further char-
acterized by an acid-sensitive (Z)-N-acylenamine motif (C7–C11)
tethered to a glycine residue. These structural features coupled
with an interesting bioactivity profile have made these natural
products attractive targets for synthesis.
The forward synthesis began with a Crimmins aldol reaction of
commercially available thiazolidinethione propionimide 8 and
trans-cinnamaldehyde (7). Enolization of 8 with TiCl4 and Hunig’s
base afforded non-Evans syn aldol 14 in 50% isolated yield (dr
>20:1). Protection of the free alcohol as its TBS ether with TBSOTf
and 2,6-lutidine proceeded in 75% yield. Reductive removal of
the auxiliary furnished requisite aldehyde 15 in 82% yield
(Scheme 2).
The first enantioselective total synthesis of (+)-crocacin C (1)
was reported in 2000 by Rizzacasa and co-workers,4 which was
quickly followed by both Chakraborty and Jayaprakash5 and Dias
and de Oliveira6 in 2001. In 2008, we reported a concise synthesis
of 1,7 which was shortly followed by Gillis and Burke.8 In addition,
there are five formal synthesis of 1 by Gurjar et al.,9 Raghavan,4
Furstner and co-workers10 and Yadav et al. (two approaches).11,12
Recently, all syntheses of the crocacins were reviewed.13 Herein
we report the first generation approach to 1, which was not suc-
cessful, in addition to a detailed description of the second success-
ful approach to crocacin C (1).
At this juncture, we began exploring options for executing the
asymmetric crotoylboration reaction with 15. Mindful of the fact
the desired product was the anti-Felkin diastereomer, we subjected
15 to two well-known asymmetric crotylboration reagents known
for their ability to override substrate-derived bias in double asym-
metric reactions.24 In the event, reaction with Brown’s reagent 9
gave a 61% yield of two inseparable diastereomers 16 and 17
(3:1 ratio by 1H NMR spectroscopy) (Scheme 3). Roush’s reagent
10 performed similarly in the crotylboration reaction, albeit in
60% yield (dr = 4:1).
Structural assignment of diastereomers 16 and 17 was achieved
by 13C acetonide analysis.25 Toward this end, the inseparable iso-
mers were treated with TBAF to remove the silyl ether, affording
intermediary diols in 88% yield, which were carried forward. Iso-
propylidenation with dimethoxypropane and PPTS afforded chro-
matographically separable acetonide diastereomers 18 and 19 in
76% and 19% yields, respectively. Analysis of the 13C NMR spectra
of 18 and 19 revealed that major isomer 18 was the 1,3-syn diaste-
reomer with the ketal carbon resonating at 99.2 and methyls at
19.6 (axial Me) and 30.0 (equatorial Me), which are consistent with
the chair-like conformation adopted by 1,3-syn acetonides. anti-
Diastereomer 19, on the other hand, possessed a ketal carbon at
100.6 ppm and acetonide methyls at 25.5 and 23.6, which are char-
acteristic of the twist-boat conformation of 1,3-anti acetonides
(Scheme 4).25
2. Results and discussion
Current natural product total synthesis places a high premium
on synthetic efficiency, which is characterized by economy (e.g.,
atom,14 step15 and redox16) and selectivity (e.g., regio-, stereo-
and chemo-),17 among other metrics.18 The realization of an effi-
cient total synthesis therefore mandates the attendant synthetic
strategy maximize both economy and selectivity.
2.1. First generation retrosynthesis
The retrosynthetic analysis of crocacin C (1) is shown in Scheme
1. To maximize convergence we opted for a chemoselective cross-
metathesis reaction between known dienamide 519 and diene 6.
It is important to note that the presence of a cyclic protecting
group (i.e., acetonide) would be essential to the success of the pro-
posed chemoselective cross-metathesis step. In its absence, the
1,7-diene system would certainly cyclize to form a cyclohexene
derivative and styrene via a ring-closing metathesis (RCM) path-
way. As such, we hypothesized an acetonide (or related cyclic pro-
tecting group) would preclude RCM and enable a cross-metathesis
pathway by eliminating conformational isomers capable of cycliz-
ing. A survey of the literature revealed Crimmins had employed
this tactic to effect a cross-metathesis reaction between diene 11
and ethyl acrylate (12), isolating dienoate 13 in near quantitative
yield and validating our hypothesis (Eq. 1.20
The results clearly indicated chiral reagents 9 and 10 were un-
able to overcome the stereochemical bias of aldehyde 15 to furnish
the desired anti-Felkin diastereomer. In light of these unfortunate
results, recourse was made to an entirely different synthetic plan.
2.3. Second generation retrosynthesis
Our second approach to (+)-crocacin C (1) wanted to retain the
high levels of convergence from the first; therefore, we maintained
the disconnection at the C14–C15 olefin (Scheme 5). Chakraborty
and Jayaprakash5 employed the vinylogous Horner–Wadsworth–
Emmons olefination with phosphonate 2026 to efficiently forge this
bond, so our challenge lied in the concise preparation of aldehyde
PMP
PMP
CO2Et
12
O
O
O
O
CO2Et
ð1Þ
Me
Me
CH2Cl2
95%
11
13
Diene 6, in turn, would be prepared via a reagent-controlled
asymmetric crotylboration reaction utilizing Brown’s reagent 921
or Roush’s reagent 1022 and an aldehyde derived from the Crim-
mins aldol reaction23 of propionate synthon 8 and trans-cinnamal-
dehyde (7).
21. Access to homochiral 21 was thought to proceed from Evans’
dipropionate synthon 22 and commercially available trans-cinna-
maldehyde (7).27
The power of this method lies in its ability to (1) exert stereo-
control in the aldol reaction to access either syn aldol diastereo-

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G. Sirasani et al. / Bioorg. Med. Chem. 18 (2010) 3648–3655
Crotylboration
MeO MeO
Me
O
15
NH2
14
Me
Me
Chemoselective
Cross-Metathesis
Crimmins Aldol
(+)-crocacin C (1)
Me
O
Me
O
Me
O
+
NH2
Me
Me
5
6
S
O
CHO
Me
+
+
R2B
Me
N
S
9: R = (-)-Ipc
10: R = (+)-DIPT
7
Bn
8
Scheme 1. First-generation retrosynthesis of 1.
S
S
O
TiCl4, i-Pr2NEt
HO
O
1.) TBSOTf, 2,6-lutidine
CH2Cl2, -78 °C (75%)
then 7
Me
N
S
Ph
N
S
CH2Cl2
Me
Bn
Bn
2.) DIBAL-H, CH2Cl2,
-78 °C (82%)
50% (dr>20:1)
14
8
TBSO
CHO
Ph
Me
15
Scheme 2. Synthesis of aldehyde 15.
mer; and (2) utilize the newly formed hydroxyl to direct the ste-
reochemical course of the reduction by proper reagent selection,
leading to either a 1,3-syn or 1,3-anti diol.28
dard conditions and subjected to 13C NMR analysis. Resonances
from the 13C NMR of 27 (23.5 and 25.8 ppm for the methyls;
100.8 ppm for the ketal carbon) were consistent with those found
in a twist-boat conformation, which is indicative of a 1,3-anti diol
disposition (Scheme 7).25
2.4. Total synthesis of crocacin C (1)
With 26 in hand, we turned our attention to installing the
methyl ethers in target 1. Toward this end, we reductively removed
the oxazolidinone auxiliary with LiBH4 (66% yield) and differenti-
ated the primary from the secondary alcohols with the bulky
TBDPS group (90% yield). The latter tactic had been utilized by Riz-
zacasa and co-workes4 and Dias and de Oliveira (Scheme 8).6
After some consideration, we opted for a shorter route to alco-
hol 31 that avoided protecting groups, such as silyl ethers, alto-
gether. Methylation of diol 26 would directly accomplish our
goal. Thus, various methylation protocols were screened to install
both requisite methyl ethers.30 Ultimately, the combination of
The synthesis commenced with the preparation of ketoimide 22
by an Evans aldol reaction29 of oxazolidinone 23 and propionalde-
hyde (dr >20:1), followed by Parikh–Doering oxidation,30 which
proceeded in 71% overall yield. Enolization of 22 with TiCl4 and i-
Pr2NEt and subsequent addition of trans-cinnamaldehyde (7) affor-
ded desired aldol 25 (dr >20:1) in 75% yield (Scheme 6).
Stereoselective substrate-based reduction of the C17 ketone
with NMe4BH(OAc)3 afforded desired 1,3-anti diol 26 in 88% yield
as a single diastereomer.28 To confirm the relative 1,3-anti stereo-
chemistry, diol 26 was converted into acetonide 27 following stan-

G. Sirasani et al. / Bioorg. Med. Chem. 18 (2010) 3648–3655
3651
1,3-syn
1,3-anti
TBSO OH
(-)-Ipc2B
Me
9
TBSO
TBSO
OH
61% (16:17 = 3:1)
+
CHO
Ph
Ph
Ph
(+)-DIPT2B
Me
Me
Me
16
Me
Me
17
Me
15
10
60% (16:17 = 4:1)
undesired (major)
desired (minor)
Scheme 3. Double asymmetric crotylboration reaction with aldehyde 15.
19.6 (ax) and 30.0 (eq)
25.5 and 23.6
Me
O
Me
O
99.2
Me
O
Me
O
100.6
TBSO
OH
1.) TBAF, THF (88%)
2.) DMP, PPTS
+
Ph
Ph
Ph
Me
16, 17
Me
Me
Me
Me
Me
anti-19
syn-18
(19%)
(76%)
undesired (major)
desired (minor)
Scheme 4. Structural assignment of diastereomers 18 and 19 via 13C acetonide analysis.
conjugated E,E-dienoate 33 in 57% yield as one diastereomer.
Saponification of the ester, activation of the intermediary acid with
methyl chloroformate and treatment with aqueous ammonia
delivered crocacin C (1) in 63% yield from 33.5
1,3-anti reduction
MeO MeO
Me
O
15
NH2
14
3. Conclusion
Me
Me
Vinylogous
Evans Dipropionate
Horner-Wadsworth-
Emmons
Two synthetic strategies for the concise asymmetric synthesis
of (+)-crocacin C (1) have been presented. The first was unsuccess-
ful due to undesired substrate control in the asymmetric crotylb-
oration reaction, which resulted in an undesired diastereomer.
The second-generation strategy, based on Evans’ dipropionate syn-
thon methodology, enabled a concise total synthesis of 1 in ten
steps from commercially available Evans’ propionimide 22 and cin-
namaldehyde (7) in (5% overall yield) without recourse to protect-
ing groups.
Aldol
(+)-crocacin C (1)
Me
O
MeO MeO
(EtO) (O)P
CHO
+
2
OEt
20
Me
21
Me
4. Experimental
4.1. General
O
O
O
CHO
All reactions containing water or air sensitive reagents were
performed in oven-dried glassware under nitrogen or argon. Tetra-
hydrofuran and dichloromethane were passed through two col-
umns of neutral alumina. Toluene was passed through one
column of neutral alumina and one column of Q5 reactant. Diiso-
propylamine, chloroform and 2,6-lutidine were distilled from
CaH2 prior to use. Preparation of 9 and use in Brown crotylation
reaction with 15 were performed according to Ref. 21 Reagent 10
was prepared according to Ref. 22. trans-Cinnamaldehyde (7) was
distilled prior to use. All other reagents were purchased from com-
mercial sources and used without further purification. All solvents
for work-up procedures were used as received. Flash column chro-
matography was performed according to the procedure of Still (see
Ref. 32) using ICN Silitech 32-63 D 60Å silica gel with the indicated
solvents. Thin layer chromatography was performed on Analtech
60F254 silica gel plates. Detection was performed using UV light,
Me
+
N
O
Me
7
Bn
22
Scheme 5. Second-generation retrosynthesis of 1.
MeOTf and 2,6-di-tert-butyl-4-methylpyridine at 0 °C provided 32
in 49% yield with unproductive elimination accounting for the
remaining mass balance (Scheme 9).
Reductive removal of the chiral auxiliary in 32 with LiBH4 and
subsequent oxidation of the intermediary alcohol with the Dess–
Martin periodinane31 provided aldehyde 21 in 59% yield over two
steps. Endgame began with a stereoselective, vinylogous Horner–
Wadsworth–Emmons reaction with phosphonate 20 to prepare

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G. Sirasani et al. / Bioorg. Med. Chem. 18 (2010) 3648–3655
O
O
O
HO
O
n-Bu2BOTf, Et3N
EtCHO
Me
Me
N
O
N
O
CH2Cl2, -78 °C
Me
Bn
23
Bn
75%
dr > 20:1
24
O
O
O
SO3•Pyr, Et3N
TiCl4, i-Pr2NEt, 7
Me
N
O
DMSO/CH2Cl2, 0 °C
95%
CH2Cl2, -78 °C
Me
Bn
75%
dr > 20:1
22
O
HO
O
O
N
O
Me
Me
Bn
25
Scheme 6. Evans dipropionate aldol reaction with 7.
O
HO
HO
O
NMe4BH(OAc)3
25
N
O
MeCN/AcOH, -40 °C
Me
26
Me
Bn
88%
dr > 20:1
25.8 and 23.5
Me Me
100.8
O
O
O
O
Me2C(OMe)2, PPTS
73%
N
O
Me
Me
Bn
27
Scheme 7. 13C NMR acetonide analysis of diol 26.
KMnO4 stain, PMA stain and subsequent heating. 1H and 13C NMR
spectra were recorded at the indicated field strength in CDCl3 at rt.
Chemical shifts are indicated in parts per million (ppm) downfield
from tetramethylsilane (TMS, d = 0.00) and referenced to the CDCl3.
Splitting patterns are abbreviated as follows: s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet), comp (overlapping sig-
nals of chemically nonequivalent protons), br (broad).
washed with brine solution (20 mL), dried (Na2SO4) and filtered.
The solvent was concentrated under reduced pressure, and the res-
idue was purified by flash chromatography eluting with EtOAc/
hexanes (1:9) to afford 380 mg (50%) of 14 as a yellow oil. 1H
and 13C NMR consistent with reference (see Ref. 33).
4.3. Aldol 14 O-TBS ether
4.2. Aldol 14
To a solution of aldol 14 (225 mg, 0.57 mmol) in CH2Cl2 (6.0 mL)
at ꢀ78 °C were added distilled 2,6-lutidine (152 mg, 1.42 mmol)
and TBSOTf (164 mg, 0.62 mmol). After stirring the reaction mix-
ture for 1 h at ꢀ78 °C, water (3.0 mL) was added. The reaction mix-
ture was stirred an additional 5 min at rt and extracted with CH2Cl2
(2 ꢁ 20 mL). The combined organic layers were washed with aque-
ous NaHCO3 (10 mL), brine solution (15 mL), dried (Na2SO4) and
filtered. The solvent was concentrated under reduced pressure,
and the residue was purified by flash chromatography eluting with
EtOAc/hexanes (0.4:9.6) to afford 217 mg (75%) of product as a yel-
To a solution of propionimide 8 (507 mg, 1.91 mmol) in CH2Cl2
(12 mL) at 0 °C was added TiCl4 (725 mg, 3.82 mmol) and the yel-
low slurry was stirred for 5 min. Freshly distilled i-Pr2NEt (271 mg,
2.10 mmol) was slowly added at 0 °C to give a red solution, which
was stirred for an additional 20 min at 0 °C. The reaction mixture
was cooled to ꢀ78 °C, and freshly distilled trans-cinnamaldehyde
7 (278 mg, 2.10 mmol) was added dropwise. After stirring at
ꢀ78 °C for 1 h, the mixture was warmed to 0 °C over 3 h. The reac-
tion mixture was quenched by the addition of saturated NH4Cl
(12 mL) and stirred for 5 min at 0 °C. The reaction mixture was ex-
tracted with CH2Cl2 (2 ꢁ 30 mL). The combined organic layers were
low oil. ½a 2D0
ꢂ
+63.2 (c 0.5, CH2Cl2); IR (neat) 3154, 2930, 2857, 2360,
2254, 1793, 1694, 1471, 1376, 1259 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 7.41–7.23 (m, 10H), 6.56 (d, J = 16.0 Hz, 1H), 6.18 (dd,

G. Sirasani et al. / Bioorg. Med. Chem. 18 (2010) 3648–3655
3653
O
OH
OH
OH
OH
O
OH
OH
TBDPSCl,
imidazole
LiBH4
MeOH
66%
Ph
Ph
N
O
Ph
OH
90%
Me
Me
Me
Me
Me
Bn
28
26
MeO
OMe
KH, MeI
97%
OTBDPS
Ph
OTBDPS
Me
Me
30
Me
29
MeO
OMe
TBAF
THF
Ph
OH
Me
31
Me
95%
Scheme 8. Synthesis of alcohol 31.
O
MeO MeO
O
MeOTf
2,6-di-t-Bu-4-Me-Pyr
CHCl3, 0 °C
49%
N
O
26
Me
Me
Bn
32
MeO MeO
1.) LiBH4, THF/MeOH
LDA, 20
CHO
THF/DMPU
-78 °C
2.) Dess-Martin
periodinane
Me
Me
57%
21
59%
MeO MeO
Me
O
1.) LiOH
1
OEt
2.) ClCO2Me, Et3N
then NH4OH
Me
Me
33
63% overall
Scheme 9. Completion of the synthesis.
J = 15.6, 7.6 Hz, 1H), 5.42–5.37 (m, 1H), 5.20–4.89 (m, 1H), 4.70 (t,
J = 8.0 Hz, 1H), 3.33 (dd, J = 11.2, 7.2 Hz, 1H), 3.24 (dd, J = 13.2,
3.2 Hz, 1H), 3.05 (dd, J = 13.2, 10.8 Hz, 1H), 2.85 (d, J = 11.6 Hz,
1H), 1.12 (d, J = 6.8 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H);
13C NMR (100 MHz, CDCl3) d 201.0, 176.3, 136.8, 136.7, 132.1,
130.4, 129.4, 128.9, 128.6, 127.7, 127.2, 126.5, 75.9, 69.1, 45.3,
37.1, 31.3, 25.9, 25.7, 18.1, 14.4, ꢀ3.8, ꢀ4.6; HRMS (FAB) calcd
for C28H37NS2SiO2+Na+ = 534.1933, found 534.1945.
rated aqueous Rochelle’s salt solution (4.0 mL) and stirred for
45 min at rt. The reaction mixture was extracted with CH2Cl2
(2 ꢁ 15 mL). The combined organic layers were washed brine solu-
tion (10 mL), dried (Na2SO4) and filtered. The solvent was concen-
trated under reduced pressure, and the residue was purified by
flash chromatography eluting with EtOAc/hexanes (0.3:9.7) to af-
ford 100 mg (82%) of aldehyde 15 as a yellow oil. 1H and 13C
NMR consistent with reference (see Ref. 34).
4.4. Aldehyde 15
4.5. Homoallylic alcohols 16 and 17
To a solution of TBS-protected aldol 14 (205 mg, 0.40 mmol) in
CH2Cl2 (4.0 mL) at ꢀ78 °C was added DIBAL-H (0.8 mL, 1.0 M in
hexanes, 0.8 mmol) and stirred for 30 min. Additional DIBAL-H
(0.4 mL, 1.0 M in hexanes, 0.4 mmol) was added at ꢀ78 °C and stir-
red for another 20 min, and the reaction was quenched with satu-
A solution of (E)-crotylboronate 10 (0.49 mL, 1.0 M solution in
toluene, 0.49 mmol) in toluene (1.0 mL) was treated with pow-
dered 4 Å molecular sieves and then cooled to ꢀ78 °C. A solution
of freshly prepared aldehyde 15 (100 mg, 0.33 mmol) in toluene
(1.0 mL) was slowly added over a period of 10 min. After stirring

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G. Sirasani et al. / Bioorg. Med. Chem. 18 (2010) 3648–3655
the reaction mixture for 20 h, at ꢀ78 °C, it was treated with 2 N
NaOH (3.0 mL) to hydrolyze DIPT. The biphasic mixture was
warmed to 0 °C and stirred for 20 min at 0 °C, the reaction mixture
was extracted with ether (2 ꢁ 20 mL). The combined organic layers
were washed brine solution (10 mL), dried (K2CO3) and filtered.
The solvent was concentrated under reduced pressure, and the res-
idue was purified by flash chromatography eluting with EtOAc/
hexanes (0.3:9.7) to afford 70 mg (60%) of alcohols 16 and 17 as
a colorless foam. IR (neat) 3155, 2958, 2931, 2250, 1471, 1383,
freshly distilled i-Pr2NEt (0.68 g, 5.25 mmol). After stirring for 1 h,
the reaction mixture was cooled to ꢀ78 °C and freshly distilled
aldehyde 7 (0.69 g, 5.25 mmol) was added drop wise. The reaction
mixture was stirred at ꢀ78 °C for 30 min then warmed to ꢀ40 °C
over a period of 1 h. The reaction mixture was warmed to 0 °C
and quenched by the addition of phosphate buffer (7.6 mL, pH 7)
and stirred an additional 5 min. The reaction mixture was ex-
tracted with CH2Cl2 (2 ꢁ 20 mL). The combined organic layers were
washed with aqueous NaHCO3 (15 mL), brine solution (15 mL),
dried (Na2SO4) and filtered. The solvent was concentrated under
reduced pressure, and the residue was purified by flash chromatog-
raphy eluting with EtOAc/hexanes (1:5) to afford 1.50 g (75%) of 25
1257 cmꢀ1 1H NMR (400 MHz, CDCl3): d 7.27–7.09 (m, 5H), 6.39
;
(d, J = 16.0 Hz, 1H), 6.10 (dd, J=16.0, 7.2 Hz, 1H), 5.69–5.60 (m,
1H), 5.0–4.91 (m, 2H), 4.24 (t, J = 6.4 Hz, 1H), 3.38 (d, J = 7.6, 1H),
2.20–2.14 (m, 1H), 2.10 (bs, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.83 (d,
J = 5.2 Hz, 3H), 0.79 (s, 9H), ꢀ0.03 (s, 3H), ꢀ0.09 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 141.9, 139.4, 136.9, 136.8, 131.8, 131.4,
130.4, 128.7, 128.6, 127.6, 127.5, 126.5, 126.4, 115.5, 114.9, 78.8,
77.9, 75.7, 42.1, 41.6, 40.6, 25.6, 25.8, 18.1, 18.0, 16.6, 12.7, 7.7,
ꢀ3.0, ꢀ3.6, ꢀ4.0, ꢀ4.4; HRMS (FAB) calcd for C22H36SiO2–
H = 359.2406, found 359.2393.
as a yellow oil. ½a D20
ꢂ
ꢀ165.0 (c 1.0, CH2Cl2); IR (neat) 3524, 2252,
1774, 1713, 1391, 1358, 1215, 909, 731 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 7.35–7.13 (m, 10H), 6.63 (dd, J = 16.0, 1.2 Hz, 1H), 6.13
(dd, J = 16.0, 5.6 Hz, 1H), 4.84 (q, J = 7.2 Hz, 1H), 4.78 (bs, 1H),
4.73–4.68 (m, 1H), 4.22–4.12 (m, 2H), 3.24 (dd, J = 13.6, 3.2 Hz,
1H), 3.02–3.00 (m, 2H), 2.74 (dd, J = 13.6, 9.6 Hz, 1H), 1.45 (d,
J = 7.6 Hz, 3H), 1.13 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 211.1, 170.0, 153.9, 136.7, 134.9, 130.9, 129.3, 128.9, 128.5,
127.5, 127.4, 126.5, 71.9, 66.6, 55.3, 52.3, 49.7, 37.8, 13.0, 10.5;
HRMS (FAB) calcd for C25H27NO5 + Na+ 444.1786, found 444.1778.
4.6. Acetonides 18 and 19
TBAFꢃ3Y2J (92 mg, 0.29 mmol) was added to a solution of alco-
hols 16 and 17 (70 mg, 0.19 mmol) in THF (2.0 mL) at 0 °C. The
reaction was warmed to rt and stirred for 12 h, diluted with water
(4 mL) and extracted with CH2Cl2 (2 ꢁ 10 mL). The combined or-
ganic layers were washed brine solution (10 mL), dried (Na2SO4)
and filtered. The solvent was concentrated under reduced pressure,
and the residue was purified by flash chromatography eluting with
EtOAc/hexanes (2:8) to afford 42 mg (88%) of intermediary diols.
The crude diols were dissolved in 2,2-dimethoxypropane (15 mL)
and a catalytic amount of PPTS was added. The reaction mixture
was stirred for 3 h then filtered through a plug of cotton. The sol-
vent was concentrated under reduced pressure, and the residue
was purified by preparative TLC eluting with EtOAc/hexanes (1:9)
to afford 32 mg (76%) 18 as a colorless foam and 8 mg (19%) of
minor acetonide 19 as a colorless foam.
4.8. Diol 26
To a stirred solution of Me4NBH(OAc)3 (5.63 g, 21.40 mmol) in
MeCN (10 mL) was added glacial AcOH (10 mL). After stirring for
30 min, the reaction mixture was cooled to ꢀ40 °C and a solution
of 25 (1.50 g, 3.57 mmol) in MeCN (10 mL) was added via cannula.
After stirring for 6 h at this same temperature, the reaction mixture
was transferred to a refrigerator and allowed to age for 16 h at
ꢀ20 °C. Aqueous sodium tartrate (0.5 M, 25 mL) was added. The
reaction mixture was warmed to rt over 1 h then diluted with addi-
tional sodium tartrate (0.5 M, 25 mL) and CH2Cl2 (50 mL). The or-
ganic layer was separated, and the aqueous layer was back-
extracted with CH2Cl2 (2 ꢁ 25 mL). The combined organic layers
were washed with aqueous NaHCO3 (30 mL), brine solution
(30 mL), dried (Na2SO4) and filtered. The solvent was concentrated
under reduced pressure, and the residue was purified by flash
chromatography eluting with EtOAc/hexanes (2:3) to afford
4.6.1. Major acetonide 18
½
a 2D0
ꢂ
+29.5 (c 0.5, CH2Cl2); IR (neat) 3154, 3082, 2977, 2938, 2360,
2253, 1605, 1452, 1382, 1201 cmꢀ1 1H NMR (500 MHz, CDCl3) d
;
1.32 g (88%) of 26 as a yellow oil. ½a D20
ꢀ80.8 (c 1.0, CH2Cl2); IR
ꢂ
7.41–7.39 (m, 2H), 7.33–7.30 (m, 2H), 7.25–7.21 (m, 1H), 6.61 (dd,
J = 16.0, 1.5 Hz, 1H), 6.20 (dd, J=16.0, 5.5 Hz, 1H), 5.98–5.91 (m,
1H), 5.09–5.01 (m, 2H), 4.63–4.61 (m, 1H), 3.64 (dd, J = 10.0,
2.0 Hz, 1H), 2.34–2.29 (m, 1H), 1.68–1.64 (m, 1H), 1.48 (s, 3H), 1.47
(s, 3H), 0.95 (d, J = 1.5 Hz, 3H), 0.94 (d, J = 1.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 142.0, 137.0, 130.2, 129.2, 128.5, 127.4, 126.4,
113.4, 99.2, 74.3, 38.2, 34.6, 30.0, 19.6, 14.5, 5.3; HRMS (CI) calcd
for C19H26O2 + H+ = 287.2011, found 287.2000.
(neat) 3460, 3028, 2976, 2360, 2341, 2252, 1779, 1698, 1455,
1385, 1209, 908, 732; 1H NMR (400 MHz, CDCl3) d 7.40–7.20 (m,
10H), 6.64 (dd, J = 16.0, 1.2 Hz, 1H), 6.26 (dd, J = 16.0, 5.6 Hz, 1H),
4.77–4.75 (m, 2H), 4.26–4.16 (m, 3H), 3.98 (d, J = 8.4 Hz, 1H),
3.73 (q, J = 6.9 Hz, 1H), 3.31 (bs, 1H), 3.25 (dd, J = 13.2, 3.4 Hz,
1H), 2.81 (dd, J = 13.2, 9.6 Hz, 1H), 1.97–1.90 (m, 1H), 1.31 (d,
J = 7.2 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 177.1, 153.3, 136.8, 135.0, 130.5, 130.3, 129.4, 129.0, 128.5,
127.5, 127.4, 126.4, 78.4, 72.8, 66.2, 55.5, 40.3, 39.8, 37.9,15.0,
11.6; HRMS (FAB) calcd for C25H29 NO5 + Na+ 446.1943, found
446.1945.
4.6.2. Minor acetonide 19
½
a 2D0
+50.0 (c 0.2, CH2Cl2); IR (neat) 3155, 2986, 2930, 2200, 1458,
ꢂ
1380, 1224, 1172, 1096 cmꢀ1; 1H NMR (500 MHz, CDCl3) d 7.38 (d,
J = 7.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 6.57
(d, J = 15.5 Hz, 1H), 6.18 (dd, J = 15.8, 6.3 Hz, 1H), 5.94–5.87 (m,
1H), 5.07–5.02 (m, 2H), 4.50 (dt, J = 6.5, 1.5 Hz, 1H), 3.29 (dd,
J = 8.0, 3.5 Hz, 1H), 2.36–2.29 (m, 1H), 2.00–1.93 (m, 1H), 1.40 (s,
3H), 1.39 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 140.3, 137.0, 130.4, 128.4, 127.6, 127.3,
126.3, 115.0, 100.6, 77.8, 70.7, 41.2, 37.9, 25.5, 23.6, 17.1, 13.1;
HRMS (CI) calcd for C19H26O2 + H+ = 287.2011, found 287.2021.
4.9. Acetonide 27
To a stirred solution of diol 26 (80.0 mg, 0.19 mmol) in dime-
thoxypropane (19 mL) was added a catalytic amount of PPTS. The
reaction mixture was stirred for 3 h. The solvent was concentrated
under reduced pressure, and the residue was purified by flash
chromatography eluting with EtOAc/hexanes (1:4) to afford
65.0 mg (73%) of 27 as a yellow oil. ½a D20
ꢀ50.2 (c 1.0, CH2Cl2); IR
ꢂ
(neat) 3154, 3029, 2986, 2253, 1780, 1698, 1455, 1383, 1263,
4.7. Aldol 25
1222, 1107, 1022, 969, 909, 650 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.34–7.14 (m, 10H), 6.54 (dd, J = 15.8, 0.8 Hz, 1H), 6.09 (dd,
To a solution of dipropionimide 22 (1.38 g, 4.77 mmol) in
CH2Cl2 (19 mL) at ꢀ10 °C was added TiCl4 (1.00 g, 5.25 mmol) then
J = 15.8, 6.0 Hz, 1H), 4.66–4.54 (m, 1H), 4.57–4.54 (m, 1H), 4.12–
4.11 (m, 2H), 4.04–3.96 (m, 1H), 3.67 (dd, J = 9.2, 6.8 Hz, 1H),

G. Sirasani et al. / Bioorg. Med. Chem. 18 (2010) 3648–3655
3655
3.20 (dd, J = 13.2, 3.2 Hz, 1H), 2.74 (dd, J = 13.2, 9.6 Hz, 1H), 1.93–
References and notes
1.85 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H),
0.95 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.1, 153.2,
137.0, 135.3, 130.5, 129.5, 129.0,128.5, 127.4, 127.3, 127.2, 126.4,
100.8, 76.2, 70.0, 66.0, 55.4, 42.9, 38.9, 38.0, 25.8, 23.5, 14.0,
12.8; HRMS (FAB) calcd for C28H33NO5 + Na+ 486.2256, found
486.2254.
1. Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot. 1994, 47, 881.
2. Jansen, R.; Washausen, P.; Kunze, B.; Reichenbach, H.; Hofle, G. Eur. J. Org. Chem.
1999, 1085.
3. 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.
4. Raghavan, S.; Reddy, S. R. Tetrahedron Lett. 2004, 45, 5593.
5. (a) Chakraborty, T. K.; Jayaprakash, S. Tetrahedron Lett. 2001, 42, 497; (b)
Chakraborty, T. K.; Jayaprakash, S.; Laxman, P. Tetrahedron 2001, 57, 9461.
6. Dias, L. C.; de Oliveira, L. G. Org. Lett. 2001, 3, 3951.
7. Sirasani, G.; Paul, T.; Andrade, R. B. J. Org. Chem. 2008, 73, 6386.
8. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084.
9. Gurjar, M. K.; Khaladkar, T. P.; Borhade, R. G.; Murugan, A. Tetrahedron Lett.
2003, 44, 5183.
10. Besev, M.; Brehm, C.; Furstner, A. Collect. Czech. Chem. Commun. 2005, 70, 1696.
11. Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synlett 2007, 2049.
12. Yadav, J. S.; Reddy, P. V.; Chandraiah, L. Tetrahedron Lett. 2007, 48, 145.
13. Andrade, R. B. Org. Prep. Proced. Int. 2009, 41, 359.
14. Trost, B. M. Science 1991, 254, 1471.
15. Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41,
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18. Hoffmann, R. W. Elements of Synthesis Planning; Springer: Berlin, 2009.
19. Moriconi, E. J.; Meyer, W. C. J. Org. Chem. 1971, 36, 2841.
20. (a) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959; (b) Crimmins, M. T.;
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Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
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4.10. Imide 32
To a stirred solution of the diol 26 (70.0 mg, 0.17 mmol) in
CHCl3 (1.5 mL) at 0 °C, was added 2,6-di-tert-butyl-4-methylpyri-
dine (1.19 g, 5.81 mmol) followed by the addition of MeOTf
(0.82 g, 4.98 mmol). The reaction mixture was stirred for 28 h at
0 °C, quenched with MeOH (2 mL) and extracted with CH2Cl2
(3 ꢁ 5 mL), washed with brine solution (5 mL), dried (Na2SO4)
and filtered. The solvent was concentrated under reduced pressure,
and the residue was purified by flash chromatography eluting with
EtOAc/hexanes (1:4) to afford 37.0 mg (49%) of 32 as a yellow oil.
½
a 2D0
ꢂ
ꢀ74.5 (c 1.0, CH2Cl2); IR (neat) 3154, 2983, 2253, 1780,
1698, 1470, 1383, 1264, 1094, 907, 733, 650 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 7.36–7.14 (m, 10H), 6.50 (d, J = 21.2, Hz, 1H),
6.08 (dd, J = 21.2, 9.6 Hz, 1H), 4.57–4.56 (m, 1H), 4.13–4.08 (m,
3H), 3.94 (dd, J = 9.6, 4.8 Hz, 1H), 3.41–3.36 (m, 4H), 3.25–3.20
(m, 4H), 2.69 (dd, J = 17.6, 13.0 Hz, 1H), 1.90–1.88 (m, 1H), 1.20
(d, J = 6.4 Hz, 3H), 0.90 (d, J = 9.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 175.2, 153.1, 136.8, 135.4, 132.3, 129.5, 129.2, 128.9,
128.6, 127.6, 127.3, 126.5, 84.9, 81.8, 66.0, 60.1, 56.5, 55.7, 41.6,
40.7, 37.9, 14.1, 11.0; HRMS (FAB) calcd for C27H33NO5+-
Na+ = 474.2256, found 474.2228.
28. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.
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Acknowledgments
Financial support of this work by the Department of Chemistry
at Temple University is gratefully acknowledged. We also kindly
thank Professors Chris Schafmeister for access to LCMS instrumen-
tation and Scott McN. Sieburth for helpful discussions.
34. Crimmins, M. T. et al J. Org. Chem. 2005, 70, 2225.