Synthesis and spectroscopic correlation of the diastereoisomers of 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid: implications for the structures of papuamides A-D and mirabamides A-D

Article abstract of DOI:10.1016/j.tetasy.2008.09.031

All 4 diastereomeric possibilities for the 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid (Dhtda) residue, found in the cyclic depsipeptide natural products papuamides A-D and mirabamides A-D, were stereoselectively synthesized using a Z-selective

Full text of DOI:10.1016/j.tetasy.2008.09.031

Tetrahedron: Asymmetry 19 (2008) 2546–2554
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and spectroscopic correlation of the diastereoisomers
of 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid: implications
for the structures of papuamides A–D and mirabamides A–D
*
Gurusankar Ramamoorthy, Cristina M. Acevedo, Edgardo Alvira, Mark A. Lipton
Department of Chemistry, Purdue University, West Lafayette, IN 47907-1392, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2008
Accepted 24 September 2008
All 4 diastereomeric possibilities for the 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid (Dhtda)
residue, found in the cyclic depsipeptide natural products papuamides A–D and mirabamides A–D, were
stereoselectively synthesized using a Z-selective Wittig reaction of both enantiomers of 2,4-dimethylhex-
2-enyl-triphenylphosphonium bromide with all four diastereoisomers of ethyl-3-formyl-2-methyl-
1,4-dioxaspiro[4,4]nonane-2-carboxylate. To elucidate the configuration of Dhtda, the 1H and 13C NMR
spectra of the synthetic isomers were compared to those of the natural residue. On the basis of that
comparison, it is suggested that the likely configuration of the diastereomer present in Dhtda residue
is either (2R,3S,8S) or (2S,3R,8S) in the papuamides and mirabimides.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Papuamides 1a–d, cytotoxic, antiviral cyclic depsipeptides iso-
lated from marine sponges Theonella mirabilis and swinhoei, are
the first marine-derived peptides reported to contain a 2,3-dihy-
droxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid moiety.1 More re-
cently, four new cyclic depsipeptides called mirabamides A–D
2a—d were isolated from the marine sponge Siliquariaspongia mira-
bilis and found to have anti-HIV activity and structural similarities
with papuamides, differing only in the chlorination of the homo-
proline residue and the glycosylation of the b-methoxytyrosine
residue.2 Although nearly all of the stereochemistry of papuamides
A–D 1a–d has been elucidated, that of the 2,3-dihydroxy-2,6,
8-trimethyldeca-(4Z,6E)-dienoic acid (Dhtda) residue remained
undefined (Fig. 1).
As part of our efforts directed toward the synthesis and struc-
tural elucidation of papuamide A 1a, we herein report the synthe-
ses of all four diastereomers of Dhtda using a Z-selective Wittig
reaction between (S)-isomer of triphenylphosphonium bromide 7
and all four diastereomers of the aldehyde obtained from the com-
mercially available diethyl tartrate 8. It was reasoned that compar-
ison of the spectroscopic data of the four synthetic isomers with
those of the natural residue would permit the assignment of the
relative configuration of the Dhtda fragment.3
The synthetic pathway for the S-phosphonium bromide 7
(Scheme 1) is a modification of the procedure reported by Miki
in the synthesis of Probetaenone I.4 The synthesis began with the
oxidation of commercially available S-(ꢀ)-2-methyl-1-butanol (3)
to an aldehyde using TEMPO and iodobenzene diacetate (BIAB).
Owing to the high volatility of the intermediate aldehyde, it was
subjected to an in situ Horner–Wadsworth–Emmons reaction with
triethyl 2-phosphonopropionate (4) under Masamune–Roush con-
ditions5 using LiCl and DBU. The product was a 9:1 mixture of E
and Z olefins that was separated by column chromatography to af-
ford the E isomer 5 in 70% yield.6
The a,b-unsaturated ester 5 was then reduced to alcohol 6 using
DIBAL-H in toluene at ꢀ78 °C with no sign of reduction or isomer-
ization of the double bond.6 Finally, enantiomerically pure tri-
phenyl-phosphonium bromide 7 was obtained from alcohol 6 in
one step and without any sign of alkene isomerization using the
PPh3ꢁHBr complex in acetonitrile.
The synthesis of the other half of Dhtda (Scheme 2) started with
the protection of diethyl-L-tartrate 8 as its ketal 9. Treatment of 9
with LHMDS and CH3I in the presence of LiCl at ꢀ78 °C gave the
monoalkylated product 10 as a single diastereomer, whereas in
Seebach’s work using the acetonide analogue of 9 (LDA/HMPA/
CH3I) both diastereomers were obtained in an 86:14 ratio and
79% yield, with 15% of the dimethylated product and 6% of starting
material.7,8 The configuration of the two diastereomers was estab-
lished by NOE experiments. Intriguingly, product 10 results from
methylation of what would appear to be the more hindered face
* Corresponding author.
E-mail address: lipton@purdue.edu (M. A. Lipton).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.031

G. Ramamoorthy et al. / Tetrahedron: Asymmetry 19 (2008) 2546–2554
2547
CONH2
CONH2
OH
OH
OMe
O
OMe
O
O
O
O
O
O
O
H
H
H
N
H
N
N
N
O
N
H
N
H
N
H
N
H
N
H
N
H
HN
HO
O
HN
HO
O
O
N
NH
O
O
NH
NH2
O
O
O
R3
R3
*
*
O
O
O
O
O
NH
R1
O
O
NH
R1
OH
OH
*
*
N
O
O
Dhtda
MeO
MeO
N
N
N
H
N
H
HO
HO
*
*
OR2
OR2
1a
. Papuamide A: R1=CH3, R2=R3=H
1b. Papuamide B: R1=R2= R3=H
1c
. Papuamide C: R1=CH3, R2=R3=H
1d. Papuamide D: R1=R2=R3=H
2b. Mirabamide B: R1=CH3, R2=α-rhamnose, R3=Cl
2a. Mirabamide A: R1=CH3, R2=α-rhamnose, R3=Cl
2c. Mirabamide C: R1=CH3, R2=H, R3=Cl
2d
. Mirabamide D: R1=CH3, R2= α-rhamnose, R2=H
Figure 1. Structures of papuamides A–D and mirabamides A–D. Undefined stereogenic carbons are marked with an asterisk.
O
1. TEMPO, BIAB
CH2Cl2
DIBAL
OEt
OH
PhCH3, -78 °C
2. LiCl, DBU, CH3CN
O
80%
3
5
EtO2C
P(OEt)2
4
70% (9:1 E:Z)
PPh3·HBr
CH3CN, 85 °C
OH
PPh3Br
81%
7
6
Scheme 1.
O
EtO2C
CO2Et
EtO2C
HO
CO2Et
OH
, CSA
LHMDS, LiCl, MeI
O
O
PhCH3, 110 °C
87%
THF, -78 °C to 25 °C
72%
8
9
CO2Et
O
CO2Et
EtO2C
O
EtO2C
1. NaOEt,
EtOH, 0 °C
O
O
10
(40%)
+
2. AcOH, 0 °C
10
11
(43%)
Scheme 2.
of the enolate intermediate. Treatment of 10 with LHMDS and
quenching it with NH4Cl resulted in retention of configuration with
only the starting material being returned. When the base was
changed to sodium ethoxide and the reaction was quenched with
HOAc at 0 °C, a 1:1 mixture of diastereomers 10 and 11 was ob-
tained and separated by column chromatography.
Selective monoreduction of the diastereomeric ethyl esters 10
and 11 using DIBAL-H in toluene at ꢀ78 °C (Scheme 3) resulted

2548
G. Ramamoorthy et al. / Tetrahedron: Asymmetry 19 (2008) 2546–2554
CO2Et
CO2Et
EtO2C
1. DIBAL,
PhCH3, -78 °C
CSA
O
O
O
O
7
2. KHMDS, THF,
18-c-6, -78 °C
MeOH, 25 °C
63%
65% (over 2 steps)
10
12
OH
H
OH
O
1. aq.LiOH, MeOH,
THF, 25 °C
OEt
N
CO2Me
2. EDCI, HOBT, DIEA
GlyOMe.HCl,
OH
OH
O
CH2Cl2, 25 °C
82% (over 2 steps)
14
13
(2R,3S,8S)-
Scheme 3.
in a complex mixture. Unreacted starting material was recovered
by filtration through silica gel and the remaining mixture of prod-
ucts was carried onto the next step without further purification.
Other sterically hindered hydride sources were tested with no
improvement in yield or selectivity and selective saponification
proved no more successful. The ‘salt free’ Z-Selective Wittig reac-
tion9 of phosphonium salt 7 with both diastereomers 10 and 11
in the presence of KHMDS and 18-crown-6 afforded the protected
Dhtda ethyl esters (2R,3R,8S)-12 and (2R,3S,8S)-12, respectively, in
good yield. The same synthetic pathway was applied to diethyl-
amide (2R,3S,8S)-14. The other diastereomeric amides (2R,3R,8S)-
14, (2S,3S,8S)-14, and (2S,3R,8S)-14 were also obtained using the
same procedure.
With the four unique diastereomers in hand, 1H and 13C NMR
spectra of the four isomers of 14 were compared with the values
reported for the Dhtda fragment in the papuamides and miraba-
mides using the universal NMR database approach developed by
Kishi.10 The 1H and 13C NMR of all the diastereomers of Dhtda were
recorded in CD3OD, 4:1—CD3CN–H2O, and DMSO-d6.1 Figures 2 and
3 show the differences in 13C and 1H NMR data in CD3OD between
the different diastereomers of 14 and the authentic Dhtda frag-
ment in papuamide B.
D-tartrate ent-8 to obtain protected Dhtda esters (2S,3S,8S)-12
and (2S,3R,8S)-12.
Deprotection of the ketal in 12 was carried out using CSA in
methanol to obtain Dhtda ethyl ester 13. Ester 13 was hydrolyzed
and the resultant carboxylic acid was converted into its glycine
As can be seen in Figure 2, the carbon chemical shifts differ sub-
stantially between the different diastereomers of 14. The spectra of
the diastereomeric glycine amides of Dhtda 14 were recorded to
Authentic vs RSS
Authentic vs RRS
1.6
1.6
1.4
1.2
1
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
Number of Carbons
Number of Carbons
Authentic vs SSS
Authentic vs SRS
1.6
1.6
1.4
1.2
1
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
Number of Carbons
Number of Carbons
Figure 2. 13C NMR differences between isomers (RSS)-, (SRS)-, (RRS)-, and (SSS)-14 in CD3OD and the authentic Dhtda fragment in papuamide B. The numbering scheme used
was that employed in the original publication on the isolation of papuamide.

G. Ramamoorthy et al. / Tetrahedron: Asymmetry 19 (2008) 2546–2554
2549
Authentic vs RRS
Authentic vs RSS
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
Number of Carbons
Number of Carbrons
Authentic vs SSS
Authentic vs SRS
0.2
0.18
0.16
0.14
0.12
0.1
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
Number of Carbons
0.08
0.06
0.04
0.02
0
Number of Carbons
Number of Carbons
Figure 3. 1H NMR differences between isomers (RSS)-, (SRS)-, (RRS)-, and (SSS)-14 and the Dhtda fragment in papuamide B in CD3OD. The numbering scheme used in the plots
is the same as in the original publication.
P
once again showed larger deviations (
r ¼ 0:76 and 0.78 ppm),
and both (RSS)-14 and (SRS)-14 showed similar small deviations
P
(
r
¼ 0:38 and 0.39 ppm). Even with these additional data, the
1H coupling constants and 13C chemical shifts values were still
indistinguishable for the syn-diastereomers.
The 1H NMR of authentic Dhtda was also reported in DMSO-d6
as a tripeptide in the original publication.1 Therefore, the 1H NMR
spectra of all four diastereomers of 14 were taken in DMSO-d6
mimic as closely as possible the environment within the natural
products. There is a good general agreement in the 13C NMR spec-
tra between the various isomers of 14 and the authentic Dhtda res-
(Fig. 5) and consistently the two anti-diastereomers (RRS)-14 and
P
(SSS)-14 showed cumulatively larger deviations (
0.54 ppm, respectively). The two syn-diastereomers (RSS)-14 and
r ¼ 0:54 and
idue. The isomers (RRS)-14 and (SSS)-14 show larger deviations
P
P
(SRS)-14 showed smaller deviations (
r
¼ 0:15 and 0.17 ppm,
from the natural product (
r ¼ 5:08 and 5.36 ppm, respectively),
respectively), while the coupling constant data did not yield any
further distinction. It should be noted that the substantial differ-
ence in chemical shifts seen between the syn- and anti-diastereo-
meric pairs in CD3OD was consistently observed in the other
NMR solvents. When the combined deviation of both 1H NMR
chemical shifts values in all solvents is taken into consideration,
the NMR database suggests that diastereomer (RSS)-14 or its enan-
tiomer (SRR)-14 best matches the natural product. It is therefore
suggested that the configuration of the Dhtda residue in the papua-
mides is either (2R,3S,8S) or (2S,3R,8R).
whereas the other diastereomers (RSS)-14 and (SRS)-14 have smal-
P
ler deviations (
r
¼ 3:43 and 3.40 ppm, respectively).
In the case of the 1H NMR differences (Fig. 3), it was observed
that diastereomers (RRS)-14 and (SSS)-14 have the larger devia-
P
tions (
r ¼ 0:64 and 0.61, respectively) from authentic Dhtda,
which implies a syn-relationship between the C-2 and C-3 hydro-
xyl substituents in Dhtda.
The deviation of the 1H NMR chemical shifts of the two syn-
P
P
diastereomers (RSS)-14 (
r
¼ 0:20 ppm) and (SRS)-14 (
r ¼
0:24 ppm) was roughly comparable. To distinguish between these
two possibilities, we next turned to the vicinal coupling constants
in the 1H NMR spectrum. It was found that both diastereomers
The 1H NMR of chemical shifts of all four diastereomers of
Dhtda in 4:1-CD3CN–H2O were also compared with the recently re-
ported authentic Dhtda of mirabamides A-D in 5:1—CD3CN–H2O2
(Fig. 6). The syn-diastereomers (RSS)- and (SRS)-14 showed lesser
deviations from the authentic Dhtda than the corresponding anti-
P
P
(RSS)-14
(
J ¼ 2:6 Hz) and (SRS)-16
(
J ¼ 2:4 Hz) had the
closest values of coupling constants for protons H4, H5, H7, and
H13, and a much lower cumulative deviation from those of the
authentic residue.
diastereomers (RRS)-and (SSS)-14. Between the syn-diastereomers
P
(RSS)-14 (
(SRS)-14 (
r
r
¼ 0:25) showed smaller cumulative deviation than
The original publication on the isolation of the papuamides also
reported 1H NMR spectra in 4:1 CD3CN–H2O.1 To distinguish be-
tween the two syn-diastereomers, their 1H NMR spectra were re-
corded in the same solvent mixture for comparison to authentic
Dhtda (Fig. 4). The two anti-diastereomers (RRS)-14 and (SSS)-14
P
¼ 0:28) as in the papuamides. This further proves
and supports that the configuration of Dhtda fragment that is pres-
ent in both papuamides A–D and mirbamides A–D is either
(2R,3S,8S) or (2S,3R,8R).

2550
G. Ramamoorthy et al. / Tetrahedron: Asymmetry 19 (2008) 2546–2554
Authentic vs RSS
Authentic vs RRS
0.25
0.2
0.25
0.2
0.15
0.1
0.05
0
0.15
0.1
0.05
0
Number of Carbons
Number of Carbons
Authentic vs SSS
Authentic vs SRS
0.25
0.2
0.25
0.2
0.15
0.1
0.05
0
0.15
0.1
0.05
0
Number of Carbons
Number of Carbons
Figure 4. 1H NMR chemical shift differences between isomers (RSS)-, (SRS)-, (RRS)-, and (SSS)-14 and the authentic Dhtda fragment in papuamide A in 4:1—CD3CN–H2O.1 The
numbering scheme used in the plots is the same as in the original publication.
Authentic vs RSS
Authentic vs RRS
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
Number of Carbons
Number of Carbons
Authentic vs SRS
Authentic vs SSS
0.2
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
Number of Carbons
Number of Carbons
Figure 5. 1H NMR differences between isomers (RSS)-, (SRS)-, (RRS)-, and (SSS)-14 and the authentic Dhtda fragment in papuamide A in DMSO-D6. The numbering scheme
used in the plots is the same as in the original publication.
we were able to conclude that the enantiomeric pair of (RSS)- and
(SRR)-14 best matches the spectroscopic data of Dhtda in the pap-
uamides and mirabamides. It is therefore suggested that the con-
figuration of Dhtda in the papuamides and mirabamides is either
(2R,3S,8S) or (2S,3R,8R), a conclusion supported by the recent total
synthesis of papuamide B.3
3. Conclusion
The synthesis of all four diastereomers of the fatty acid Dhtda
has been accomplished, starting from both enantiomers of diethyl
tartrate and (S)-(ꢀ)-2-methylbutane-1-ol, in 11–12 steps and 9%
overall yield. Using 1H NMR and 13C NMR data in various solvents,

G. Ramamoorthy et al. / Tetrahedron: Asymmetry 19 (2008) 2546–2554
2551
Authentic vs RSS
Authentic vs RRS
0.25
0.2
0.15
0.1
0.05
0
0.25
0.2
0.15
0.1
0.05
0
Number of Carbons
Number of Carbons
Authentic vs SSS
Number of Carbons
Authentic vs SRS
0.25
0.2
0.25
0.2
0.15
0.1
0.05
0
0.15
0.1
0.05
0
Number of Carbons
Number of Carbons
Figure 6. 1H NMR differences between isomers (RSS)-, (SRS)-, (RRS)- and (SSS)-14 and the authentic Dhtda fragment in mirabamide A in 4:1—CD3CN–H2O. The numbering
scheme used in the plots is the same as in the original publication.
ꢀ78 °C and allowed to warm to room temperature with vigorous
4. Experimental
stirring until the suspended solid was fully dissolved. The reaction
mixture was extracted with EtOAc (3ꢂ) and the combined organic
4.1. General information
layer was washed with water (1ꢂ), satd NaCl(aq) (2ꢂ), dried over
Na2SO4, and concentrated in vacuo. The crude alcohol was purified
4.1.1. Ethyl (2E,4S)-2,4-dimethyl-2-hexenoate 5
by flash column chromatography (25% EtOAc/hexanes) to furnish 6
To a solution of (S)-2-methyl-1-butanol 3 (1.20 mL, 11.4 mmol)
in CH2Cl2 (8 mL), TEMPO (180 mg, 1.2 mmol) and iodobenzene
diacetate (4.40 g, 13.7 mmol) were added at 25 °C, and the mixture
was stirred for 4 h under a N2 atmosphere. The reaction mixture
was washed with satd Na2S2O3(aq), satd NaHCO3(aq), water (2ꢂ)
and brine, and dried over Na2SO4. The organic layer containing
the crude aldehyde was diluted with CH2Cl2 to a volume of
15 mL and used in the next step without further purification.
To a slurry of LiCl (2.93 g, 68.2 mmol) in CH3CN (10 mL) were
added triethyl 2-phosphonopropionate 4 (2.7 mL, 12.5 mmol) and
DBU (1.2 mL, 11.9 mmol), and the resultant mixture was stirred
for 15 min at 25 °C. The solution of the crude aldehyde in CH2Cl2
was added to the reaction mixture at 25 °C and stirred for 12 h
under a N2 atmosphere. The reaction mixture was diluted with
diethyl ether (20 mL) and washed with water (2ꢂ) and satd
NaCl(aq), dried over Na2SO4, and concentrated in vacuo. The crude
product was purified by flash chromatography (5% Et2O/hexanes)
(500 mg, 83%) as a colorless liquid. ½a D25
ꢃ
¼ þ22:5 (c 1.3, CHCl3); 1H
NMR (300 MHz, CDCl3) d 5.18 (dd, J = 10.0, 1.5 Hz, 1H), 4.00 (s, 2H),
2.28 (m, 1H), 1.68 (s, 3H), 1.58 (br s, 1H), 1.42–1.22 (m, 2H), 0.93
(d, J = 6.5 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 133.4, 132.7, 69.0, 33.7, 30.2, 20.6, 13.8, 11.9; HRMS calcd
128.1201, found 128.1202; IR (CHCl3) mmax 3432 (br), 2962, 2873,
1459, 1382, 1074, 1037 cmꢀ1
.
4.3. (2E,4S)-2,4-Dimethyl-2-hexenyltriphenylphosphonium
bromide 7
To a solution of alcohol 6 (500 mg, 3.91 mmol) in CH3CN (8 mL)
was added triphenylphosphonium bromide (1.61 g, 4.69 mmol) at
25 °C and the reaction mixture was stirred for 6 h at 95 °C. The
reaction mixture was concentrated under reduced pressure and
the crude product was purified by flash chromatography (5%
MeOH/CH2Cl2) to afford
7 (1.45 g, 81%) as a tan solid.
to afford the ester
½ ꢃ
5 (1.35 g, 70%) as a colorless liquid.
a 2D5
ꢃ
¼ þ12:4 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.74–
a 2D5
¼ þ20:0 (c 1.7, CHCl3). 1H NMR (300 MHz, CDCl3) d 6.53 (dd,
½
7.55 (m, 15H), 4.92 (q, J = 5.7, 3.1 Hz, 1H), 4.26 (m, 2H), 2.00 (m,
1H), 1.39 (d, J = 2.4 Hz, 3H), 0.88 (m, 2H), 0.55 (d, J = 6.6 Hz, 3H),
0.50 (t, J = 7.32, 3H); 13C NMR (75 MHz, CDCl3) d 143.1, 142.9,
135.3, 135.2, 134.2, 134.1, 130.6, 130.4, 121.0, 120.9, 119.0,
117.9, 34.7, 34.6, 34.6, 34.1, 29.7, 29.6, 19.9, 19.8, 18.8, 18.8,
11.8; IR (CH2Cl2) mmax 2968, 2943, 2925, 2293, 2252, 1440, 1375,
J = 10.0, 1.5 Hz, 1H), 4.19 (q, J = 7.2, 14.4 Hz, 2H), 2.4 (m, 1H),
1.83 (s, 3H), 1.40–1.20 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H), 1.00 (d,
J = 6.5 Hz, 3H), 0.86 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
168.5, 147.8, 126.5, 60.3, 34.9, 29.6, 19.7, 14.3, 12.5, 11.9; HRMS
calcd 170.1307, found 170.1300; IR (CHCl3) mmax 2960, 2937,
1710, 1479, 1274, 1227, 1177, 1095, 1027 cmꢀ1
.
1112, 1039, 918, 752, 720, 692 cmꢀ1
.
4.2. (2E,4S)-2,4-Dimethyl-2-hexen-1-ol 6
4.4. Diethyl (2R,3R)-1,4-dioxaspiro[4,4]nonane-2,3-
To a cooled solution of ester 5 (800 mg, 4.71 mmol) in CH2Cl2
(5 mL), DIBAL in toluene (1.0 M, 11.8 mL, 11.8 mmol) was slowly
added at ꢀ78 °C and the mixture was stirred for 2 h at ꢀ78 °C.
The reaction mixture was quenched with 2 M HCl (10 mL) at
dicarboxylate 9
A solution of (+)-diethyl-
pentanone (10.7 mL, 121 mmol), and 10-camphorsulfonic acid
L-tartrate 8 (5.0 g, 24.3 mmol), cyclo-

2552
G. Ramamoorthy et al. / Tetrahedron: Asymmetry 19 (2008) 2546–2554
(560 g, 2.43 mmol) in toluene (60 mL) was heated in a Dean-Stark
apparatus at 150 °C for 24 h. The reaction mixture was diluted with
EtOAc (20 mL) and washed using satd NaHCO3(aq) (1ꢂ), water (2ꢂ),
satd NaCl(aq) (1ꢂ) then dried over Na2SO4, and concentrated in va-
cuo. The crude acetal was purified by flash column chromatogra-
phy (10% EtOAc/hexanes) to give 9 (5.80 g, 87%) as a colorless
Na2SO4, and concentrated under reduced pressure. The crude prod-
uct was filtered through silica gel to afford the crude aldehyde
(300 mg) as a clear liquid that was used for the next reaction with-
out further purification.
To a stirred suspension of the phosphonium ion 7 (618 mg,
1.36 mmol) in THF (5 mL) was slowly added KHMDS in THF
(0.91 M, 1.6 mL, 1.50 mmol) at ꢀ78 °C, and the resultant mixture
was stirred for 15 min whereupon a solution of 18-crown-6 in
THF (0.5 mL) was added and the stirring continued for another
15 min. A solution of the crude aldehyde (300 mg) in THF (3 mL)
was added to the reaction mixture at ꢀ78 °C and stirred for 8 h
at ꢀ78 °C. The reaction was quenched by the addition of satd
NH4Cl(aq) (1ꢂ5 mL) and extracted with diethyl ether (3ꢂ). The
combined organic layers were washed with water (3ꢂ) and satd
NaCl(aq), dried over Na2SO4, and concentrated in vacuo. The crude
product was purified by flash column chromatography (5% Et2O/
hexanes) to give (RSS)-12 (270 mg, 65% based on recovered SM)
liquid. ½a 2D5
ꢃ
¼ ꢀ32:5 (c 3.4, CHCl3). 1H NMR (300 MHz, CDCl3) d
4.63 (s, 2H), 4.18 (q, 4H, J = 6.9 Hz), 1.83 (m, 2H), 1.77 (m, 2H),
1.60 (m, 4H), 1.22 (t, 6H, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) d
169.6, 123.3, 76.9, 61.8, 36.8, 23.4, 14.1; MS(EI-CI) 273 (M+1); IR
(CH2Cl2) mmax 2976, 2878, 1757, 1739, 1336, 1199, 1124,
1026 cmꢀ1
.
4.5. Diethyl (2R,3R)-2-methyl-1,4-dioxaspiro[4,4]nonane-2,3-
dicarboxylate 10
To a cooled mixture of ester 9 (2.2 g, 8.09 mmol), anhydrous
LiCl (2.1 g, 48.5 mmol), and methyl iodide (1.5 mL, 24.3 mmol) in
THF (8 mL) was added a solution of LHMDS in THF (1.0 M,
9.7 mL, 9.71 mmol) slowly at ꢀ78 °C. The mixture was slowly
warmed to 25 °C and stirred for 16 h. The reaction mixture was
poured into EtOAc (20 mL) and washed with water (3ꢂ), satd
NaCl(aq) (1ꢂ), dried over Na2SO4, and concentrated under reduced
pressure. The crude product was purified by flash column chroma-
tography (10% EtOAc/hexanes) to afford 10 (1.66 g, 72%) as a color-
as
a
colorless liquid.
½
a 2D5
ꢃ
¼ þ15:9 (c 1.1, CHCl3); 1H NMR
(300 MHz, CDCl3)
d
6.21 (d, J = 11.7 Hz, 1H), 5.39 (t, 1H,
J = 9.9 Hz), 5.21 (d, 1H, J = 9.3 Hz), 4.19 (d, 1H, J = 9.3 Hz), 4.19
(m, 2H), 2.30 (m, 1H), 1.94 (m, 3H), 1.75 (d, 3H, J = 1.2 Hz), 1.69
(m, 5H), 1.39 (s, 3H), 1.32 (m, 2H), 1.27 (t, 3H, J = 7.2 Hz), 0.95 (d,
3H, J = 6.6 Hz), 0.85 (t, 3H, J = 7.5 Hz);13C NMR (75 MHz, CDCl3) d
173.3, 140.2, 138.7, 130.0, 121.5, 119.4, 82.8, 76.6, 61.3, 37.9,
37.0, 34.5, 30.3, 24.0, 23.2, 20.6, 20.0, 16.7, 14.1, 12.1; HRMS calcd
less oil. ½a 2D5
ꢃ
¼ ꢀ56:1 (c 1.75, CHCl3); 1H NMR (300 MHz, CDCl3) d
336.2301, found 336.2306; IR (CHCl3)
mmax 2961, 2868, 1735, 1453,
4.98 (s, 1H), 4.26 (m, 4H), 2.18 (m, 1H), 1.98 (m, 1H), 1.69 (m,
6H), 1.42 (s, 3H), 1.31 (m, 6H); 13C NMR (75 MHz, CDCl3) d 172.6,
169.1, 122.3, 83.1, 79.8, 62.3, 61.7, 37.5, 37.3, 24.2, 23.3, 20.4,
14.5, 14.4; HRMS calcd 286.1416, found 286.1418; IR (CH2Cl2) mmax
1336, 1264, 1109, 1024 cmꢀ1
.
4.8. Ethyl (2R,3R)-3-[(1Z,3E,5S)-3,5-dimethylhepta-1,3-dienyl]-
2-methyl-1,4-dioxaspiro[4.4]nonane-2-carboxylate (RRS)-12
2989, 2873, 1754, 1736, 1336, 1243, 1199, 1119, 1023 cmꢀ1
.
Prepared by the same procedure used to make (RSS)-12.
4.6. Diethyl (2R,3S)-2-methyl-1,4-dioxaspiro[4,4]nonane-2,3-
dicarboxylate 11
½
a 2D5
ꢃ
¼ þ18:9 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) d 6.21 (d,
1H, J = 11.7 Hz), 5.25 (d, 1H, J = 9.9 Hz), 5.18 (dd, 1H, J = 9.9,
11.4 Hz) 4.77 (d, 1H, J = 9.9 Hz), 4.19 (m, 2H), 2.33 (m, 1H), 2.15
(m, 1H), 1.99 (m, 1H), 1.80 (m, 3H), 1.75 (d, 3H, J = 1.2 Hz), 1.69
(m, 6H), 1.49 (s, 3H), 1.39 (m, 1H), 1.30 (t, 3H, J = 7.2 Hz), 1.26
(m, 1H), 0.97 (d, 3H, J = 6.6 Hz), 0.87 (t, 3H, J = 7.2 Hz); 13C NMR
(75 MHz, CDCl3) d 172.3, 141.0, 138.5, 129.9, 121.2, 119.8, 83.5,
80.5, 61.2, 38.2, 36.9, 34.7, 30.3, 23.9, 23.2, 22.1, 20.8, 16.8, 14.2,
12.2; HRMS calcd 336.2301, found 336.2309; IR (CHCl3) mmax
To a stirred mixture of flame dried and powdered 4 Å molecular
sieves in absolute ethanol (2 mL) was added a solution of 10 (1.0 g,
3.50 mmol) in absolute ethanol (2 mL) and the mixture stirred for
10 min, then cooled to 0 °C and a solution of sodium ethoxide in
ethanol (2.7 M, 1.6 mL, 4.20 mmol) was added. The reaction was
stirred for 1 h and quenched with glacial acetic acid (250 lL) at
0 °C. The mixture was filtered through CeliteTM and concentrated
in vacuo. The residue was dissolved in EtOAc (10 mL), washed with
water (1ꢂ) and satd NaCl(aq) (1ꢂ), and the organic layer was dried
over Na2SO4 and concentrated in vacuo. The mixture of 10 and 11
was separated by flash column chromatography (10% EtOAc/hex-
anes) to furnish 10 (400 mg, 40%) and 11 (430 mg, 43%) as colorless
2961, 2925, 2868, 1749, 1732, 1456, 1336, 1232, 1106, 1024 cmꢀ1
.
4.9. Ethyl (2S,3R)-3-[(1Z,3E,5S)-3,5-dimethylhepta-1,3-dienyl]-
2-methyl-1,4-dioxaspiro[4.4]nonane-2-carboxylate (SRS)-12
Prepared by the same procedure used to make (RSS)-12.
oils. ½a 2D5
ꢃ
¼ ꢀ24:4 (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) d 4.28 (s,
½
a 2D5
ꢃ
¼ þ28:0 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) d 6.20 (d,
1H), 4.21 (m, 4H), 2.06 (m, 2H), 1.82 (m, 2H), 1.470 (m, 6H), 1.67 (s,
3H), 1.29 (m, 6H); 13C NMR (75 MHz, CDCl3) d 171.5, 167.6, 121.4,
83.2, 82.6, 61.9, 61.8, 38.3, 36.9, 23.9, 23.6, 22.7, 14.4; HRMS calcd
286.1416, found 286.1412; IR (CH2Cl2) mmax 2977, 2873, 1762,
1H, J = 11.7 Hz), 5.38 (dd, 1H, J = 10.2, 11.4 Hz), 5.22 (d, 1H,
J = 9.6 Hz), 5.19 (dd, 1H, J = 9.9Hz), 4.19 (m, 2H), 2.31 (m, 1H),
1.92 (m, 3H), 1.74 (d, 3H, J = 1.2 Hz), 1.67 (m, 5H), 1.39 (s, 3H),
1.36 (m, 1H), 1.27 (t, 3H, J = 7.2 Hz), 1.26 (m, 1H), 0.96 (d, 3H,
J = 6.6 Hz), 0.85 (t, 3H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) d
173.6, 140.5, 139.0, 121.8, 119.6, 83.1, 61.6, 38.2, 37.3, 34.8, 30.5,
24.2, 23.4, 20.9, 20.3, 16.9, 14.4, 12.4; HRMS calcd 336.2379, found
336.2380; IR (CHCl3) mmax 2961, 2873, 1734, 1453, 1374, 1336,
1739, 1374, 1197, 1124, 1026 cmꢀ1
.
4.7. Ethyl (2R,3S)-3-[(1Z,3E,5S)-3,5-dimethylhepta-1,3-dienyl]-
2-methyl-1,4-dioxaspiro[4.4]nonane-2-carboxylate (RSS)-12
1267, 1108, 1024 cmꢀ1
.
To a solution of 10 (1.0 g, 3.50 mmol) in toluene (10 mL) at
ꢀ78 °C was slowly added DIBAL in toluene (1.0 M, 4.2 mL,
4.20 mmol), and the resultant mixture was stirred for 1 h. The
reaction was quenched with MeOH (8 mL) at ꢀ78 °C and warmed
to 25 °C. The slurry thus produced was diluted with ethyl acetate
(15 mL) and satd aqueous sodium potassium tartrate (15 mL), stir-
red for 45 min, and the two phases separated. The aqueous phase
was extracted with ethyl acetate (3ꢂ) and the combined organic
layer was washed with water (2ꢂ) and satd NaCl(aq), dried over
4.10. Ethyl (2S,3S)-3-[(1Z,3E,5S)-3,5-dimethylhepta-1,3-dienyl]-
2-methyl-1,4-dioxaspiro[4.4]nonane-2-carboxylate (SSS)-12
Prepared by the same procedure used to make (RSS)-12.
½
a 2D5
ꢃ
¼ þ13:7 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) d 6.21 (d,
1H, J = 11.7 Hz), 5.26 (d, 1H, J = 9.6 Hz), 5.18 (dd, 1H, J = 9.9,
11.4 Hz), 4.77 (d, 1H, J = 9.9 Hz), 4.19 (m, 2H), 2.33 (m, 1H), 2.15
(m, 1H), 1.99 (m, 1H), 1.80 (m, 3H), 1.75 (d, 3H, J = 1.2 Hz), 1.69

G. Ramamoorthy et al. / Tetrahedron: Asymmetry 19 (2008) 2546–2554
2553
(m, 6H), 1.49 (s, 3H), 1.39 (m, 1H), 1.30 (t, 3H, J = 7.2 Hz), 1.26 (m,
1H), 0.97 (d, 3H, J = 6.6 Hz), 0.87 (t, 3H, J = 7.2 Hz); 13C NMR
(75 MHz, CDCl3) d 172.6, 141.3, 138.7, 130.1, 121.4, 120.0, 83.7,
80.7, 61.4, 38.4, 37.2, 34.8, 30.5, 24.1, 23.4, 22.3, 21.0, 17.0, 14.5,
12.4; HRMS calcd 336.2301, found 336.2306; IR (CHCl3) mmax
3H); 13C NMR (75 MHz, CDCl3) d 175.5, 140.2, 138.7, 131.0,
124.2, 77.2, 72.1, 62.5, 34.7, 30.5, 22.8, 20.9, 16.7, 14.4, 12.3; HRMS
calcd 270.1831, found 270.1832; IR (CH2Cl2) mmax 3466, 2962,
2925, 2873, 1731, 1455, 1375, 1247, 1117, 1018 cmꢀ1
.
2960, 2868, 1749, 1732, 1456, 1374, 1337, 1233, 1106, 1024 cmꢀ1
.
4.15. Methyl N-[(2R,3S,4Z,6E,8S)-2,3-dihydroxy-2,6,8-
trimethyldeca-4,6-dienoyl]glycinate (RSS)-14
4.11. Ethyl (2R,3S,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-
4,6-dienylcarboxylate (RSS)-13
To a solution of 13 (65 mg, 0.24 mmol) in 1:1 MeOH–THF
(700
(300
l
L) was added a solution of LiOH (65 mg, 1.53 mmol) in water
To a solution of 12 (150 mg, 0.45 mmol) in 1:1 MeOH–CH2Cl2
(2 mL) was added 10-camphorsulfonic acid (20 mg, 0.09 mmol)
and the reaction mixture was stirred for 24 h at 25 °C. The reaction
was concentrated in vacuo and diluted with EtOAc (5 mL). The or-
ganic layer was washed with satd NaHCO3(aq) (1ꢂ), water (2ꢂ) and
brine (1ꢂ), dried over Na2SO4, and concentrated under reduced
pressure. The crude product was purified by flash column chroma-
tography (25% EtOAc/hexanes) to afford 13 (75 mg, 63%) as a color-
lL) at 25 °C and the reaction mixture was stirred for 3 h.
(Note: The (2R,3R,8S)- and (2S,3S,8S)-isomers needed 24 h for con-
sumption of the starting material). The reaction mixture was con-
centrated in vacuo, diluted with water and acidified to pH 2 with
2 M HCl. The aqueous solution was extracted with EtOAc (3ꢂ)
and the combined organic layer was washed with water, dried over
Na2SO4, and concentrated in vacuo. The crude acid was carried on
to the next step without further purification.
To a stirred solution of the crude acid, HOBt (48 mg, 0.31
mmol), glycine methyl ester hydrochloride (47 mg, 0.37 mmol),
and diisopropylethylamine (430 lL, 3.10 mmol) in anhydrous
less oil. ½a 2D5
ꢃ
¼ ꢀ80:1 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) d
6.14 (d, 1H, J = 11.7 Hz), 5.43 (dd, 1H, J = 9.9, 11.7 Hz), 5.24 (d,
1H, J = 9.9 Hz), 4.79 (d, 1H, J = 9.9 Hz), 4.38 (m, 2H), 3.46 (br s,
1H), 2.33 (m, 1H), 1.76 (d, 3H, J = 0.9 Hz), 1.38 (m, 1H), 1.28 (t,
3H, J = 7.2 Hz), 1.27 (s, 3H), 1.25 (m, 1H), 0.95 (d, 3H, J = 6.6 Hz),
0.85 (t, 3H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) d 176.5, 139.0,
138.6, 124.7, 77.3, 62.5, 34.7, 30.5, 22.6, 20.9, 17.0, 14.4, 12.4;
HRMS calcd 270.1831, found 270.1828; IR (CH2Cl2) mmax 3489,
CH2Cl2 (1.5 mL) was added EDCI (71 mg, 0.37 mmol) at 25 °C and
the reaction mixture was stirred for 12 h. The reaction mixture
was diluted with CH2Cl2 (5 mL) and washed with 0.5 M HCl (2ꢂ),
water (1ꢂ), and brine (1ꢂ). The organic layer was dried over
Na2SO4 and concentrated in vacuo. The crude product was purified
by flash column chromatography (60% EtOAc/hexanes) to afford 14
2962, 2925, 2855, 1736, 1456, 1377, 1251, 1118, 1019 cmꢀ1
.
(62 mg, 82%) as a colorless, viscous oil. ½a D25
¼ ꢀ16:8 (c 2.5, CHCl3);
ꢃ
4.12. Ethyl (2R,3R,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-
4,6-dienylcarboxylate (RRS)-13
1H NMR (400 MHz, CD3OD) d 6.11 (d, 1H, J = 11.9 Hz), 5.44 (dd, 1H,
J = 10.4, 11.6 Hz), 5.27 (d, 1H, J = 9.6 Hz), 4.85 (d, 1H, J = 10.3 Hz),
3.98 (AB, 2H, JAB = 17.8 Hz,
DAB = 68.6 Hz), 3.72 (s, 3H), 2.36 (m,
Prepared by the same procedure used to make (RSS)-13.
1H), 1.80 (br s, 3H), 1.39 (m, 1H), 1.28 (m, 1H), 1.24 (s, 3H), 0.97
(d, 3H, J = 6.8 Hz), 0.87 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz,
CD3OD) d 178.9, 171.8, 139.4, 138.5, 132.2, 126.5, 78.6, 72.2,
52.6, 41.8, 35.6, 31.4, 23.2, 21.1, 17.0, 12.5; HRMS calcd
314.1967, found 314.1965; IR (CH2Cl2) mmax 3379, 2959, 2929,
½
a 2D5
ꢃ
¼ þ44:7 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) d 6.05 (d,
1H, J = 11.7 Hz), 5.38 (d, 1H, J = 10.2 Hz), 5.32 (dd, 1H, J = 10.2,
12.6 Hz), 4.62 (d, 1H, J = 9.9 Hz), 4.20 (m, 2H), 3.46 (br s, 1H),
2.32 (m, 1H), 1.79 (d, 3H, J = 1.2 Hz), 1.46 (s, 3H), 1.36 (m, 1H),
1.28 (m, 1H), 1.26 (t, 3H, J = 7.2 Hz), 0.95 (d, 3H, J = 6.6 Hz), 0.86
(t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 175.5, 139.9, 138.8,
130.9, 124.3, 77.1, 72.2, 62.5, 34.7, 30.6, 22.8, 20.9, 16.8, 14.4,
12.4; HRMS calcd 270.1831, found 270.1830; IR (CH2Cl2) mmax
2872, 1744, 1655, 1528, 1451, 1439, 1370, 1214, 1020 cmꢀ1
.
4.16. Methyl N-[(2R,3R,4Z,6E,8S)-2,3-dihydroxy-2,6,8-
trimethyldeca-4,6-dienoyl]glycinate (RRS)-14
3438, 2962, 2927, 2866, 1729, 1599, 1452, 1247, 1119, 1018 cmꢀ1
.
The procedure for making (RSS)-14 was followed, except that the
4.13. Ethyl (2S,3R,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-
4,6-dienylcarboxylate (SRS)-13
saponification required 12 h to reach completion. ½a D25
¼ þ38:5 (c
ꢃ
3.75, CHCl3); 1H NMR (400 MHz, CD3OD) d 8.14 (br s, 1H), 5.97 (d,
1H, J = 11.8 Hz), 5.52 (dd, 1H, J = 10.1, 11.8 Hz), 5.27 (d, 1H,
J = 9.5 Hz), 4.63 (d, 1H, J = 10.1 Hz), 3.97 (m, 1H), 3.71 (m, 1H), 3.71
(s, 3H), 2.34 (m, 1H), 1.77 (br s, 3H), 1.39 (s, 3H), 1.38 (m, 1H), 1.28
(m, 1H), 0.97 (d, 3H, J = 6.5 Hz), 0.88 (t, 3H, J = 7.4 Hz); 13C NMR
(100 MHz, CD3OD) d 177.8, 171.7, 139.1, 138.2, 132.4, 126.4, 78.5,
72.7, 52.6, 41.6, 35.5, 31.5, 23.1, 21.0, 16.7, 12.5; HRMS calcd
314.1967, found 314.1968; IR (CH2Cl2) mmax 3395, 2956, 2925,
Prepared by the same procedure used to make (RSS)-13.
½
a 2D5
ꢃ
¼ þ110:4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) d 6.15 (d,
1H, J = 11.7 Hz), 5.46 (dd, 1H, J = 9.9, 11.7 Hz), 5.26 (d, 1H,
J = 9.9 Hz), 4.79 (d, 1H, J = 9.9 Hz), 4.26 (q, 2H, 7.5 Hz), 3.46 (br s,
1H), 2.34 (m, 1H), 1.76 (d, 3H, J = 1.2 Hz), 1.38 (m, 1H), 1.29 (t,
3H, J = 7.2 Hz), 1.27 (s, 3H), 1.26 (m, 1H), 0.97 (d, 3H, J = 6.6 Hz),
0.87 (t, 3H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) d 176.5, 139.2,
138.4, 130.7, 124.7, 77.2, 71.9, 62.5, 34.7, 30.6, 22.6, 21.0, 17.0,
14.4, 12.4; HRMS calcd 270.1831, found 270.1834; IR (CH2Cl2) mmax
3467, 2961, 2925, 2868, 1735, 1456, 1375, 1250, 1176, 1117,
2873, 1747, 1656, 1530, 1450, 1439, 1367, 1210, 1183, 1013 cmꢀ1
.
4.17. Methyl N-[(2S,3R,4Z,6E,8S)-2,3-dihydroxy-2,6,8-
trimethyldeca-4,6-dienoyl]glycinate (SRS)-14
1018 cmꢀ1
.
The procedure for making (RSS)-14 was followed. ½a D25
¼ þ55:0 (c
ꢃ
4.14. Ethyl (2S,3S,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-
4,6-dienylcarboxylate (SSS)-13
1.0, CHCl3); 1H NMR (400 MHz, CD3OD) d 6.11 (d, 1H, J = 11.8 Hz),
5.44 (dd, 1H, J = 10.4, 11.6 Hz), 5.28 (d, 1H, J = 9.6 Hz), 4.84 (d, 1H,
J = 10.3 Hz), 4.00 (AB, 3H, JAB = 17.8 Hz,
D AB = 68.6 Hz), 3.72 (s,
Prepared by the same procedure used to make (RSS)-13.
3H), 2.36 (m, 1H), 1.80 (br s, 3H), 1.39 (m, 1H), 1.29 (m, 1H), 1.23
(s, 3H), 0.97 (d, 3H, J = 6.6 Hz), 0.89 (t, 3H, J = 7.4 Hz); 13C NMR
(100 MHz, CD3OD) d 178.9, 171.8, 139.3, 138.6, 132.1, 126.5, 78.6,
72.3, 52.6, 41.8, 35.6, 31.4, 23.2, 21.1, 16.9, 12.5; HRMS calcd
314.1967, found 314.1966; IR (CH2Cl2) mmax 3395, 2959, 2930,
½
a 2D5
ꢃ
¼ þ3:4 (c 1.25, CHCl3); 1H NMR (300 MHz, CDCl3) d 6.05 (d,
1H, J = 11.7 Hz), 5.37 (d, 1H, J = 10.2 Hz), 5.32 (d, 1H, J = 10.5 Hz),
4.63 (d, 1H, J = 9.9 Hz), 4.20 (m, 2H), 3.46 (br s, 1H), 2.32 (m, 1H),
1.80 (d, 3H, J = 1.2 Hz), 1.45 (s, 3H), 1.35 (m, 1H), 1.26 (m, 1H),
1.25 (t, 3H, J = 7.2 Hz), 0.97 (d, 3H, J = 6.6 Hz), 0.84 (t, J = 7.5 Hz,
2873, 1746, 1657, 1530, 1452, 1439, 1370, 1215, 1020 cmꢀ1
.

2554
G. Ramamoorthy et al. / Tetrahedron: Asymmetry 19 (2008) 2546–2554
4.18. Methyl N-[(2S,3S,4Z,6E,8S)-2,3-dihydroxy-2,6,8-
trimethyldeca-4,6-dienoyl]glycinate (SSS)-14
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70, 1753.
3. During the preparation of this manuscript, a total synthesis of papuamide B
appeared that arrived at similar conclusions as our own: Xie, W.; Ding, D.; Zi,
W.; Li, G.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 1.
4. Miki, S.; Sato, Y.; Tabuchi, Y.; Oikawa, H.; Ichihara, A.; Sakamura, S. J. Chem. Soc.,
Perkin Trans. 1 1990, 1228.
5. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush,
W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
6. Ley, S. V.; Armstrong, A.; Diez-Martin, D.; Ford, M. J.; Grice, P.; Knight, J. G.;
Kolb, H. C.; Madin, A.; Marby, C. A.; Mukherjee, S.; Shaw, A. N.; Slawin, A. M. Z.;
Vile, S.; White, A. D.; Williams, D. J.; Woods, M. J. Chem. Soc., Perkin Trans. 1
1991, 667.
The procedure for making (RRS)-14 was followed. ½a D25
¼ ꢀ3:2
ꢃ
(c 2.5, CHCl3); 1H NMR (400 MHz, CD3OD)
d 5.97 (d, 1H,
J = 11.9 Hz), 5.51 (dd, 1H, J = 10.5, 11.9 Hz), 5.27 (d, 1H,
J = 9.6 Hz), 4.63 (d, 1H, J = 9.9 Hz), 3.91 (AB, 3H, JAB = 17.7 Hz,
D
AB = 48.1 Hz), 3.71 (s, 3H), 2.33 (m, 1H), 1.77 (br s, 3H), 1.40 (s,
3H), 1.37 (m, 1H), 1.28 (m, 1H), 0.97 (d, 3H, J = 6.7 Hz), 0.86 (t,
3H, J = 7.4 Hz); 13C NMR (100 MHz, CD3OD) d 177.8, 171.7, 139.1,
138.2, 132.4, 126.4, 78.5, 72.7, 52.6, 41.6, 35.5, 31.5, 23.1, 21.0,
16.7, 12.5; HRMS calcd 314.1967, found 314.1965; IR (CH2Cl2) mmax
3395, 2956, 2930, 2868, 1747, 1654, 1527, 1452, 1436, 1367, 1212,
1016 cmꢀ1
.
7. Seebach, D.; Abei, J. D.; Gander-Coquoz, M.; Naef, R. Chem. Acta 1987, 70,
1192.
Acknowledgments
8. (a) Crich, D.; Hao, X. J. Org. Chem. 1998, 63, 3796; (b) Crich, D.; Hao, X. J. Org.
Chem. 1999, 64, 4016.
9. Bruce, E. M.; Allen, B. R. Chem. Rev. 1989, 89, 863.
We are grateful to the NIH (AI50888) for financial support of
this work. C.M.A. also thanks the Sloan Foundation and the NIH
for graduate research assistantships.
10. Kobayashi, Y.; Lee, J.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 13, 2177.