Asymmetric total synthesis of the caspase-1 inhibitor (-)-berkeleyamide A

Article abstract of DOI:10.1021/jo1001033

The asymmetric total synthesis of (-)-berkeleyamide A (1), a naturally occurring caspase-1 inhibitor, has been achieved by employing Evans' syn-aldol reaction of N-acyl-(4R)-benzyl oxazolidin-2-one 3 as the key step.

Full text of DOI:10.1021/jo1001033

pubs.acs.org/joc
low micromolar range. The structure of berkeleyamide A
Asymmetric Total Synthesis of the Caspase-1
Inhibitor (-)-Berkeleyamide A
was elucidated using detailed NMR studies, and its stereo-
chemistry at C10 was assigned as 10S with remaining
uncertainty over the configuration of the C11 and C14
stereogenic centers.6 The intriguing biological properties
and ambiguity of the absolute stereochemistry at C11 and
C14 prompted us to initiate the total synthesis of berkeley-
amide A. During the course of our work, Brimble and
co-workers7 confirmed the absolute stereochemistry of 1 as
10S,11R,14S by total synthesis using [3 þ 2]-dipolar cycload-
dition as a key step. However, the crucial cycloaddition
reaction suffers from moderate diastereoselectivity (2.1:1:1)
and lower yield (∼35%) of the required diastereomer.
Herein we report our modular asymmetric synthetic ap-
proach for the synthesis of berkeleyamide A (1) using Evans’
aldol reaction as a key step for C-C bond formation between
chiral imide 3 and aldehyde 4 with the introduction of the
required chirality at C10 and C11 (Scheme 1). As depicted in
the retrosynthetic analysis, crucial N-acyl-(4R)-benzyl oxa-
zolidin-2-one 3 was envisioned from L-leucine by assuming
the natural L-configuration in the biosynthetic pathway,
whereas the other aldol coupling partner, aldehyde 4, was
envisioned from β-keto ester 5. Thus, our disconnection
approach offers a flexible strategy to synthesize all possible
diastereomers of 1 by simply incorporating either L- or
D-amino acid and adopting Evans’ (or) non-Evans’ syn/
anti-aldol synthetic approach.8-10
Swapnil J. Kulkarni,† Yakambram Pedduri,†
Amar G. Chittiboyina,*,† and Mitchell A. Avery*,†,‡,§
†Department of Medicinal Chemistry, School of Pharmacy,
‡National Center for Natural Product Research, School of
Pharmacy, and §Department of Chemistry, The University of
Mississippi, University, Mississippi 38677
mavery@olemiss.edu
Received January 21, 2010
The asymmetric total synthesis of (-)-berkeleyamide A
(1), a naturally occurring caspase-1 inhibitor, has been
achieved by employing Evans’ syn-aldol reaction of
N-acyl-(4R)-benzyl oxazolidin-2-one 3 as the key step.
As shown in Scheme 2, aldehyde 4 was synthesized from
commercially available Meldrum’s acid 6, which was con-
verted to β-keto ester 5 by typical acylation followed by
decarboxylative methanolysis.11 The ketone functionality in
5 was then protected as the 1,3-dioxalane12 and the corre-
sponding ester converted to the required aldehyde 4 by a
standard two-step protocol, complete reduction to the alco-
hol followed by DMP oxidation in multigram quantities with
overall good yield.
Interleukin-1β converting enzyme (ICE), also known as
caspase-1, is responsible for cleavage and activation of
interleukin-1β (IL-1β) to its active form (17K), which in turn
is involved in the pathogenesis of several inflammatory
disorders.1 Caspase-1 has been implicated in diseases such
as rheumatoid arthritis, multiple sclerosis, stroke, liver fail-
ure, and neurodegenerative disorders such as Huntington’s
disease.2,3 Subsequent research over the years suggests that
ICE plays a pivotal role in regulation of proinflammatory
cytokines, and its inhibition is a potential therapeutic target
for the treatment of immune-mediated inflammatory dis-
eases.4
Next, commercially available N-Boc-L-leucine was con-
verted to N-Boc-L-leucinal (7) following the literature
method.13 The resulting aldehyde was subjected to HWE
olefination using triethyl phosphonoacetate14 followed by
hydrogenation to give aminoester 8 in 85% yield (Scheme 3).
Subsequent ester hydrolysis of 8 furnished γ-N-Boc-ami-
no acid 9 in good yield. Large-scale synthesis of 9 was
achieved, obviating the need for chromatographic purifica-
tion. Our initial attempts toward the asymmetric aldol
Recently, several interesting secondary metabolites have
been isolated from rare microbes evolved in extreme ecosys-
tems, such as Berkeley Pit Lake, in search of potential
anticancer and antimicrobial agents.5 One such secondary
metabolite, Berkeleyamide A 1, was isolated from the fungi
Pencillium rubrum, which inhibited caspase-1 and the signal
transducing enzyme matrix metalloproteinase-3 (MMP-3) in
(6) Stierle, A. A.; Stierle, D. B.; Patacini, B. J. Nat. Prod. 2008, 71, 856–
860.
(7) Sperry, J.; Harris, E. B. J.; Brimble, M. A. Org. Lett. 2010, 12, 420–
423.
(8) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894–902.
(9) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392–393.
(10) Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993, 34, 4321–4324.
(11) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43,
2087–2088.
(12) Hwu, J. R.; Leu, L. C.; Robl, J. A.; Anderson, D. A.; Wetzel, J. M.
J. Org. Chem. 1987, 52, 188–191.
(1) Dinarello, C. A.; Wolff, S. M. N. Engl. J. Med. 1993, 328, 106–113.
(2) O’Brien, T.; Lee, D. Mini-Rev. Med. Chem. 2004, 4, 153–165.
(3) Talanian, R. V.; Brady, K. D.; Cryns, V. L. J. Med. Chem. 2000, 43,
3351–3371.
(4) Howley, B.; Fearnhead, H. O. J. Cell Mol. Med. 2008, 12, 1502–1516.
(5) Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem. Rev. 2009, 109,
3012–3043.
(13) Goel, O. P.; Krolls, U.; Stier, M.; Kesten, S. Org. Synth. 1989, 67, 69–
75.
(14) Martin, M. E.; Rice, K. G. Bioconjugate Chem. 2008, 19, 370–376.
DOI: 10.1021/jo1001033
r
Published on Web 03/31/2010
J. Org. Chem. 2010, 75, 3113–3116 3113
2010 American Chemical Society

Kulkarni et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis of Berkeleyamide A
SCHEME 3. Synthesis of γ-Azido-oxazolidinone Fragment 3a
aReagents and Conditions: (a) (i) triethyl phosphonoacetate, 1 M
NaHMDS in THF, THF, 0 °C, 7, -20 to 0 °C, 0.5 h; (ii) 5% Pd/C, H2,
20 psi, EtOAc, 1.5 h, 85%; (b) LiOH H2O, THF/MeOH/H2O (5:1:1), rt,
2 h, 79%; (c) 4.0 M HCl in 1,4-dioxane, 0 °C to rt, 12 h; (d) imidazol-1-
3
sulfonyl azide HCl, K2CO3, CuSO4 5H2O, MeOH, rt, 14 h, 77%; (e)
3
pivaloyl chloride, TEA, LiCl, (4R)-benzyl-2-oxazolidinone, THF,
-20 °C to rt, 6 h, 75%.
SCHEME 2. Synthesis of Aldehyde Fragment 4a
SCHEME 4. Synthesis of Berkeleyamide A via Evans’
syn-Aldol Reactiona
aReagents and conditions: (a) 1,2-bis(trimethylsilyloxy)ethane,
TMSOTf, CH2Cl2, rt, 8 h, 95%; (b) 2.3 M LiAlH4 in THF, THF, 0 °C to
rt, 2 h, 78%; (c) Dess-Martin periodinane, CH2Cl2, rt, 1 h, 92%.
reaction using a chiral imide derived from acid 9 gave the
required aldol product, albeit with poor diastereoselectivity
and low yield. The enolizable N-Boc-carbamate15 function-
ality in 9 was then converted into the azide in two-steps Boc-
deprotection followed by azido transfer reaction using shelf-
stable imidazol-1-sulfonyl azide16 to furnish γ-azido acid 10
in 77% yield. Re-evaluation of the asymmetric aldol reaction
using the chiral imide of 10 was then pursued. Accordingly,
acid 10 was coupled with (4R)-benzyl-2-oxazolidinone chiral
auxiliary using a standard procedure17 to obtain the correct
stereochemistry in the aldol reaction based on literature
precedents.18
aReactions and conditions: (a) TiCl4, (-)-sparteine, 4, CH2Cl2, 0 °C,
3 h, 74%; (b) 5% Pd/C, ammonium formate, MeOH, 1 h, 85%; (c)
Pd(CH3CN)2Cl2, acetone, H2O, rt, 4 h, 77%.
With the required fragments 3 and 4 in hand, our antici-
pated plan to use an asymmetric Evans’ aldol reaction to
couple these segments and to set the C10 and C11 stereo-
chemistry as required proceeded smoothly. Although initial
efforts involving a soft enolization method using TiCl4 as a
Lewis acid in the presence of a conventional base, triethyl
aldehyde 4 to afford the aldol product 2 as a single diaster-
eomer exclusively in 74% yield. The stereochemical outcome
of the aldol reaction can be rationalized using a Zimmer-
man-Traxler six-membered chairlike transition state
(Scheme 4). As anticipated, the facial selectivity of the
aldehyde was directed by the chiral auxiliary of the enolate
resulting in re face attack to deliver Evans’ syn-aldol product.
The absolute configuration of the resulting alcohol at the
C10 position was further confirmed by Mosher ester analysis
to be 10S as in the natural product 1 (Supporting
Information). Furthermore, the syn selectivity of the aldol
product was confirmed by 1H NMR analysis of Mosher ester
derivatives (J10-11 = 2.95 Hz). The conversion of the aldol
adduct 2 to natural product 1 required azide reduction,
lactamization, and ketal deprotection. Gratifyingly, after a
few attempts, transfer hydrogenation using 5% Pd/C di-
rectly provided the lactam 11 in one pot from 2 in 85% yield
€
amine or DIPEA (Hunig’s base), provided the required aldol
product, the best conversion was achieved with Crimmin’s
modification19 using (-)-sparteine as base. As shown in
Scheme 4, chiral imide 3 was treated with TiCl4/(-)-spar-
teine to generate Z-enolate A, which was treated with
(15) Gessier, F.; Schaeffer, L.; Kimmerlin, T.; Flogel, O.; Seebach, D.
Helv. Chim. Acta 2005, 88, 2235–2249.
(16) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–3800.
(17) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271–2273.
(18) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33,
65–75.
(19) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997,
119, 7883–7884.
3114 J. Org. Chem. Vol. 75, No. 9, 2010

Kulkarni et al.
JOCNote
and recovered chiral auxiliary without loss of its optical
purity. Final ketal deprotection20 of 11 was then successfully
achieved with Pd(CH3CN)2Cl2 in moist acetone to yield
berkeleyamide A (1) in 77% yield. The spectral and other
data of 1 are in full agreement with the reported data of the
natural product.21 The 2D NOESY correlations of 1 are also
consistent as reported.
In summary, a concise synthesis of the caspase-1 inhibitor
(-)-berkeleyamide A has been achieved in nine steps starting
from N-Boc-L-leucinal with 18% overall yield. Our synthetic
endeavor of (-)-berkeleyamide A is very efficient, scalable,
and highly diastereoselective with the flexibility to develop
various analogues of the natural product. Using this modu-
lar approach, synthesis of the remaining diastereomers and
structure-activity relationships of (-)-1 against caspase-1
are in progress and will be disclosed in due course.
(84 mL, 168 mmol) at 0 °C. The reaction mixture was allowed to
warm to room temperature and stirred for an additional 2 h. The
mixture was concentrated to remove organic solvents and
diluted with Et2O (100 mL). The layers were separated, and
the aqueous layer was carefully acidified with 1 N HCl at 0 °C
and extracted with methylene chloride (3 ꢀ 50 mL), and the
combined organic layers were washed with brine, dried over
MgSO4, and concentrated to afford 9 as a white solid (11.46 g,
79%): mp 110-111 °C; [R]20 = -6.60 (c 1.06, MeOH); νmax
D
(neat)/cm-1 3331, 2948, 1709, 1657, 1534, 1454, 1394, 1365,
1276, 1253, 1167, 1116, 1026, 901, 872, 847; 1H NMR (500 MHz,
MeOD) δ 3.61 (br s, 1H), 2.33 (t, J = 7.5 Hz, 2H), 1.79 (ddd, J =
12.2, 8.1, 3.9 Hz, 1H), 1.72-1.63 (m, 1H), 1.63-1.51 (m, 1H),
1.46 (s, 9H), 1.42-1.33 (m, 1H), 1.28-1.18 (m, 1H), 0.99-0.87
(m, 6H); 13C NMR (126 MHz, MeOD) δ 175.9, 156.9, 78.3, 44.3,
30.9, 30.2, 27.4, 24.7, 22.2, 21.1; HRMS (ESIþ) calcd for
C13H26NO4 260.1862, found 260.1856.
(4R)-4-Amino-6-methylheptanoic Acid Hydrochloride (9a): To
a solution of 9 (10.24 g, 39.5 mmol) in anhydrous 1,4-dioxane
(20 mL) was added 4 M HCl in dioxane (50 mL, 200 mmol) at
0 °C. The reaction mixture was allowed to warm to room
temperature and stirred for 12 h under argon to yield thick
slurry. The mixture was concentrated, and resulting solid was
dispersed in anhydrous ether and filtered under inert atmo-
Experimental Section
Ethyl (2E,4S)-4-[(tert-butoxycarbonyl)amino]-6-methylhept-
2-enoate (7a): To a solution of triethyl phosphonoacetate (16.4
g, 73.0 mmol) in THF (200 mL) was added solution of 1.0 M
NaHMDS (65.7 mL, 65.7 mmol) slowly at 0 °C. The resulting
orange solution cooled to -20 °C, and a solution of freshly
prepared N-Boc-L-leucinal (15.72 g, 73.0 mmol) in THF (50 mL)
was added dropwise at the same temperature. After addition,
the mixture was warmed to 0 °C and stirred under argon for an
additional 30 min and then quenched with saturated aqueous
ammonium chloride solution at 0 °C. The organic layer was
separated, concentrated, and the residue was dissolved in
EtOAc (200 mL), washed with water and brine, dried over
MgSO4, and filtered. The filtrate was partially concentrated
and subjected to reduction without further purification as a pale
sphere to furnish 9a as a white solid: mp 147-148 °C; [R]20
=
D
-4.41 (c 0.64, MeOH); νmax (neat)/cm-1 2873, 1724, 1702, 1602,
1503, 1438, 1298, 1234, 1121, 896; 1H NMR (400 MHz, D2O) δ
3.35-3.26 (m, 1H), 2.46 (t, J = 7.5 Hz, 2H), 1.95-1.78 (m, 2H),
1.68-1.56 (m, 1H), 1.49-1.36 (m, 2H), 0.84 (dd, J = 6.5, 3.0 Hz,
6H); 13C NMR (126 MHz, D2O) δ 177.2, 49.5, 41.0, 29.6, 27.5,
23.8, 21.7, 21.2; HRMS (ESIþ) calcd for C8H18NO2 160.1338,
found 160.1342.
(4R)-4-Azido-6-methylheptanoic acid (10): The reagent imida-
zole-1-sulfonyl azide hydrochloride (3.86 g, 18.40 mmol) was
added to the suspension of 9a (3.0 g, 15.33 mmol), potassium
carbonate (7.84 g, 56.7 mmol), and copper(II) sulfate pentahy-
drate (0.380 g, 0.153 mmol) in 80 mL of MeOH. After being
stirred for 14 h, the resulting gray colored mixture was concen-
trated, diluted with water, and adjusted the pH to 2 with concd
HCl at 0 °C. The resulting aqueous layer was extracted with
ethyl acetate (3 ꢀ 30 mL), and the combined organic layer was
washed with water and brine, dried over magnesium sulfate, and
concentrated. The residue was purified by column chromatog-
raphy (hexanes/EtOAc, 9:1) to afford 10 (2.2 g, 77%) as a
colorless liquid: [R]20D = þ10.77 (c 1.17, MeOH); νmax (neat)/
cm-1 2959, 2873, 2097, 1707, 1416, 1369, 1267, 1245, 1172, 922;
1H NMR (500 MHz, CDCl3) δ 3.38 (ddd, J = 13.6, 8.9, 4.6 Hz,
1H), 2.51 (m, 2H), 1.98 (m, 1H), 1.75 (m, 2H), 1.52 (ddd, J =
14.4, 8.7, 5.9 Hz, 1H), 1.32 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H); 13C
NMR (126 MHz, CDCl3) δ 178.7, 60.0, 43.3, 30.5, 29.5, 25.0,
22.9, 22.1; HRMS (ESIþ) calcd for C8H15N3O2 186.1243, found
186.1247.
(4R)-3-[(4R)-4-Azido-6-methylheptanoyl]-4-benzyl-1,3-oxa-
zolidin-2-one (3). To a stirred solution of 10 (1.0 g, 5.4 mmol) in
THF (40 mL) was added TEA (1.52 mL, 10.8 mmol) followed
pivaloyl chloride (0.66 mL, 5.4 mmol) at -20 °C. After being
stirred for 2 h, LiCl (275 mg, 6.48 mmol) and (4R)-benzylox-
azolidin-2-one (860 mg, 4.86 mmol) were added; the mixture
was allowed to warm to 0 °C and then to room temperature
slowly and was stirred for an additional 4 h. The mixture was
concentrated, and residue was partitioned between 5% aqu-
eous KHSO4 (20 mL) and ethyl acetate (50 mL). The organic
layer was washed with 1 M sodium bicarbonate (2 ꢀ 10 mL)
and brine (10 mL) and then dried over magnesium sulfate and
concentrated. The residue was purified by column chroma-
tography (EtOAc/hexanes, 3:17) to yield 3 (1.4 g, 75%) as a
viscous liquid: [R]20D = -73.48 (c 1.14, MeOH); νmax (neat)/
cm-1 2958, 2097, 1777, 1698, 1454, 1386, 1351, 1210, 1106,
yellow oil: [R]20 = -23 (c 1.50, MeOH); νmax (CHCl3)/cm-1
D
3354, 2959, 1701, 1691, 1657, 1519, 1367, 1282, 1167, 1045; 1H
NMR (500 MHz, CDCl3) δ 6.81 (dd, J = 15.4, 4.9 Hz, 1H), 5.90
(d, J = 15.6 Hz, 1H), 4.50 (d, J = 7.9 Hz, 1H), 4.32 (br s, 1H),
4.17 (q, J = 7.0 Hz, 2H), 1.67 (dt, J = 13.1, 6.5 Hz, 1H), 1.42 (s,
9H), 1.36 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 0.91 (d, J = 6.6 Hz,
6H); 13C NMR (126 MHz, CDCl3) δ 166.4, 155.0, 148.9, 120.4,
77.3, 60.4, 49.8, 43.8, 28.4, 24.7, 22.7, 14.2; HRMS (ESIþ) calcd
for C15H27NO4Na 308.1838, found 308.1827.
Ethyl (4R)-4-[(tert-butoxycarbonyl)amino]-6-methylheptano-
ate (8): To the solution of 7a in EtOAc (100 mL) was added
5% Pd/C catalyst (1.0 g), and the reaction mixture was stirred
under H2 atmosphere for 1.5 h at 20 psi in a Parr shaker. The
catalyst was removed by filtration through a pad of Celite, and
the organic solvent was evaporated under reduced pressure.
Then the crude obtained was purified by column chromatogra-
phy using Et2O/hexanes (1:5) to afford 8 (18.0 g, 85%) as
colorless thick liquid: [R]20 = -6.20 (c 1, MeOH); νmax
D
(CHCl3)/cm-1 3357, 2957, 1712, 1689, 1519, 1450, 1390, 1366,
1248, 1168, 1044, 1028; 1H NMR (500 MHz, CDCl3) δ 4.25 (d,
J = 9.0 Hz, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.71-3.56 (m, 1H),
2.33 (t, J = 7.6 Hz, 2H), 1.80 (m, 1H), 1.58 (m, 2H), 1.40 (s, 9H),
1.28 (m, 2H), 1.23 (t, J = 6.8 Hz, 3H), 0.88 (d, J = 6.5 Hz, 6H);
13C NMR (126 MHz, CDCl3) δ 173.7, 155.6, 78.9, 60.4, 48.5,
45.2, 31.0, 28.4, 24.9, 23.0, 22.3, 14.2; HRMS (ESIþ) calcd for
C15H29NO4Na 310.1994, found 310.2002.
(4R)-4-[(tert-Butoxycarbonyl)amino]-6-methylheptanoic acid
(9): To a solution of 8 (16.0 g, 55.7 mmol) in THF/MeOH
(400 mL, 5:1) was added an aqueous solution of 2 M LiOH
(20) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron
Lett. 1985, 26, 705–708.
(21) Our optical rotation value [R]20D is greater than the data for [R]20
reported in refs 6 and 7.
D
J. Org. Chem. Vol. 75, No. 9, 2010 3115

Kulkarni et al.
JOCNote
1050, 745, 701; 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.2
Hz, 2H), 7.29-7.23 (m, 1H), 7.19 (d, J = 6.9 Hz, 2H), 4.67
(ddd, J = 10.7, 7.0, 3.2 Hz, 1H), 4.23-4.14 (m, 2H), 3.47-3.38
(m, 1H), 3.28 (dd, J = 13.4, 3.3 Hz, 1H), 3.14-2.98 (m, 2H),
2.77 (dd, J = 13.4, 9.5 Hz, 1H), 1.95 (dtd, J = 11.4, 7.5, 4.2 Hz,
1H), 1.79 (ddt, J = 20.2, 8.1, 6.1 Hz, 2H), 1.54 (ddd, J = 14.5,
8.8, 5.9 Hz, 1H), 1.34 (ddd, J = 13.7, 8.3, 5.2 Hz, 1H), 0.94 (dd,
J = 6.6, 1.4 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.5,
153.4, 135.3, 129.4, 128.9, 127.3, 66.3, 60.1, 55.1, 43.4, 37.8,
32.2, 29.1, 25.1, 22.9, 22.1; HRMS (ESIþ) calcd for
C18H25N4O3 345.1927, found 345.1937.
in ethyl acetate, washed with water and brine, dried over magne-
sium sulfate, and concentrated. The residue was purified by
column chromatography (isopropanol/hexanes, 1:9) to afford 11
(86 mg, 85%) as a colorless viscous liquid: [R]20D = -11.4 (c 0.35,
MeOH); νmax (CHCl3)/cm-1 3224, 2925, 2954, 1687, 1454, 1269,
1128, 1030, 820, 735; 1H NMR (500 MHz, CDCl3) δ7.30-7.20 (m,
5H), 6.04 (s, 1H), 4.44 (d, J = 9.7 Hz, 1H), 4.00-3.91 (m, 2H),
3.77-3.63 (m, 3H), 2.96 (dd, J = 30.2, 13.9 Hz, 2H), 2.36 (dd, J =
15.2, 6.5 Hz, 2H), 1.82 (dt, J = 14.6, 12.2 Hz, 2H), 1.71-1.64 (m,
1H), 1.64-1.55 (m, 1H), 1.43-1.35 (m, 1H), 1.32-1.23 (m, 1H),
0.91 (d, J = 6.6 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 177.7,
136.1, 130.6, 128.1, 126.6, 111.5, 66.5, 65.3, 65.0, 51.0, 46.5, 46.4,
43.9, 41.7, 27.7, 25.3, 22.9, 22.4; HRMS (ESIþ) calcd for
C20H30NO4 348.2175, found 348.2176.
(-)-Berkeleyamide A (1): To a solution of 11 (23 mg, 0.066
mmol) in acetone (0.5 mL) and water (24 μL, 1.3 mmol) was
added bis(acetonitrile)dichloropalladium(II) (3.43 mg, 0.013
mmol). The mixture was stirred for 4 h and concentrated. The
residue was purified by column chromatography (isopropanol/
hexanes, 1:9) to afford 1 (15 mg, 77%) as a colorless viscous
liquid: [R]20D = -34.2 (c 0.48, MeOH), [R]20D = -31.1 (c 0.11,
MeOH); νmax (CHCl3)/cm-1 3257, 2955, 2927, 1704, 1686, 1454,
1367, 1271, 1077, 1030, 734; 1H NMR (400 MHz, CDCl3) δ 7.33
(t, J = 7.2, 3H), 7.30-7.24 (m, 1H), 7.24-7.17 (d, 2H), 6.11 (s,
1H), 4.37 (ddd, J = 8.8, 5.3, 3.4, 1H), 3.74 (s, 2H), 3.65 (td, J =
11.9, 7.7, 1H), 3.12 (s, 1H), 2.85 (dd, J = 17.3, 3.2, 1H), 2.71 (dd,
J = 17.3, 8.9, 1H), 2.52-2.42 (m, 1H), 2.31 (dt, J = 13.0, 7.6,
1H), 1.72 (ddd, J = 13.2, 9.3, 4.2, 1H), 1.60 (td, J = 13.4, 6.6,
1H), 1.44-1.34 (m, 1H), 1.28 (dt, J = 13.7, 7.0, 1H), 0.91 (d, J =
6.6, 6H); 13C NMR (101 MHz, CDCl3) δ 208.5, 177.2, 133.6,
129.5, 128.7, 127.1, 66.9, 50.8, 50.7, 46.4, 46.1, 45.5, 28.8, 25.3,
22.8, 22.3; HRMS (ESIþ) calcd for C18H26NO3 304.1913, found
304.1902.
(4R)-3-{(2R,4S)-4-Azido-2-[(1S)-2-(2-benzyl-1,3-dioxolan-2-yl)-
1-hydroxyethyl]-6-methylheptanoyl}-4-benzyl-1,3-oxazolidin-2-one
(2): To a stirred solution of 3 (280 mg, 0.81 mmol) in dichloro-
methane (4 mL) was added freshly distilled TiCl4 (94 μL, 0.85
mmol) slowly at 0 °C. After 15 min, to this yellow suspension was
added the (-)-sparteine (374 μL, 1.6 mmol) dropwise to give a
dark red solution, which was stirred for 1 h at the same tempera-
ture. Then a solution of 4 (184 mg, 0.89 mmol) in dichloromethane
(2 mL) was added dropwise at 0 °C. After 2 h, the mixture was
quenched with half-saturated aqueous solution of NH4Cl. The
organic layer was separated, and aqueous layer was further
extracted with dichloromethane. The combined organic layer
was washed with water and brine, dried over magnesium sulfate,
and concentrated. The residue was purified using column chro-
matography (hexanes/EtOAc, 3:1) to give the aldol product 2 (330
mg, 74%) as a colorless viscous liquid: [R]20 = -50.3 (c 1.2,
D
MeOH); νmax (neat)/cm-1 3506, 2958, 2103, 1779, 1693, 1386,
1350, 1210, 1196, 1110, 702; 1H NMR (500 MHz, CDCl3) δ7.34(t,
J = 7.3 Hz, 2H), 7.30 - 7.20 (m, 8H), 4.64 (ddd, J = 10.2, 6.6, 3.0
Hz, 1H), 4.28 (ddd, J = 10.4, 5.3, 2.9 Hz, 1H), 4.23-4.17 (m, 1H),
4.15-4.05 (m, 2H), 3.93 (dq, J = 12.1, 6.9 Hz, 2H), 3.75 (ddd, J =
9.2, 4.8, 2.4 Hz, 1H), 3.71-3.63 (m, 2H), 3.41 (dd, J = 11.2, 6.1
Hz, 1H), 3.35 (dd, J= 13.3, 3.2 Hz, 1H), 2.95 (q, J= 13.9 Hz, 2H),
2.69 (dd, J = 13.2, 10.1 Hz, 1H), 2.21 (ddd, J = 14.2, 10.6, 3.7 Hz,
1H), 1.85 (dd, J = 11.0, 6.8 Hz, 2H), 1.82-1.73 (m, 1H), 1.70
(ddd, J = 14.1, 8.7, 2.8 Hz, 1H), 1.55 (ddd, J = 14.4, 8.4, 6.4 Hz,
1H), 1.36 (ddd, J = 13.7, 7.7, 5.7 Hz, 1H), 0.93 (d, J = 6.6 Hz,
6H); 13C NMR (126 MHz, CDCl3) δ 173.9, 153.2, 135.9, 135.5,
130.7, 129.4, 129.0, 128.1, 127.3, 126.6, 111.4, 68.9, 65.9, 65.3, 64.9,
59.3, 55.7, 44.8, 43.8, 43.5, 40.6, 37.7, 32.1, 25.1, 22.7, 22.3; HRMS
(ESIþ) calcd for C30H39N4O6 551.2870, found 551.2875.
Acknowledgment. This investigation was conducted in
a facility constructed with support from research facilities
improvement program Grant No. C06 Rr-14503-01 from
the National Center for Research Resources, National
Institutes of Health. Partial support to S.J.K. from Grant
No. 5P20RR021929 from the National Center for Research
Resources is also acknowledged.
(3R,5S)-3-[(1S)-2-(2-Benzyl-1,3-dioxolan-2-yl)-1-hydroxyethyl]-
5-isobutylpyrrolidin-2-one (11): To a solution of 2 (160 mg, 0.291
mmol) in MeOH (15 mL) were added ammonium formate (366
mg, 5.81 mmol) and 5% Pd/C (60 mg) and stirred for 1 h at room
temperature. The mixture was concentrated and residue dissolved
Supporting Information Available: Full experimental pro-
C
NMR spectra for compounds 1-4 and 8-11. This material is
available free of charge via the Internet at http://pubs.acs.org.
cedures and data for all remaining new compounds; 1H and 13
3116 J. Org. Chem. Vol. 75, No. 9, 2010