Reptilian chemistry: Enantioselective syntheses of novel components from a crocodile exocrine secretion

Article abstract of DOI:10.1055/s-2000-8229

Enantioselective syntheses of the two naturally-occurring diastereomers of dianeackerone (1a and 1b) and of a closely related steroidal β-oxo ester (2), characterized from the paracloacal glandular secretion of the African dwarf crocodile, Osteolaemus tetraspis, are described.

Full text of DOI:10.1055/s-2000-8229

1936
SPECIAL TOPIC
Reptilian Chemistry: Enantioselective Syntheses of Novel Components from a
Crocodile Exocrine Secretion
Zhicai Yang, Athula B. Attygalle, Jerrold Meinwald*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853, USA
Fax +1(607)2553407; E-mail: circe@cornell.edu
Received 4 August 2000
Abstract: Enantioselective syntheses of the two naturally-occur-
O
O
ring diastereomers of dianeackerone (1a and 1b) and of a closely re-
lated steroidal b-oxo ester (2), characterized from the paracloacal
glandular secretion of the African dwarf crocodile, Osteolaemus tet-
raspis, are described.
1a
1b
Key words: enantioselective alkylation, crocodile, dianeackerone,
natural products, steroids
The "ruling reptiles" (Archosauria), which dominated ter-
restrial animal communities during the Mesozoic era
(245-65 million years ago), are now represented on earth
by only about two dozen species of crocodilians.1 All of
these surviving species possess a pair of skin glands, des-
ignated the paracloacal glands, secretions of which are
thought to serve a pheromonal role.2 We recently elucidat-
ed the structures of the major constituents of the paraclo-
acal gland secretion of the African dwarf crocodile
(Osteolaemus tetraspis), and we have established the ab-
solute configuration of both naturally occurring diastere-
omers of dianeackerone (1a and 1b), the secretion’s chief
volatile component, by synthesis.3,4 In this paper, we re-
port in detail the enantioselective syntheses of 1a and 1b,
as well as the synthesis of a steroidal b-oxo ester 2, which
would appear to serve as the immediate biosynthetic pre-
cursor of the dianeackerones.
O
O
O
2
The methodology described by Enders and co-workers,5,6
based on the alkylation of optically active hydrazones de-
rived from (S)-(-)-1-amino-2-(methoxymethyl)pyrroli-
dine (SAMP) and its (R)-(+) enantiomer provided highly
stereoselective syntheses of phosphonium salts 3a and 3b
(Scheme 1). Asymmetric alkylation of the SAMP-hydra-
zone (+)-4 or (-)-47 provided the products (+)-5 or (-)-5
in good yield and more than 95% de.8 Treatment of hydra-
OMe
1. LDA, ether
0o C;
2. PhCH2CH2I
OMe
1. MeI;
2. 10% HCl
pentane
N
N
N
N
-110 to 0o C
(R)-(+)-4
(2R,2'R)-( +)-5 (65%)
(2S,2'S)-(–)-5 (58%)
(S)-(–)-4
1. BH3 –THF;
2. NBS, PPh3
DMF
PPh3
CHO
120oC
Br
PPh3
Br
(R)-(–)-6 (80%)
(S)-(+)-6 (76%)
(R)-(–)-7 (68%)
(S)-(+)-7 (58%)
(R)- 3a (65%)
(S)- 3b (60%)
Scheme 1
Synthesis 2000, No. 13, 1936–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Syntheses of Novel Components from a Crocodile Exocrine Secretion
1937
zones (+)-5 or (-)-5 with CH3I, followed by acidic hy- alkene 14 as a 9:1 mixture of cis- and trans-isomers. Sub-
drolysis with HCl in a two phase system readily formed sequent hydrogenation and deprotection provided the de-
the aldehydes (+)-6 or (-)-6. Reduction of (+)-6 or (-)-6 sired 1b, [a]D +3.2 (c 0.2, CHCl3) {Lit.3 [a]D +4 (c 0.8,
with borane-THF complex, followed by bromination with CHCl3)}.
NBS in the presence of Ph3P, yielded the bromides (+)-7
or (-)-7 in good yield. Reaction of these bromides with
1. BuLi/THF
Ph3P gave the desired chiral phosphonium salts, 3a or 3b.
1. 5% Pd/C/H2
/MeOH
O
2.
8
1a (70%)
1b (78%)
3a
O
Similarly, the chiral precursor 8 was prepared via the
SAMP-hydrazone (-)-4 (Scheme 2). Asymmetric alkyl-
ation of (-)-4 with t-butyl bromoacetate produced the hy-
drazone 9 in 60% yield and better than 95% de.8 Ozonol-
ysis of 9 in CH2Cl2 at -78 ∞C gave the corresponding
aldehyde 10. Reaction of the aldehyde 10 with CH3MgI at
-78 ∞C yielded an unstable alcohol, which was immedi-
ately oxidized by Jones’ reagent to afford the ketone 11.
Protection of the carbonyl group in 11 with ethylene gly-
col and trimethyl orthoformate in the presence of p-TsOH
provided the ketal 12 in excellent yield. Reduction of the
ester 12 with LiAlH4, followed by oxidation with PDC,
supplied the desired aldehyde 8.
3b
2. PPTS/acetone
(3S,7R ) 13 (66%)
(3S,7S) 1 4 (82%)
Scheme 3
While 1a and 1b are the major volatile constituents of the
O. tetraspis paracloacal glandular fluid, the bulk of the se-
cretion is made up of a series of steroidal esters of aromat-
ic acids closely related to dianeackerone. Of these
compounds, the b-oxo ester 2 is especially interesting,
since it would appear to be the immediate precursor (upon
hydrolysis and decarboxylation) of dianeackerone itself.
A retrosynthetic analysis of b-oxo ester 2 suggested that
this target compound should be obtained by the reaction
of aldehyde 15 with cholesteryl diazoacetate 169(Scheme
4), which is readily prepared via by the treatment of cho-
lesterol with the acid chloride 1710 (Scheme 5).
OMe
1. LDA, 0oC
N
2. BrCH2CO2t-Bu
–110oC
N
O3
t-BuO2C
(–)-4
60%
CH2Cl2, –78oC
82%
9
2
O
1. MeMgCl
–78oC
t-BuO2C
CHO
t-BuO2C
2. CrO3
89%
CHO
10
11
15
(CH2OH)2
82%
HC(OMe)3
+
p-TsOH
1. LiAlH4
ether
O
O
O
O
O
OHC
t-BuO2C
2. PDC
CH2Cl2
N2HC
O
62%
8
12
16
Scheme 2
Scheme 4
Coupling of aldehyde 8 with the Wittig reagent derived
from phosphonium salt 3a provided the alkene 13 as a
mixture of cis- and trans-isomers (cis:trans, approx. 9:1)
(Scheme 3). Hydrogenation of 13 with Pd/C in MeOH,
followed by deprotection with PPTS provided 1a, [a]D
-8.7 (c 0.2, CHCl3) {Lit.3 [a]D -9 (c 0.1, CHCl3)}. In a
completely analogous fashion, coupling of aldehyde 8
cholesterol
Et3N
O
O
CH2Cl2, 0 °C
S NH N CH
O
16
66%
Cl
17
with the Wittig reagent prepared from 3b furnished the Scheme 5
Synthesis 2000, No. 13, 1936–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

1938
Z. Yang et al.
SPECIAL TOPIC
Using the methodology described earlier, aldehyde 15
was synthesized as outlined in Scheme 6. Alkylation of
the SAMP-hydrazone (-)-4 afforded hydrazone 18 in ex-
cess of 95% de.8 Ozonolysis of the 18 yielded a crude al-
dehyde, which was immediately reduced with borane-
THF complex to give alcohol 19. Protection of 19 with
benzyl bromide in the presence of NaH, followed by the
removal of the silyl ether with HCl, provided alcohol 20
in good yield. Bromination of 20 with NBS in the pres-
ence of Ph3P provided bromide 21, which was converted
into the chiral phosphonium salt 22. Coupling of the
Wittig, the reagent derived from 22, with aldehyde (-)-6
generated a mixture of cis- and trans-alkene 23 (cis:trans,
approx. 9:1). Hydrogenation and hydrogenolysis of 23
with Pd/C in MeOH gave the alcohol 24 in good yield.
Oxidation of 24 with N-morpholine N-oxide (NMO) me-
diated by tetrapropylammonium perruthenate (TPAP) af-
forded aldehyde 15. Coupling of 15 with the diazoacetate
16 in the presence of a catalytic amount of SnCl2 afforded
the desired b-oxo ester 2.
1. LDA, ether
0oC;
OMe
N
N
2. ICH2CH2OTBDMS
–78oC
TBDMSO
(-)-4
65%
18
1. O3, CH2Cl2
–78oC;
2. BH3-THF
0oC
67%
HO
TBDMSO
1. BnBr, NaH
THF;
OBn
OH
2. 3 M HCl
85%
20
19
NBS, PPh3
DMF, 50oC
79%
PPh3
120oC
Br
Ph3P
Br
OBn
OBn
We would like to emphasize, in conclusion, is only by
virtue of having synthesized the dianeackerone diastereo-
mers by the Enders’ technique of stereoselective alkyl-
ation was it possible to assign absolute configurations to
the natural products. The same technique has also enabled
us to confirm the structure of cholesteryl b-oxo ester 2 by
synthesis.
84%
21
22
1. BuLi
THF, r.t.
2. (–)-6
66%
5% Pd/C
H2, MeOH
GC/MS analyses were performed using a Hewlett-Packard (HP)
5890 gas chromatograph installed with a 30 m ¥ 0.25 mm fused sil-
ica column coated with DB-5 (J & W Scientific, Folsom, CA) cou-
pled to an HP-5970 Mass Selective Detector. MS analyses were
performed using a Micromass Autospec instrument operated in
electron ionization (EI), chemical ionization (CI) (CH4 as the re-
agent gas), or electrospray ionization modes. 1H and 13C NMR spec-
tra were recorded on a Varian XL 400 instrument using CDCl3 or
C6D6 as solvent. Chemical shifts (d) are given in ppm downfield
from TMS.
OBn
84%
23
NMO
TPAP
CH2Cl2
OH
15
85%
16, SnCl2
61%
24
CH2Cl2
Alkylation of Butyraldehyde (+)-(R)-1-Amino-2-(methoxyme-
thyl)pyrrolidinehydrazone [(+)-4] with 2-Phenylethyl Iodide
To a solution of LDA (1.5 M, 5.8 mL, 8.7 mmol) in anhyd Et2O (20
mL), hydrazone (+)-4 (1.6 g, 8.7 mmol) in anhyd Et2O (10 mL) was
added dropwise at 0 ∞C over 10 min. The mixture was stirred at
0 ∞C under N2 for 5 h and then cooled to -110 ∞C using a dry-ice/
liquid N2 bath. 2-Phenylethyl iodide (1.64 mL, 11.3 mmol) in Et2O
(20 mL) was added dropwise over 30 min. The mixture was slowly
warmed up to 0 ∞C and quenched with sat. NH4Cl (20 mL). The or-
ganic layer was separated, the aqueous layer was extracted with
EtOAc (2 ¥ 50 mL). The combined organic layers were washed with
brine, dried (Na2SO4), filtered, and concentrated in vacuo. The res-
idue was purified by chromatography on silica gel (EtOAc/hexanes,
1:9) to afford (R)-2-ethyl-4-phenylbutyraldehyde (2’R)-1’-amino-2’-
(methoxymethyl)pyrrolidinehydrazone [(+)-5] as a colorless oil.
2
Scheme 6
13C NMR (100 MHz, CDCl3): d = 143.0, 142.8, 128.4 (2C), 128.2
(2C), 125.5, 74.7, 63.5, 59.2, 50.5, 43.9, 35.1, 33.6, 26.7, 26.5, 22.0,
11.4.
GC/MS (EI): m/z = 288 (M+), 243, 197, 184, 139, 123, 105, 91, 70.
HRMS (EI): m/z calcd for C18H28N2O (M+): 288.2202. Found:
288.2202.
Yield: 1.63 g (65%); [a]D +64 (c 1.4, CHCl3).
(-)-5
1H NMR (400 MHz,CDCl3): d = 0.92 (t, 3H, J = 7.2 Hz), 1.40-1.56
(m, 2H), 1.71-2.00 (m, 5H), 2.15-2.24 (m, 1H), 2.58-2.74 (m,
3H), 3.34-3.50 (m, 4H), 3.39 (s, 3H), 3.36 (m, 1H), 6.49 (d, 1H,
J = 6.8 Hz), 7.16-7.30 (m, 5H).
Prepared from (-)-4 using above procedure, colorless oil, [a]D = -
64.9 (c 1.2, CHCl3).
(-)-(R)-2-Ethyl-4-phenylbutyraldehyde [(-)-6]
A mixture of hydrazone (+)-5 (900 mg, 3.12 mmol) and CH3I (4
mL) was warmed to reflux under N2 for 4 h. The surplus CH3I was
Synthesis 2000, No. 13, 1936–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Syntheses of Novel Components from a Crocodile Exocrine Secretion
1939
removed in vacuo, and the residue was treated with 10% HCl (10
mL) in pentane (20 mL) with stirring at r.t. for 1 h. The organic layer
was separated, the aqueous layer was extracted with pentane (2 ¥ 40
mL). The combined organic layers were washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was pu-
rified by chromatography on silica gel (EtOAc/hexanes, 1:9) to af-
ford aldehyde (-)-6 as a colorless oil.
(R)-2-Ethyl-4-phenylbutyltriphenylphosphonium Bromide (3a)
The mixture of bromide (-)-7 (152 mg, 0.63 mmol) and Ph3P (165
mg, 0.63 mmol) was heated at 120 ∞C under Ar for 18 h, and then
cooled to r.t. The resulting solid was washed twice with H2O and
dried in vacuum overnight to give phosphonium salt 3a (207 mg,
65%) as a white solid.
3b
Yield: 440 mg (80%); [a]D -1.8 (c 4.0, CHCl3).
Prepared from (+)-7 using above procedure, white solid.
1H NMR (400 MHz,CDCl3): d = 0.94 (t, 3H, J = 7.2 Hz), 1.54-1.64
(m, 1H), 1.64-1.81 (m, 2H), 1.95-2.05 (m, 1H), 2.22-2.29 (m,
1H), 2.57-2.70 (m, 2H), 7.18-7.32 (m, 5H), 9.62 (d, 1H, J = 2.8
Hz).
13C NMR (100 MHz, CDCl3): d = 205.1, 141.5, 128.4 (2C), 128.3
(2C), 126, 52.6, 33.2, 30.1, 21.8, 11.3.
GC/MS (EI): m/z = 176 (M+), 158, 115, 105, 104, 91, 77.
HRMS (EI): m/z calcd for C12H16O (M+): 176.1201. Found:
Alkylation of Hydrazone (-)-4 with tert-Butyl Bromoacetate
To a solution of hydrazone (-)-4 (1.23 g, 6.68 mmol) in anhyd Et2O
(20 mL), LDA (1.5 M, 4.5 mL, 6.75 mmol) was added dropwise at
0 ∞C over 10 min. The mixture was stirred at 0 ∞C under Ar for 5 h
and then cooled to -110 ∞C using a liquid N2/95% EtOH bath. t-Bu
bromoacetate (1.5 mL, 10 mmol) in Et2O (20 mL) was added drop-
wise over 30 min. The mixture was slowly warmed up to 0 ∞C and
quenched with sat. NH4Cl (20 mL). The organic layer was separat-
ed, the aqueous layer was extracted with EtOAc (2 ¥ 50 mL). The
combined organic layers were washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo. The residue was purified by
chromatography on silica gel (EtOAc/hexanes, 1:9) to afford hydra-
zone 9 as a colorless oil.
176.1201.
(+)-6
Prepared from (-)-5 using above procedure, colorless oil,
[a]D = +1.5 (c 1.2, CHCl3).
Yield: 1.2 g (60%); [a]D -74.3 (c 0.7, CHCl3).
(-)-(R)-2-Ethyl-4-phenyl-1-butyl Bromide [(-)-7]
1H NMR (400 MHz, CDCl3): d = 0.90 (t, 3H, J = 7.2 Hz), 1.42 (s,
9H), 1.48 (m, 2H), 1.72-1.97 (m, 5H), 2.29 (dd, 1H, J = 14.8,
6.4 Hz), 2.39 (dd, 1H, J = 14.8, 8.0 Hz), 2.60 (m, 1H), 2.69 (dd,
1H, J = 16.8, 8.0 Hz), 3.35 (s, 3H), 3.38 (m, 2H), 3.56 (m, 1H), 6.51
(d, 1H, J = 6.0 Hz).
13C NMR (100 MHz, CDCl3): d = 172.0, 140.1, 80.0, 74.7, 63.4,
59.1, 50.2, 40.6, 39.1, 28.1 (3C), 26.5, 26.2, 22.0, 11.3.
GC/MS (EI): m/z = 298 (M+), 253, 242, 225, 197, 183, 128, 110, 82,
70, 57.
HRMS (EI): m/z calcd for C16H30N2O3 (M+): 298.2256. Found:
298.2258.
To a solution of aldehyde (-)-6 (260 mg, 1.47 mmol) in THF (8
mL), borane-THF complex (1 M, 2.95 mL, 2.95 mmol) was added
dropwise at 0 ∞C. The mixture was stirred at 0 ∞C under N2 for 1 h
and then quenched with 1 M HCl (5 mL) at 0 ∞C. The organic layer
was separated, the aqueous layer was extracted with EtOAc (2 ¥ 40
mL). The combined organic layers were washed with 3% NaHCO3
and brine, dried (Na2SO4), filtered, and concentrated in vacuo to
provide the crude alcohol (260 mg).
1H NMR (400 MHz, CDCl3): d = 0.95 (t, 3H, J = 7.2 Hz), 1.61 (br
s, 1H), 1.41-1.78 (m, 5H), 2.67 (t, 2H, J = 8.0 Hz), 3.62 (d, 2H,
J = 5.6 Hz), 7.20-7.32 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 142.7, 128.3 (4C), 125.7, 65.0,
41.5, 33.2, 32.3, 23.2, 11.0.
(-)-tert-Butyl (3S)-3-Ethyl-4-oxobutyrate (10)
GC/MS (EI): m/z = 178 (M+).
Ozone was bubbled into a solution of hydrazone 9 (2.6 g, 8.7 mmol)
in CH2Cl2 (20 mL) at -78 ∞C until no starting material was detected
by TLC. The reaction mixture was bubbled with N2 while warming
up to r.t. The mixture was concentrated in vacuo, and the residue
was purified by chromatography on silica gel (EtOAc/hexanes, 1:9)
to afford aldehyde 10 as a colorless oil.
The above crude alcohol (260 mg, 1.46 mmol) and Ph3P (765 mg,
2.92 mmol) were dissolved in DMF (4 mL). NBS (520 mg, 2.92
mmol) was added to the solution in small portions at r.t over 20 min.
The reaction mixture was warmed to 55 ∞C under N2 overnight and
then cooled to r.t. The mixture was diluted with Et2O (100 mL),
washed with 3% NaHCO3 and brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by chromatography
on silica gel (EtOAc/hexanes, 1:9) to give bromide (-)-7 as a color-
less oil.
Yield: 1.33 g (82%); [a]D -39.4 (c 1.5, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.97 (t, 3H, J = 7.2 Hz), 1.44 (s,
9H), 1.55 (m, 1H), 1.77 (m, 1H), 2.35 (dd, 1H, J = 16.0, 6.0 Hz),
2.62 (dd, 1H, J = 16.0, 8.0 Hz), 2.70 (m, 1H), 9.71 (d, 1H, J = 1.2
Hz).
Yield: 240 mg (68%); [a]D -10.5 (c 2.0, CHCl3).
13C NMR (100 MHz, CDCl3): d = 203.2, 171.2, 80.9, 49.3, 34.1,
1H NMR (400 MHz, CDCl3): d = 0.93 (t, 3H, J = 7.2 Hz), 1.45-
1.79 (m, 5H), 2.57-2.72 (m, 2H), 3.52 (d, 2H, J = 4.8 Hz), 7.20-
7.32 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 142.1, 128.4 (2C), 128.3 (2C),
125.8, 40.4, 38.7, 34.1, 32.9, 25.1, 10.8.
GC/MS (EI): m/z = 240 (M+), 160, 145, 131, 105, 91, 77.
HRMS (EI): m/z calcd for C12H1779Br (M+): 240.0513. Found:
28.0 (3C), 21.6, 11.2.
GC/MS (EI): m/z 171 (M+-Me), 158, 129, 113, 101,85, 73, 57.
(-)-tert-Butyl (3S)-3-Ethyl-4-oxopentanoate (11)
To a solution of aldehyde 10 (633 mg, 3.4 mmol) in Et2O (10 mL),
CH3MgCl (3.0 M, 1.24 mL, 3.7 mmol) was added dropwise at -78
∞C. The mixture was stirred at -78 ∞C for 30 min and then quenched
with sat. NH4Cl at -78 ∞C. The organic layer was separated, the
aqueous layer was extracted with Et2O (2 ¥ 20 mL). The combined
organic layers were washed with brine, dried (Na2SO4) for 5 min,
filtered, and concentrated in vacuo. The residue was dissolved in ac-
etone (10 mL), and Jones’ reagent was added dropwise at 0 ∞C with-
in 2 min (a red color was retained). The reaction was quenched at 0
∞C with H2O (20 mL), and extracted with pentane (3 ¥ 40 mL). The
240.0511.
(+)-7
Prepared from (+)-6 using above procedure, colorless oil,
[a]D = +10.8 (c 1.5, CHCl3).
Synthesis 2000, No. 13, 1936–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

1940
Z. Yang et al.
SPECIAL TOPIC
combined organic layers were washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo. The residue was purified by
chromatography on silica gel (EtOAc/hexanes, 1:9) to afford ketone
11 as colorless oil.
GC/MS (EI): m/z = 172 (M+), 157, 144, 130, 113, 99, 87, 71, 55.
HRMS (CI): m/z calcd for C9H17O3 (MH+): 173.1178. Found:
173.1177.
Yield: 611 mg (89%); [a]D -45.7 (c 0.9, CHCl3).
(3S,7R)-3,7-Diethyl-9-phenylnon-5-en-2-one Ethylene Ketal
(13)
1H NMR (400 MHz, CDCl3): d = 0.91 (t, 3H, J = 7.2 Hz), 1.43 (s,
9H), 1.42-1.53 (m, 1H), 1.58-1.69 (m, 1H), 2.22 (s, 3H), 2.28 (dd,
1H, J = 16.8, 4.8 Hz), 2.65 (dd, 1H, J = 16.8, 9.6 Hz), 2.85-2.92
(m, 1H).
13C NMR (100 MHz, CDCl3): d = 210.9, 171.7, 80.6, 49.4, 36.1,
29.4, 28.0 (3C), 24.3, 11.3.
GC/MS (EI): m/z = 200 (M+), 185, 172, 144, 127, 116, 109, 98, 85,
73, 71, 57.
HRMS (EI): m/z calcd for C11H20O3 (M+): 200.1412. Found:
200.1411.
To a suspension of phosphonium salt 3a (50 mg, 0.1 mmol) in THF
(2 mL), n-BuLi (1.5 M, 0.073 mL, 0.11 mmol) was added dropwise
at r.t. The mixture was stirred at r.t. under Ar until the solid dis-
solved and a red solution appeared. Aldehyde 8 (19 mg, 0.11 mmol)
in THF (1 mL) was added at r.t., and the mixture was stirred over-
night at r.t. under Ar. The mixture was filtered through a pad of sil-
ica gel and the white precipitate was washed with Et2O (20 mL).
The filtrate was concentrated in vacuo, and the residue was purified
by chromatography on silica gel (EtOAc/hexanes, 1:9) to give alk-
ene 13 as a colorless oil.
Yield: 21 mg (66%).
(+)-tert-Butyl (3S)-3-Ethyl-4,4’-dioxoethylenepentanoate (12)
A mixture of ketone 11 (610 mg, 3.05 mmol), trimethyl orthofor-
mate (1.62 mL, 12.2 mmol), p-TsOH (6 mg, 0.03 mmol) in ethylene
glycol (4 mL) was stirred at r.t. under Ar overnight. The mixture
was diluted with sat. NaHCO3, extracted with pentane (3 ¥ 40 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was pu-
rified by chromatography on silica gel (EtOAc/hexanes, 1:9) to af-
ford ketal 12 as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 0.87 (t, 3H, J = 7.2 Hz), 0.96 (t,
3H, J = 7.2 Hz), 1.25 (m, 1H), 1.27 (s, 3H), 1.33 (m, 1H), 1.46 (m,
1H), 1.56 (m, 2H), 1.65 (m, 1H), 1.73 (m, 1H), 2.05 (m, 1H), 2.27
(m, 1H), 2.33 (m, 1H), 2.51 (ddd, 1H, J = 13.6, 11.2, 5.2 Hz), 2.64
(ddd, 1H, J = 13.6, 11.2, 5.2 Hz), 3.93 (m, 4H), 5.15 (m, 1H,
J = 10.8, 1.0 Hz), 5.55 (m, 1H, J = 10.8, 7.2 Hz), 7.14-7.29 (m,
5H).
13C NMR (100 MHz, CDCl3): d = 143.1, 134.6, 129.7, 128.3 (2C),
128.2 (2C), 125.5, 112.6, 64.4 (2C), 48.4, 38.8, 37.5, 33.8, 28.6,
28.2, 22.9, 20.9, 13.0, 11.8.
Yield: 616 mg (82%); [a]D +11.4 (c 2.2, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.94 (t, 3H, J = 7.2 Hz), 1.21 (m,
1H), 1.25 (s, 3H), 1.44 (s, 9H), 1.65 (m, 1H), 2.09 (m, 1H), 2.10 (dd,
1H, J = 16.8, 6.4 Hz), 2.31 (dd, 1H, 16.8, 8.4 Hz), 3.91 (m, 4H).
13C NMR (100 MHz, CDCl3): d = 173.0, 111.8, 79.8, 64.5, 64.4,
44.9, 36.1, 28.0 (3C), 23.5, 20.8, 12.3.
MS (CI): m/z = 245 (MH+).
HRMS (CI): m/z calcd for C13H25O4 (MH+): 245.1753. Found:
MS (CI): m/z = 317 (MH+).
HRMS (CI): m/z calcd for C21H33O2 (MH+): 317.2483. Found:
317.2481.
Dianeackerone (1a)
The cis/trans mixture of alkene 13 (10 mg, 0.031 mmol) and 5% Pd/
C (5 mg) in MeOH (1 mL) were stirred overnight at r.t. under H2 (1
atm). The mixture was filtered through a pad of silica gel and the
solid was washed with MeOH (20 mL). The filtrate was concentrat-
ed in vacuo to afford a crude product as a light yellow oil (8 mg).
245.1754.
(-)-(S)-3-Ethyl-4,4’-dioxoethylenepentanal (8)
[a]D -10 (c 0.5, CHCl3).
To a solution of ester 12 (616 mg, 2.52 mmol) in H2O (20 mL),
LiAlH4 (190 mg, 5.0 mmol) was added in portions at r.t. The mix-
ture was stirred at r.t. for 2 h and then treated with H2O (0.2 mL),
15% NaOH (0.2 mL) and H2O (0.6 mL). The mixture was filtered
and concentrated in vacuo to provide the crude alcohol (341 mg).
1H NMR (400 MHz, CDCl3): d = 0.87 (t, 3H, J = 7.2 Hz), 0.96 (t,
3H, J = 7.2 Hz), 1.26 (s, 3H), 1.20-1.42 (m, 10H), 1.52-1.62 (m,
4H), 2.59 (t, 2H, J = 8.8, 7.6 Hz), 3.90-3.95 (m, 4H), 7.17-7.30
(m, 5H).
13C NMR (100 MHz, CDCl3): d = 143.3, 128.3 (2C), 128.2 (2C),
125.5, 112.9, 64.4, 64.3, 47.9, 38.5, 35.3, 33.5, 33.1, 30.5, 25.7,
25.6, 23.3, 20.7, 13.0, 10.7.
GC/MS (EI): m/z = 174 (M+).
1H NMR (400 MHz, CDCl3): d = 0.94 (t, 3H, J = 7.6 Hz), 1.12-
1.22 (m, 1H), 1.28 (s, 3H), 1.53-1.58 (m, 1H), 1.63-1.72 (m, 4H),
3.58-3.76 (m, 2H), 3.92-3.99 (m, 4H).
13C NMR (100 MHz, CDCl3): d = 112.5, 64.4, 64.2, 62.2, 46.6,
32.6, 23.8, 20.2, 12.5.
MS (CI): m/z = 319 (MH+).
HRMS (CI): m/z calcd for C21H35O2 (MH+): 319.2637. Found:
319.2633.
The crude alcohol (341 mg, 1.96 mmol) was dissolved in CH2Cl2
(10 mL), and PDC (1.47 g, 3.92 mmol) was added. The mixture was
stirred at r.t. under Ar for 24 h and then filtered through a pad of sil-
ica gel. The filtrate was concentrated in vacuo, and the residue was
purified by chromatography on silica gel (EtOAc/hexanes, 1:9) to
afford aldehyde 8 as a colorless oil.
The above crude product was dissolved in acetone and H2O (9:1, 4
mL), and PPTS (6 mg, 0.025 mmol) was added. The mixture was
refluxed for 1 h under N2 and then cooled to r.t., diluted with Et2O
(20 mL), washed with brine, dried (Na2SO4), filtered, and concen-
trated in vacuo. The residue was purified by chromatography on sil-
ica gel (EtOAc/hexanes, 1:9) to afford dianeackerone 1a as a
colorless oil.
Yield: 275 mg (62%); [a]D -8.4 (c 1.5, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.94 (t, 3H, J = 7.6 Hz), 1.25 (m,
1H), 1.26 (s, 3H), 1.69 (m, 1H), 2.20 (m, 1H), 2.25 (ddd, 1H,
J = 16.0, 4.0, 1.2 Hz), 2.37 (ddd, 1H, 16.0, 8.4, 4.0 Hz), 3.88 (m,
4H), 9.63 (dd, 1H, J = 4.0, 1.2 Hz).
13C NMR (100 MHz, CDCl3): d = 201.9, 111.4, 64.0, 44.4, 43.5,
23.2, 21.1, 12.3.
Yield: 6 mg (70%); [a]D +3.2 (c 0.2, CHCl3).
1H NMR (400 MHz, C6D6): d = 0.75 (t, 3H, J = 7.2 Hz), 0.83 (t, 3H,
J = 7.2 Hz), 1.16-1.52 (m, 13H), 1.76 (s, 3H), 2.14 (m, 1H), 2.55
(m, 2H), 7.15-7.25 (m, 5H).
Synthesis 2000, No. 13, 1936–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Syntheses of Novel Components from a Crocodile Exocrine Secretion
1941
13C NMR (100 MHz, C6D6): d = 210.34, 143.62, 129.06 (2C),
129.04 (2C), 126.36, 54.94, 38.90, 35.81, 33.84, 33.83, 32.15,
28.85, 26.36, 25.16, 25.12, 12.23, 11.27.
GC/MS (EI): m/z = 274 (M+), 227, 186, 172, 157, 145, 123, 105, 99,
91, 86, 71, 55.
HRMS (EI): m/z calcd for C19H30O (M+): 274.2297. Found:
274.2298.
∞C under Ar for 3 h and the solvent was removed in vacuo. The res-
idue was dissolved in benzene (30 mL) and mixed with Florisil (15
g). The mixture was filtered and washed with benzene (30 mL). The
filtrate was concentrated in vacuo at 30 ∞C and the residue was pu-
rified by chromatography on Florisil (Et2O/pentane, 1:4) to give the
diazoacetate 16 as a yellow solid.
Yield: 1.5 g (66%); [a]D -23.6 (c 1.8, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.68 (s, 3H), 0.86 (d, 3H, J = 6.4
Hz), 0.87 (d, 3H, J = 6.4 Hz), 0.92 (d, 3H, J = 6.4 Hz), 1.02 (s, 3H),
1.11-1.65 (m, 20H), 1.79-2.03 (m, 6H), 2.29-2.39 (m, 2H), 4.69
(m, 1H), 4.71 (s, 1H), 5.39 (d, 1H, J = 5.2 Hz).
13C NMR (100 MHz, CDCl3): d = 166.4, 139.6, 122.8, 74.6, 56.7,
56.2, 50.0, 42.3, 39.7, 39.5, 38.3, 36.9, 36.6, 36.2, 35.8, 31.9, 31.8,
28.2, 28.0 (2C), 24.3, 23.8, 22.8, 22.5, 21.0, 19.3, 18.7, 11.8.
(3S,7S)-3,7-Diethyl-9-phenylnon-5-en-2-one Ethylene Ketal
(14)
The phosphonium salt 3b (62 mg, 0.12 mmol) in THF (2 mL) was
converted to the ylide with n-BuLi (1.5 M, 0.088 mL, 0.13 mmol)
by a procedure similar to that described for the ketal 13. The ylide
was coupled to aldehyde 8 (23 mg, 0.13 mmol) in THF (1 mL), and
the product was purified to give alkene 14 as a colorless oil.
Yield: 34 mg (82%).
Alkylation of Hydrazone (-)-4 with 2-Iodoethanol tert-Bu-
tyldimethylsilyl Ether
1H NMR (400 MHz, CDCl3): d = 0.86 (t, 3H, J = 7.2 Hz), 0.97 (t,
3H, J = 7.2 Hz), 1.24 (m, 1H), 1.27 (s, 3H), 1.35 (m, 1H), 1.42-
1.60 (m, 4H), 1.73 (m, 1H), 2.05 (m, 1H), 2.26 (m, 1H), 2.32 (m,
1H), 2.52 (ddd, 1H, J = 13.6, 11.2, 5.6 Hz), 2.64 (ddd, 1H, J = 13.6,
11.2, 5.6 Hz), 3.94 (m, 4H), 5.15 (m, 1H), 5.55 (ddd, 1H, J = 10.8,
7.2, 4.0 Hz), 7.14-7.29 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 143.1, 134.7, 129.7, 128.3 (2C),
128.2 (2C), 125.5, 112.6, 64.4 (2C), 48.5, 38.8, 37.7, 33.9, 28.6,
28.2, 22.9, 20.9, 13.1, 11.8.
To a solution of hydrazone (-)-4 (3.0 g, 15.3 mmol) in anhyd Et2O
(40 mL), LDA (1.5 M, 11 mL, 16.5 mmol) was added dropwise at
0 ∞C over 10 min. The mixture was stirred at 0 ∞C under Ar for 5 h
and cooled to -78 ∞C. 2-Iodoethanol tert-butyldimethylsilyl ether
(5.5 g, 19.2 mmol) in Et2O (20 mL) was added dropwise at -78 ∞C
over 30 min. The reaction mixture was slowly warmed up to 0 ∞C
and quenched with sat. NH4Cl (30 mL). The organic layer was sep-
arated, the aqueous layer was extracted with EtOAc (2 ¥ 50 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was pu-
rified by chromatography on silica gel (hexanes/EtOAc/Et3N,
95:5:2) to afford hydrazone 18 as a colorless oil
MS (CI): m/z = 317 (MH+).
HRMS (CI): m/z calcd for C21H33O2 (MH+): 317.2483. Found:
317.2482.
Yield: 3.65 g (65%) [a]D -47.9 (c 1.9, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.03 (s, 6H), 0.88 (s, 9H), 0.89 (t,
3H, J = 7.2 Hz), 1.44 (m, 2H), 1.65 (m, 2H), 1.76-1.95 (m, 4H),
2.20 (m, 1H), 2.69 (dd, 1H, J = 16.4, 8.0 Hz), 3.36 (s, 3H), 3.31-
3.43 (m, 3H), 3.54-3.67 (m, 3H), 6.46 (d, 1H, J = 6.8 Hz).
Dianeackerone (1b)
The cis/trans mixture of alkene 14 (12 mg, 0.038 mmol) was hydro-
genated by a procedure similar to that described for dianeackerone
1a to afford a light yellow oil (11 mg).
1H NMR (400 MHz, CDCl3): d = 0.88 (t, 3H, J = 7.2 Hz), 0.96 (t,
3H, J = 7.2 Hz), 1.26 (s, 3H), 1.20-1.42 (m, 10H), 1.52-1.62 (m,
4H), 2.59 (t, 2H, J = 8.4, 7.6 Hz), 3.90-3.95 (m, 4H), 7.17-7.30
(m, 5H).
13C NMR (100 MHz, CDCl3): d = 143.3, 128.3 (2C), 128.2 (2C),
125.5, 112.9, 64.4, 64.3, 47.9, 38.5, 35.2, 33.5, 33.2, 30.5, 25.8,
25.6, 23.3, 20.7, 13.0, 10.8.
13C NMR (100 MHz, CDCl3): d = 142.7, 74.7, 63.5, 61.5, 59.1,
50.4, 40.7, 36.1, 26.8, 26.5, 25.9 (3C), 22.0, 18.3, 11.4, -5.2 (2C).
GC/MS (EI): m/z = 342 (M+), 327, 297, 285, 253, 228, 184, 170,
139, 120, 96, 89, 73, 70.
HRMS (ESI): m/z calcd for C18H39N2O2Si (MH+): 343.2780.
Found: 343.2764.
MS (CI): m/z = 319 (MH+).
(-)-(S)-2-Ethyl-4-tert-butyldimethylsiloxybutan-1-ol (19)
Ozone was bubbled into a solution of hydrazone 18 (910 mg,
2.66 mmol) in CH2Cl2(10 mL) at -78 ∞C until no starting material
was detected by TLC. The reaction mixture was purged with N2
while warming up to r.t. and then concentrated in vacuo. The resi-
due was dissolved in Et2O (10 mL), and borane-THF complex (1.0
M, 6 mL, 6 mmol) was added dropwise at 0 ∞C over 10 min. The
mixture was stirred at 0 ∞C under Ar for 1 h and quenched with H2O
at 0 ∞C. The organic layer was separated and the aqueous layer was
extracted with Et2O (2 ¥ 20 mL). The combined organic layers were
washed with brine, dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by chromatography on silica gel
(hexanes/EtOAc, 5:1) to afford the alcohol 19 as a colorless oil.
The above crude product was deprotected with PPTS (4 mg, 0.016
mmol) and purified by procedures similar to those described for di-
aneackerone 1a to afford dianeackerone, 1b as a colorless oil.
Yield: 8 mg (78%); [a]D -8.7 (c 0.2, CHCl3).
1H NMR (400 MHz, C6D6): d = 0.75 (t, 3H, J = 7.2 Hz), 0.83 (t, 3H,
J = 7.2 Hz), 1.16-1.52 (m, 13H), 1.76 (s, 3H), 2.14 (m, 1H), 2.55
(m, 2H), 7.15-7.25 (m, 5H).
13C NMR (100 MHz, C6D6): d = 210.34, 143.62, 129.06 (2C),
129.04 (2C), 126.36, 54.94, 38.89, 35.89, 33.88, 33.83, 32.16,
28.84, 26.27, 25.16, 25.10, 12.23, 11.22.
GC/MS (EI): m/z = 274 (M+), 227, 186, 172, 157, 145, 123, 105, 99,
91, 86, 71, 55.
Yield: 420 mg, (67%); [a]D -6.8 (c 2.6, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.08 (s, 3H), 0.09 (s, 3H), 0.91 (s,
9H), 0.91 (t, 3H, J = 7.2 Hz), 1.28 (m, 1H, J = 7.2 Hz), 1.37 (m, 1H,
J = 7.2 Hz), 1.53 (m, 2H), 1.68 (m, 1H), 3.24 (br s, 1H), 3.46 (dd,
1H, J = 10.8, 6.4 Hz), 3.60 (dd, 1H, J = 10.8, 3.6 Hz), 3.65 (m, 1H),
3.77 (m, 1H).
13C NMR (100 MHz, CDCl3): d = 65.8, 61.9, 41.3, 35.2, 25.8 (3C),
24.4, 18.2, 11.5, -5.5, -5.5.
HRMS (EI): m/z calcd for C19H30O (M+): 274.2297. Found:
274.2297.
Cholesterol Diazoacetate (16)
To a solution of acid chloride 17 (1.39 g, 5.0 mmol) and cholesterol
(1.93 g, 5.0 mmol) in CH2Cl2 (25 mL), Et3N (1.4 mL, 10 mmol) was
added dropwise at 0 ∞C over 20 min. The mixture was stirred at 0
Synthesis 2000, No. 13, 1936–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

1942
Z. Yang et al.
SPECIAL TOPIC
GC/MS (EI): m/z = 232 (M+), 202, 191, 175, 157, 132, 105, 101, 83,
the product was purified by chromatography on silica gel (EtOAc/
75.
hexanes, 1:14) to give alkene 23 as a colorless oil.
Yield: 115 mg (66%).
(-)-(S)-4-Benzyloxy-3-ethylbutan-1-ol (20)
1H NMR (400 MHz, CDCl3): d = 0.86 (t, 3H, J = 7.2 Hz), 0.89 (t,
3H, J = 7.2 Hz), 1.23 (m, 1H), 1.34-1.52 (m, 4H), 1.61-1.76 (m,
2H), 2.09 (m, 2H), 2.30 (m, 1H), 2.49 (ddd, 1H, J = 13.6, 10.4, 5.6
Hz), 2.63 (ddd, 1H, J = 13.6, 10.4, 5.6 Hz), 3.38 (m, 2H), 4.50 (s,
2H), 5.18 (tt, 1H, J = 10.8, 1.6 Hz), 5.48 (dt, 1H, J = 10.8, 7.6 Hz),
7.15-7.34 (m, 10H).
13C NMR (100 MHz, CDCl3): d = 143.1, 138.8, 135.5, 128.5, 128.3
(2C), 128.3 (2C), 128.2 (2C), 127.5 (2C), 127.4, 125.5, 73.0, 72.9,
40.6, 38.8, 37.6, 33.9, 29.2, 28.6, 23.8, 11.8, 11.3.
GC/MS (EI): m/z = 350 (M+), 332, 304, 282, 259, 242, 213, 199,
171, 145, 117, 104, 91, 67.
HRMS (EI): m/z calcd for C25H34O (M+): 350.2610. Found:
350.2609.
To a solution of alcohol 19 (380 mg, 1.63 mmol) in THF (10 mL),
NaH (98 mg, 60% in oil, 2.45 mmol) was added at r.t. The mixture
was stirred at r.t. under Ar for 30 min, and benzyl bromide (0.29
mL, 2.45 mmol) was added dropwise. The mixture was stirred at r.t.
under Ar overnight and then cooled to 0 ∞C. H2O (2 mL) was added
dropwise at 0 ∞C, followed by the addition of 3 M HCl (5 mL, 15
mmol). The mixture was stirred at r.t. for 1 h. The organic layer was
separated and the aqueous layer was extracted with EtOAc (2 ¥ 20
mL). The combined organic layers were washed with 5% NaHCO3
and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was purified by chromatography on silica gel (hexanes/
EtOAc, 4:1) to afford alcohol 20 as a colorless oil.
Yield: 290 mg (85%); [a]D -9.0 (c 2.3, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.90 (t, 3H, J = 7.2 Hz),1.36 (m,
2H, J = 7.2 Hz), 1.58 (m, 1H), 1.70 (m, 2H), 2.72 (br s, 1H), 3.36
(dd, 1H, J = 9.2, 7.2 Hz), 3.48 (dd, 1H, J = 9.2, 4.0 Hz), 3.63 (m,
1H), 3.70 (m, 1H), 4.53 (t, 2H, J = 13.2 Hz), 7.27-7.38 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 137.9, 128.4 (2C), 127.7 (2C),
127.6, 73.9, 73.3, 61.2, 38.1, 35.8, 24.8, 11.4.
(+)-(2S,6S)-2,6-Diethyl-8-phenyloctan-1-ol (24)
The cis/trans mixture of alkene 23 (92 mg, 0.26 mmol) was hydro-
genated by a procedure similar to that described for dianeackerone
1a and the product was purified by chromatography on silica gel
(EtOAc/hexanes, 1:9) to give the alcohol 24 as a colorless oil.
GC/MS (EI): m/z = 208 (M+), 190, 178, 161, 137, 117, 107, 99, 91,
Yield: 58 mg (84%); [a]D +2.7 (c 1.6, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.87 (t, 3H, J = 7.2 Hz), 0.91 (t,
3H, J = 7.2 Hz), 1.22-1.43 (m, 12H), 1.54-1.59 (m, 2H), 1.61 (br
s, 1H), 2.58 (dd, 2H, J = 10.4, 7.6 Hz), 3.55 (d, 2H, J = 5.2 Hz),
7.15-7.30 (m, 5H).
79, 69.
HRMS (ESI): m/z calcd for C13H21O2 (MH+): 209.1541. Found:
209.1521.
13C NMR (100 MHz, CDCl3): d = 143.2, 128.3 (2C), 128.2 (2C),
125.5, 65.3, 41.9, 38.5, 35.2, 33.4, 33.2, 30.8, 25.7, 23.9, 23.3, 11.1,
10.7.
GC/MS (EI): m/z = 262 (M+), 244, 225, 215, 180, 174, 160, 145,
131, 117, 105, 104, 92, 91, 83, 69, 55.
HRMS (EI): m/z calcd for C18H30O (M+): 262.2297. Found:
262.2296.
(+)-(S)-1-Benzyloxy-4-bromo-2-ethylbutane (21)
To a solution of alcohol 20 (230 mg, 1.1 mmol), Ph3P (576 mg, 2.2
mmol) in DMF (4 mL), NBS (390 mg, 2.2 mmol) was added in por-
tions at r.t. The reaction mixture was stirred at 50 ∞C under Ar for 2
h and cooled to r.t. The mixture was diluted with Et2O (40 mL),
washed with 5% NaHCO3 and brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by chromatography
on silica gel (hexanes/EtOAc, 9:1) to afford bromide 21 as a color-
less oil.
(+)-(2S,6S)-2,6-Diethyl-8-phenyloctanal (15)
Yield: 238 mg (79%); [a]D +8.4 (c 1.0, CHCl3).
To a mixture of alcohol 24 (20 mg, 0.076 mmol), NMO (13 mg,
0.11 mmol), 4 Å molecular sieves (30 mg) in CH2Cl2 (1 mL), TPAP
(2 mg, 0.005 mmol) was added at r.t. The mixture was stirred at r.t.
under Ar for 30 min, then filtered through a pad of silica gel, and
washed with CH2Cl2. The filtrate was concentrated in vacuo, and
the residue was purified by chromatography on silica gel (EtOAc/
hexanes, 1:9) to give the aldehyde 15 as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 0.91 (t, 3H, J = 7.2 Hz), 1.32-
1.49 (m, 2H), 1.76 (m, 1H), 1.91 (m, 1H), 1.98 (m, 1H), 3.37 (dd,
1H, J = 9.2, 5.6 Hz), 3.43 (dd, 1H, J = 9.2, 4.8 Hz), 3.47 (m, 2H),
4.50 (s, 2H), 7.29-7.38 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 138.5, 128.3 (2C), 127.5 (2C),
127.4, 73.1, 72.1, 38.8, 35.1, 32.2, 23.8, 11.2.
GC/MS (EI): m/z = 270 (M+), 242, 223, 311, 190, 172, 163, 149,
Yield: 17 mg (85%); [a]D +5.9 (c 0.9, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.87 (t, 3H, J = 7.2 Hz), 0.92 (t,
3H, J = 7.2 Hz), 1.27-1.72 (m, 13H), 2.18 (m, 1H), 2.58 (dd, 2H,
J = 9.6, 5.6 Hz), 7.18-7.30 (m, 5H), 9.58 (d, 1H, J = 3.2 Hz).
13C NMR (100 MHz, CDCl3): d = 205.6, 143.1, 128.3 (2C), 128.2
(2C), 125.5, 53.4, 38.4, 35.1, 33.1, 28.9, 25.5, 24.1, 21.9, 11.5, 10.7.
GC/MS (EI): m/z = 260 (M+), 242, 231, 213, 185, 171, 145, 138,
117, 105, 104, 92, 91, 65, 55.
HRMS (EI): m/z calcd for C18H28O (M+): 260.2140. Found:
260.2140.
121, 107, 92, 91, 69, 65.
HRMS (EI): m/z calcd for C13H1979BrO (M+): 270.0619. Found:
270.0619.
(S)-3-Ethyl-4-benzyloxybutyltriphenylphosphonium Bromide
(22)
The mixture of bromide 21 (215 mg, 0.793 mmol) and Ph3P (208
mg, 0.793 mmol) was heated at 120 ∞C under Ar for 2 h and then
cooled to r.t. The resulting solid was washed with Et2O, and dried
in vacuum at 60 ∞C for 8 h to provide the phosphonium salt 22 (355
mg, 84%) as a white solid.
(-)-Cholesteryl (4S,8S)-4,8-diethyl-3-oxo-10-phenyldecanoate
(2)
(2S,6R)-1-Benzyloxy-2,6-diethyl-8-phenyloct-4-ene (23)
To a solution of aldehyde 15 (5 mg, 0.019 mmol) and diazoacetate
16 (10 mg, 0.022 mmol) in CH2Cl2(1 mL), SnCl2 (5 mg, 0.026
mmol) was added in portions at r.t. The mixture was stirred over-
night at r.t. under Ar, then diluted with CH2Cl2 (10 mL), washed
with 0.1 M HCl and brine, dried (Na2SO4), filtered and concentrated
The phosphonium salt 22 (266 mg, 0.5 mmol) in THF (5 mL) was
converted to the ylide with BuLi (1.5 M, 0.37 mL, 0.55 mmol) by
a procedure similar to that described for the ketal 13. Aldehyde (-
)-6 (105 mg, 0.6 mmol) in THF (2 mL) was coupled to the ylide and
Synthesis 2000, No. 13, 1936–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Syntheses of Novel Components from a Crocodile Exocrine Secretion
1943
in vacuo. The residue was purified by chromatography on silica gel
(hexanes/EtOAc, 9:1) to afford b-oxo ester 2 as a colorless oil.
References
(1) Ross, C. A. Crocodiles and Alligators; Facts On File Inc.:
New York, 1989.
(2) Weldon, P. J.; Ferguson, M. W. J. Brain Behav. Evol. 1993,
44, 239–245.
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E. III. J. Am. Chem. Soc. 1981, 103, 6967.
(8) Diastereomeric excess values were determined by 1H NMR
(400 MHz) analysis by comparing the spectra of SAMP or
RAMP-hydrazones of the corresponding racemic aldehyde.
(9) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54,
3258.
Yield: 8 mg (61%); [a]D -11.0 (c 0.2, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.68 (s, 3H), 0.86 (t, 3H, J = 8.0
Hz), 0.87 (d, 3H, J = 6.4 Hz), 0.88 (d, 3H, J = 6.4 Hz), 0.88 (t, 3H,
J = 8.0 Hz), 0.92 (d, 3H, J = 6.4 Hz), 1.00 (s, 3H), 1.06-1.68 (m,
35H), 1.81-1.91 (m, 2H), 1.94-2.03 (m, 2H), 2.35 (m, 2H), 2.52
(m, 1H), 2.57 (dd, 2H, J = 9.2, 6.8 Hz), 3.42 (s, 2H), 4.68 (m, 1H),
5.38 (d, 1H, J = 4.8 Hz), 7.17-7.30 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 206.4, 166.6, 143.1, 139.4, 128.3
(2C), 128.2 (2C), 125.5, 122.8, 75.0, 56.7, 56.1, 54.0, 50.0, 48.7,
42.3, 39.7, 39.5, 38.4, 38.0, 36.9, 36.6, 36.2, 35.8, 35.1, 33.2, 33.1,
33.1, 31.9, 31.8, 31.1, 28.0, 27.7, 25.6, 24.4, 24.3, 24.1, 23.8, 22.8,
22.6, 21.0, 19.3, 18.7, 11.9, 11.6, 10.7.
MS (ESI): m/z = 687 (MH+).
HRMS (CI): m/z calcd for C47H75O3 (MH+): 687.5716. Found:
687.5718.
(10) Blankley, C. J.; Sauter, F. J.; House, H. O. Org. Synth. Coll.
Vol. V. 258.
Acknowledgement
This research was supported in part by grant no. GM53830 from the
National Institutes of Health. We thank Dr. Authrine Whyte and Mr.
Kittichoat Tiyanont for their enthusiastic participation in this pro-
ject.
Article Identifier:
1437-210X,E;2000,0,13,1936,1943,ftx,en;E11100SS.pdf
Synthesis 2000, No. 13, 1936–1943 ISSN 0039-7881 © Thieme Stuttgart · New York