An enantioselective approach to (+)-laurencin

Article abstract of DOI:10.1039/b803973a

A convergent enantioselective route to an advanced intermediate for the synthesis of the marine natural product (+)-laurencin has been developed. The methodology employs ring-opening of an ephedrine-based spiro-epoxide with a chiral secondary alcohol, hemiacetal allylation and ring closing metathesis as the key steps for elaboration of the functionalized medium-ring ether moiety in laurencin. The Royal Society of Chemistry.

Full text of DOI:10.1039/b803973a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
An enantioselective approach to (+)-laurencin
Vikrant A. Adsool and Sunil V. Pansare*
Received 7th March 2008, Accepted 17th March 2008
First published as an Advance Article on the web 11th April 2008
DOI: 10.1039/b803973a
A convergent enantioselective route to an advanced intermediate for the synthesis of the marine natural
product (+)-laurencin has been developed. The methodology employs ring-opening of an
ephedrine-based spiro-epoxide with a chiral secondary alcohol, hemiacetal allylation and ring closing
metathesis as the key steps for elaboration of the functionalized medium-ring ether moiety in laurencin.
Introduction
The stereoselective construction of medium-sized oxacycles1 con-
tinues to be an area of active interest and target-oriented2 as well
as general3 strategies for assembling such ring systems have been
extensively investigated in recent years. In particular, medium-
ring ether containing marine natural products4 isolated from red
algae have attracted considerable synthetic effort. The halogenated
oxocines laurencin (1),5 laurenyne (2)6 and prelaureatin (3)7
Fig. 2 Retrosynthetic strategy for laurencin intermediate (+)-4.
(Fig. 1) are representative examples of the impressive array of
red algae metabolites that have been the focus of intense synthetic
investigations in recent years. Above all, the synthesis of laurencin
has served to showcase new methodology for the stereoselective
construction of substituted eight-membered oxacycles and several
successful strategies targeting laurencin have been reported.8
Herein, we describe a concise and enantioselective formal synthesis
of laurencin.
could be derived from an aminoalcohol (Fig. 2). The proposed
disconnections appeared to suit our methodology based on
ephedrine-derived templates.9 Consequently, an ephedrine-derived
alkylidene morpholinone was identified as a precursor to a chiral
epoxide intermediate while a glycidol derivative seemed suitable
for obtaining the required secondary alcohol (Fig. 2).
Our approach to the functionalized oxocine core in laurencin be-
gins with the morpholine-dione 510 which is readily prepared (85%)
from commercially available (1R,2S)-ephedrine hydrochloride
and ethyloxalyl chloride. Treatment of 5 with propylmagnesium
bromide and dehydration of the resulting hemiacetal cleanly
generated the alkylidene morpholinone 611 (95%, Scheme 1).
Reaction of 6 with mCPBA provided the epoxide 7 (85%) as a
single diastereomer, which was stable to chromatography. At this
stage, the stereochemistry of 7 was assigned by analogy to the
epoxidation of a similar substrate.9a While the ring opening of
substituted epoxides12 with secondary alkoxides is uncommon, it
was gratifying to see that epoxide 7 reacted with the potassium
salt of alcohol 813 to furnish the hemiacetal 9 (60%). This key
step assembled the two stereocenters adjacent to the oxygen in the
oxocine core of laurencin (Scheme 1).
Fig.
products.
1
Medium-ring ether containing halogenated marine natural
Results and discussion
We anticipated that allylation of the hemiacetal in 9 would
provide the diene precursor for the required oxocine. However,
subjecting 9 to BF3 etherate–allyltrimethylsilane provided the
spiro-acetal 10 (90%, Scheme 2) and only a trace of the allylation
product. Changing the Lewis acid to TiCl4 was not beneficial and
provided debenzylated 9 as the only isolable product in low yield.
The spiro-acetal 10 could not be allylated under these conditions.
Clearly, the benzyl ether in 9 was unsuitable for the required
transformation and an alternative was necessary. We chose to
employ the p-methoxyphenyl (PMP) protecting group which was
expected to be relatively unreactive under the allylation conditions.
Accordingly, the hemiacetal 11 was prepared from epoxide 7
For the purposes of this investigation, we chose to examine a
new route to the a,a -disubstituted oxocine core of laurencin.
ꢀ
Specifically, we targeted the ketone (+)-4 (Fig. 2), which is an
advanced intermediate in an earlier approach to laurencin.8h At
ꢀ
the outset, we reasoned that a direct entry to the a,a -disubstituted
ether motif in 4 could be achieved by an epoxide ring-opening
with a secondary alcohol, the oxocine ring system would be
accessible by a ring closing metathesis reaction and the ketone
Department of Chemistry, Memorial University, St. John’s, Newfoundland,
Canada A1B 3X7. E-mail: spansare@mun.ca; Fax: (709) 737-3702;
Tel: (709) 737-8535
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2011–2015 | 2011
©

View Article Online
Scheme 1
Scheme 3
and the potassium salt of (R)-1-(4-methoxyphenoxy)-3-buten-2-
ol14 following the procedure for 9. As projected, allylation of 11
proceeded smoothly to provide the diene 12 (60%, Scheme 2) as a
single diastereomer.
converted8h to oxocine 168f which is an advanced intermediate
in the total synthesis of (+)-laurencin (Scheme 4).
Scheme 4
Conclusion
Scheme 2
In conclusion, we have established an efficient enantioselective
route to an advanced intermediate in the synthesis of (+)-
laurencin. The present route is shorter (10 steps) and provides 4 in
higher overall yield (11.3%) compared to the reported synthesis8h
(21 steps, 4.3% overall yield from commercially available starting
materials). A notable advantage of the methodology is the ready
availability of both enantiomers of ephedrine and glycidol. This
should enable the assembly of all possible stereoisomers of
disubstituted oxocines such as 4 to provide access to analogues
of laurencin and its congeners.
Medium-ring ether construction from the diene 12 was readily
achieved by ring closing metathesis with the Grubbs(II) catalyst
at ambient temperature and the spiro-oxocine 13 was obtained in
good yield (85%). Attention to experimental detail was necessary
in the following step. Normally, removal of the ephedrine portion
in morpholinones such as 13 is readily effected with dissolving
metal reduction (Na–NH3).9 In the present case, competing, albeit
slow reduction of the p-methoxyphenyl protecting group was a
distinct possibility. Indeed, we observed that benzylic C–O bond
cleavage was faster than reduction of the p-methoxyphenyl group
and a rapid quenching of the reaction (1 min) provided the hydroxy
amide 14 in excellent yield (96%, Scheme 3). Longer reaction times
resulted in partial reduction of the p-methoxyphenyl protecting
group as well. Reduction of 14 with LAH provided the amino
alcohol 15 (84%).
Experimental section
General
All reactions requiring anhydrous conditions were performed
under a positive pressure of nitrogen using oven-dried glassware
(120 ◦C) that was cooled under nitrogen. THF was distilled
from sodium benzophenone ketyl and dichloromethane was
distilled from calcium hydride. Commercial precoated silica gel
(Merck 60F-254) plates were used for TLC. Silica gel for column
chromatography was 230–400 mesh. All melting points are
The target ketone (+)-4 was readily prepared from the amino
alcohol 15 by treatment with NaIO4 (98%) followed by removal
of the p-methoxyphenyl protection with ceric ammonium nitrate
(87%). Ketone 4 provided spectroscopic data that was in agreement
with that reported8h in the literature and has previously been
2012 | Org. Biomol. Chem., 2008, 6, 2011–2015
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
uncorrected. IR spectra were recorded on a Bruker TENSOR
to provide 1 g (50%) of 9 as a yellow oil. IR (neat): 3326, 2976,
1739, 1636, 1242, 1086 cm−1; 1H NMR (500 MHz, CDCl3): d 7.36–
7.22 (m, 10H), 5.85–5.78 (m, 1H), 5.44 (d, 1H, J = 2.7), 5.08–5.02
(m, 2H), 4.90 (br s, 1H), 4.59–4.50 (AB, 2H, J = 12.1), 3.86–
3.82 (m, 1H), 3.67–3.64 (m, 1H), 3.52–3.49 (m, 1H), 3.43–3.38 (m,
2H), 2.94 (s, 3H), 2.36–2.34 (m, 2H), 1.92–1.87 (m, 1H), 1.71–1.65
(m, 1H), 1.11 (t, 3H, J = 7.3), 0.98 (d, 3H, J = 7); 13C NMR
(125.77 MHz, CDCl3): d 168.3, 138.3, 137.8, 134.5, 128.5, 128.4,
127.9, 127.8, 127.7, 126, 117.5, 98.4, 83.9, 79.1, 73.6, 72.5, 72, 59.4,
37, 33.5, 23.2, 12.3, 11.6; [a]2D3 = −105.6 (c 1, CHCl3); MS (APCI):
454.2 (M + 1, 100); HRMS (EI): m/z 453.2509 (453.2515 calc. for
C27H35NO5, M+).
1
27 spectrometer. H NMR and 13C NMR spectra were recorded
on a Bruker AVANCE-500 instrument. Coupling constants (J)
are given in Hz. Mass spectra were obtained on an Agilent 1100
series LC/MSD chromatographic system. High-resolution mass
spectra were obtained on a Waters GCT Premier Micromass mass
spectrometer. Optical rotations were measured at the sodium
D line on a JASCO-DIP 370 digital polarimeter at ambient
temperature.
(5S,6R)-4,5-Dimethyl-6-phenyl-morpholin-2,3-dione (5). To a
cold (0 ◦C), stirred solution of (1R,2S)-(−)-ephedrine hydrochlo-
ride (10 g, 0.05 mol) in dichloromethane (40 mL) was added
DMAP (0.3 g, 2.5 mmol). Triethylamine (21.1 mL, 0.15 mol)
was added, followed by dropwise addition of ethyl◦oxalyl chloride
(6.7 mL, 0.06 mol). The mixture was stirred at 0 C for 1 h and
then at ambient temperature for 48 h. Cold water was added and
the mixture was extracted with dichloromethane (3 × 50 mL). The
combined organic layers were washed with HCl (2 M, 3 × 25 mL),
dried (Na2SO4) and concentrated under reduced pressure to yield
a pale yellow solid. This was triturated with dichloromethane–
hexane (7 : 2, 3 × 15 mL) to provide 9.3 g (85%) of the dione
as a crystalline white solid that was pure by 1H NMR. This
material was used without further purification. If necessary, it
can be recrystallized from ethyl acetate–hexane. Mp: 183–184 ◦C;
[a]2D3 = −202 (c 1, CHCl3); spectroscopic data consistent with that
reported in the literature.10b
(3R,5R,6S,8R,9S)-3-Allyl-9,10-dimethyl-5-ethyl-8-phenyl-1,4,7-
trioxa-10-azaspiro[5.5]undecan-11-one (10). To a solution of 9
◦
(320 mg, 0.7 mmol) in dichloromethane (15 mL) at −78 C was
added allyltrimethylsilane (0.67 mL, 4.2 mmol) followed by BF3
etherate (0.52 mL, 4.2 mmol). The mixture was stirred at −78 ◦C
for 15 min and then warmed to ambient temperature and stirred
for 22 h. Cold water was added and the mixture was extracted
with dichloromethane (3 × 25 mL). The combined organic layers
were dried and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (1 : 3 ethyl
acetate–hexane) to provide 220 mg (90%) of 10 as a colourless oil.
IR (neat): 2925, 1663, 1496, 1042, 700 cm−1; 1H NMR (500 MHz,
CDCl3): d 7.40–7.36 (m, 3H), 7.34–7.31 (m, 1H), 5.89–5.83 (m,
1H), 5.21 (d, 1H, J = 2.3), 5.16–5.07 (m, 2H), 4.21 (dd, 1H,
J = 7.3, 5.5), 4.05–4.00 (apparent t, 1H, J = 10), 3.88–3.82 (m,
1H), 3.67 (dd, 1H, J = 11.2, 2.7), 3.46 (dq, 1H, J = 13.2, 3),
3.07 (s, 3H), 2.40–2.34 (m, 1H), 2.22–2.16 (m, 1H), 1.55–1.49
(m, 2H), 1.12 (d, 3H, J = 5.9), 0.98 (t, J = 7.3, 3H); 13C NMR
(125.77 MHz, CDCl3): d 165.1, 138, 133.8, 128.6, 128.1, 126.1,
117.3, 95.32, 80.5, 78.0, 74.7, 64.6, 59.4, 36.3, 34.1, 23.3, 12.3,
10.3; [a]2D3 = −45.9 (c 1, CHCl3); MS (APCI): 346.3 (M + 1, 100);
HRMS (EI): m/z 345.1940 (345.1940 calc. for C20H27NO4, M+).
(2S,3S,5R,6S)-2-Ethyl-6,7-dimethyl-5-phenyl-1,4-dioxa-7-azas-
piro[2.5]octan-8-one (7). To a solution of 69b (2 g, 8.2 mmol) in
dichloromethane (30 mL) was added mCPBA (1.83 g, 10.6 mmol)
◦
at −78 C and the mixture was warmed to ambient temperature
and stirred for 40 min. Saturated aqueous NaHCO3 was added,
the mixture was extracted with ethyl acetate (3 × 20 mL) and
the combined organic layers were dried and concentrated under
reduced pressure. The residue obtained was immediately subjected
to purification by flash chromatography on silica gel (3 : 1 ethyl
acetate–hexane) to give 1.7 g (80%) of 7 as a colourless gum.
IR (neat): 2976, 1669, 1294, 1195, 930, 700 cm−1; 1H NMR
(500 MHz, CDCl3): d 7.39–7.36 (m, 2H), 7.33–7.27 (m, 3H), 5.47
(d, 1H, J = 3), 3.69 (t, 1H, J = 6.5), 3.65 (dq, 1H, J = 3, 6.5),
3.11 (s, 3H), 1.91–1.80 (m, 2H), 1.12 (t, 3H, J = 7.5), 1.03 (d, 3H,
J = 6.5); 13C NMR (125.77 MHz, CDCl3): d 163.6, 136.7, 128.7,
(2S,5S,6R)-2-((R)-1-((R)-1-(4-Methoxyphenoxy)pent-4-en-2-
yloxy)propyl)-2-hydroxy-4,5-dimethyl-6
phenylmorpholin-3-one
(11). To a solution of (R)-1-(4-methoxyphenoxy)-3-buten-2-ol14
(0.70 g, 3.6 mmol) in THF (18 mL) at 0 ◦C was added KH
(2◦52 mg, 6.3 mmol). The mixture was then stirred for 10 min at
0 C and a solution of the epoxide 7 (0.80 g, 3.1 mmol) in THF
(5 mL) was added. The reaction mixture was then warmed up
to ambient temperature, stirred for 4.5 h, cold water (10 mL)
was added, and the mixture was extracted with ethyl acetate
(3 × 20 mL). The combined organic layers were dried and
concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (2 : 1 ethyl acetate–hexane)
to provide 0.73 g (50%) of 11 as a yellow oil. IR (neat): 3327,
128.2, 125.5, 82.2, 76.03, 63.5, 59.4, 34.0, 21.0, 12.5, 10.3; [a]D23
−115.5 (c 2, CHCl3); MS (APCI): 262.1 (M + 1, 100); HRMS
(CI): m/z 262.1451 (262.1443 calc. for C15H20NO3, M + H).
=
(2S,5S,6R)-2-((R)-1-((R)-1-(Benzyloxy)pent-4-en-2-yloxy)pro-
pyl)-2-hydroxy-4,5-dimethyl-6-phenylmorpholin-3-one (9). To a
solution of the alcohol 8 (0.88 g, 4.2 mmol) in THF (20 mL)
1
2936, 1633, 1507, 1230, 756 cm−1; H NMR (500 MHz, CDCl3):
◦
at 0 C was added KH (252 mg (obtained by washing a 30 wt%
d 7.37–7.31 (m, 4H), 7.30–7.26 (m, 1H), 6.85–6.81 (m, 4H),
5.82–5.74 (m, 1H), 5.40 (br s, 1H), 5.09–5.02 (m, 2H), 3.95–3.91
(m, 3H), 3.87–3.84 (m, 1H), 3.75 (s, 3H), 3.47 (dq, 1H, J = 6,
2.5), 3.06 (s, 3H), 2.42–2.32 (m, 2H), 2.03–1.97 (m, 1H), 1.85–1.79
(m, 1H), 1.10 (t, 3H, J = 8), 1.08 (d, 3H, J = 7). 13C NMR
(125.77 MHz, CDCl3): d 169, 154.0, 153.3, 137.7, 134.4, 128.5,
127.9, 126.1, 117.9, 115.7, 114.8, 98.6, 83.3, 78.0, 72.8, 69.9, 59.9,
55.9, 36.5, 33.9, 22.3, 12.4, 11.2; [a]2D3 = −60 (c 1, CHCl3); MS
(APCI): 470.2 (M + 1, 100); HRMS (EI): m/z 469.2467 (469.2464
calc. for C27H35NO6, M+).
dispersion in mineral oil with hexane), 6.3 mmol, as a suspension
in THF (2 mL)). The mixture was then stirred for 10 min at
0
◦C and a solution of the epoxide 7 (1.1 g, 4.2 mmol) in THF
(5 mL) was added. The reaction mixture was then warmed up
to ambient temperature, stirred for 4.5 h, cold water (10 mL)
was added, and the mixture was extracted with ethyl acetate
(3 × 20 mL). The combined organic layers were dried and
concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (2 : 1 ethyl acetate–hexane)
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2011–2015 | 2013
©

View Article Online
(2S,5S,6R)-2-Allyl-((R)-1-((R)-1-(4-Methoxyphenoxy)pent-4-en-
2-yloxy)propyl)-4,5-dimethyl-6-phenylmorpholin-3-one (12). To
a solution of 11 (660 mg, 1.4 mmol) in dichloromethane (15 mL)
at −78 ◦C was added allyltrimethylsilane (1.4 mL, 8.5 mmol)
followed by BF3 etherate (1.1 mL, 8.5 mmol). The mixture
was stirred at −78 ◦C for 15 min and then warmed to ambient
temperature and stirred for 18 h. Cold water was added and
the mixture was extracted with dichloromethane (3 × 25 mL).
The combined organic layers were dried and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (1 : 3 ethyl acetate–hexane) to
provide 232 mg (60%) of 12 as a colourless oil. IR (neat): 2934,
1507, 1231, 1068, 1035, 824 cm−1; 1H NMR (500 MHz, CDCl3): d
6.88–6.84 (m, 4H), 6.54 (br s, 1H), 6.07–6.02 (m, 1H), 5.91–5.85
(m, 1H), 4.27 (s, 1H), 4.03 (dd, 1H, J = 5, 9.5), 3.95 (dd, 1H, J =
4.5, 9.5), 3.85–3.81 (m, 1H), 3.78 (s, 3H), 3.63 (m, 1H), 2.85 (d,
3H, J = 4), 2.85–2.82 (m, 1H), 2.57–2.51 (m, 1H), 2.35–2.31 (m,
1H), 2.26–2.22 (m, 1H), 1.68–1.63 (m, 1H), 1.16–1.08 (m, 1H),
1.01 (t, 3H, J = 7); 13C NMR (125.77 MHz, CDCl3): d 176.3,
154.2, 153.2, 129.7, 129.4, 115.6, 115.0, 84.1, 82.3, 79.1, 71.9,
56.0, 37.8, 31.4, 26.7, 23.6, 10.9; [a]2D3 = +27 (c 1, CHCl3); MS
(APCI): 350.1 (M + 1, 100); HRMS (EI): m/z 349.1897 (349.1889
calc. for C19H27NO5, M+).
1
1643, 1508, 1230, 1043, 823 cm−1; H NMR (500 MHz, CDCl3):
(2R,3S,5Z,8R)-8-((4-Methoxyphenoxy)methyl)-2-ethyl-3,4,7,8-
tetrahydro-3-((methylamino)methyl)-2H-oxocin-3-ol (15). To a
stirred solution of 14 (180 mg, 0.52 mmol) in THF (10 mL)
at 0 ◦C was slowly added lithium aluminium hydride (157 mg,
4.1 mmol). The mixture was then brought to room temperature
and heated to reflux for 50 h. The reaction mixture was then
cooled to room temperature and 3 N HCl (5 mL) was added. The
resulting solution was washed with ethyl acetate (2 × 15 mL).
The aqueous layer was cooled (<5 ◦C), basified (pH = 10)
with 6 N sodium hydroxide and concentrated under reduced
pressure. The residual solids were extracted with ethyl acetate
(5 × 15 mL) and the combined organic layers were dried and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (1 : 3 ethyl acetate–hexane) to
provide 145 mg (84%) of 15 as a colourless oil. IR (neat): 2930,
d 7.36–7.32 (m, 3H), 7.29–7.26 (m, 2H), 6.85–6.80 (m, 4H),
6.04–5.95 (m, 1H), 5.83–5.75 (m, 1H), 5.31 (d, 1H, J = 3.5),
5.11–5.01 (m, 4H), 3.96–3.90 (m, 3H), 3.83 (m, 1H), 3.76 (s, 3H),
3.43 (dq, 1H, J = 3.5, 7), 3.05 (s, 3H), 2.68 (dd, 1H, J = 14, 7.5),
2.59 (dd, 1H, J = 14, 7.5), 2.40–2.37 (m, 2H), 1.95–1.88 (m, 1H),
1.87–1.78 (m, 1H), 1.09 (t, 3H, J = 7), 1.06 (d, 3H, J = 7); 13C
NMR (125.77 MHz, CDCl3): d 170.2, 154.0, 153.4, 138.8, 134.6,
134.5, 128.4, 127.6, 126.1, 117.9, 117.6, 115.7, 114.8, 85.4, 84.0,
77.4, 73.7, 69.8, 59.7, 55.9, 41.4, 36.2, 34.0, 22.8, 12.7, 11.3; [a]D23
−63 (c 1, CHCl3); MS (APCI): 494.2 (M + 1, 100); HRMS (EI):
m/z 493.2824 (493.2828 calc. for C30H39NO5, M+).
=
(2R,3S,6S,7R,9R,11Z)-3,4-Dimethyl-7-ethyl-9((4-methoxyphe-
noxy)methyl)-2-phenyl-1,8-dioxa-4-azaspiro[5.7]tridec-11-en-5-one
(13). To a solution of 12 (350 mg, 0.5 mmol) in dichloromethane
(290 mL) was added the Grubbs(II) catalyst (43 mg, 0.05 mmol,
10 mol%). The reaction mixture was stirred at room temperature
for 28 h and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography on silica gel
(1 : 1 ethyl acetate–hexane) to give 280 mg (85%) of 13 as a white
solid. Mp: 67–69 ◦C; IR (neat): 2958, 1646, 1507, 1230, 823 cm−1;
1H NMR (500 MHz, CDCl3): d 7.41–7.35 (m, 2H), 7.33–7.31
(m, 3H), 6.86–6.82 (m, 4H), 6.02–5.97 (m, 1H), 5.62–5.59 (m,
1H), 5.28 (d, 1H, J = 3), 4.19 (dd, 1H, J = 9, 5), 3.86 (dd, 1H,
J = 9, 7.5), 3.77 (s, 3H), 3.74–3.72 (m, 1H), 3.56–3.52 (m, 2H),
3.32 (dd, 1H, J = 13, 5.5), 3.01 (s, 3H), 2.68 (dd, 1H, J = 13,
5.5), 2.51–2.47 (m, 1H), 2.43–2.38 (m, 1H), 1.78–1.75 (m, 1H),
1
1737, 1507, 1231, 1039, 823 cm−1; H NMR (500 MHz, CDCl3):
d 6.85–6.81 (m, 4H), 5.98–5.93 (m, 1H), 5.89–5.84 (m, 1H), 3.99
(m, 1H), 3.77–3.75 (m, 2H), 3.72 (s, 3H), 3.50 (dd, 1H, J = 1.1,
10.8), 2.70 (d, 1H, J = 13), 2.69 (m, 1H), 2.58 (d, 1H, J = 13),
2.46 (s, 3H), 2.38–2.27 (m, 2H), 2.14 (dd, 1H, J = 12.5, 6.5),
1.69–1.65 (m, 1H), 1.27–1.19 (m, 1H), 1.04 (t, 3H, J = 7); 13C
NMR (125.77 MHz, CDCl3): d 154.0, 153.2, 130.1, 129.2, 115.5,
114.8, 85.4, 80.6, 76.9, 71.7, 56.5, 55.9, 37.7, 36.6, 31.4, 24.0, 11.4;
[a]2D3 = +85 (c 1, CHCl3); MS (APCI): 336.2 (M + 1, 100); HRMS
(CI): m/z 336.2193 (336.2175 calc. for C19H30NO4, M + H).
(2R,5Z,8R)-2-Ethyl-7,8-dihydro-8-(hydroxymethyl)-2H-oxocin-
3(4H)-one (4). 8hTo a stirred solution of 15 (100 mg, 0.3 mmol)
in a mixture of methanol–water (100 : 1, 4 mL) at 0 ◦C was
added NaIO4 (255 mg, 1.2 mmol). The reaction mixture was
maintained at this temperature for 15 min and then warmed to
room temperature and stirred for 2.5 h. A cold saturated aqueous
solution of sodium bicarbonate was added and the mixture was
extracted with ethyl acetate (3 × 15 mL). The combined organic
layers were dried (sodium sulfate) and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (1 : 3 ethyl acetate–hexane) to provide 85 mg (98%) of
the ketone as a colourless gum. IR (neat): 2930, 1715, 1508, 1231,
1.42–1.37 (m, 1H), 1.10 (t, 3H, J = 7.5), 0.96 (d, 3H, J = 7); 13
C
NMR (125.77 MHz, CDCl3): d 170.3, 154.0, 153.1, 138.1, 130.2,
128.7, 128.6, 127.8, 125.7, 115.4, 115.0, 87.7, 85.7, 83.4, 72.0,
71.5, 58.9, 56.0, 33.6, 32.1, 30.0, 24.9, 13.0, 11.3; [a]2D3 = +13.5
(c 1, CHCl3); MS (APCI): 466.2 (M + 1, 100); HRMS (EI): m/z
465.2524 (465.2515 calc. for C28H35NO5, M+).
(2R,3S,5Z,8R)-2-Ethyl-8-((4-methoxyphenoxy)methyl)-3,4,7,8-
tetrahydro-3-hydroxy-N-methyl-2H-oxocine-3-carboxamide (14).
To anhydrous liquid ammonia (15 mL, distilled over sodium) was
added Na metal (87 mg, 3.8 mmol) at −78 ◦C and the mixture
was stirred for 15 min. To the resulting blue solution was added
rapidly a solution of 13 (250 mg, 0.54 mmol) in anhydrous THF
(3 mL) and the mixture was stirred for 1 min. A mixture of
methanol–water (3 : 1, 5 mL) was added and the reaction mixture
was brought to ambient temperature and stirred for 30 min to
remove ammonia. The resulting solution was concentrated under
reduced pressure and the residue was purified by flash column
chromatography on silica gel (ethyl acetate) to provide 180 mg
(96%) of 14 as a colourless gum. IR (neat): 3392, 2928, 1663,
1
1044, 823 cm−1; H NMR (500 MHz, CDCl3): d 6.87–6.83 (m,
4H), 5.89–5.84 (m, 1H), 5.71–5.66 (m, 1H), 4.06 (dd, 1H, J = 9.1,
5.9), 3.97–3.90 (m, 2H), 3.82–3.78 (m, 2H), 3.78 (s, 3H), 2.82 (dd,
1H, J = 12, 4.5), 2.45 (dd, 2H, J = 7.1, 4.5), 1.79–1.73 (m, 1H),
1.63–1.57 (m, 1H), 1.02 (t, 3H, J = 7); 13C NMR (125.77 MHz,
CDCl3): d 213.8, 154.3, 153.0, 128.4, 126.5, 115.7, 114.9, 87.6,
82.1, 71.1, 56.0, 41.3, 30.4, 26.4, 10.4; [a]2D3 = +513 (c 1, CHCl3);
MS (APCI): 291.1 (M + 1, 100) HRMS (CI): m/z 290.1519
(290.1518 calc. for C17H22NO4, M+).
2014 | Org. Biomol. Chem., 2008, 6, 2011–2015
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
To a stirred solution of the ketone (30 mg, 0.1 mmol) in
acetonitrile–water (4 : 1, 2.5 mL) at 0 ◦C was added ceric ammo-
nium nitrate (164 mg, 0.3 mmol).◦The resulting orange coloured
reaction mixture was stirred at 0 C for 10 min and then diluted
with dichloromethane (10 mL). The aqueous layer was extracted
with dichloromethane (2 × 10 mL) and the combined organic
layers were dried (sodium sulfate) and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (1 : 2 ethyl acetate–hexane) to provide 20 mg (87%) of 4
as a white solid. Mp: 71–72 ◦C; IR (solid): 3440, 3026, 1710, 1645,
H. Yamashita and S. Kitagaki, J. Org. Chem., 2004, 69, 6867; (h) M. P.
Sibi, K. Patil and T. R. Rheault, Eur. J. Org. Chem., 2004, 372; (i) E.
Alcazar, J. M. Pletcher and F. E. McDonald, Org. Lett., 2004, 6, 3877;
(j) Y. Sawada, M. Sasaki and K. Takeda, Org. Lett., 2004, 6, 2277; (k) M.
Martin, M. M. Afonso, A. Galindo and J. A. Palenzuela, Synlett, 2001,
117; (l) T. Saitoh, T. Suzuki, N. Onodera, H. Sekiguchi, H. Hagiwara
and T. Hoshi, Tetrahedron Lett., 2003, 44, 2709; (m) K. R. K. Prasad
and D. Hoppe, Synlett, 2000, 1067.
4 (a) Recent reviews: J. W. Blunt, B. R. Copp, W.-P. Hu, M. H. G. Munro,
P. T. Northcote and M. R. Prinsep, Nat. Prod. Rep., 2007, 24, 31; (b) J. C.
Morris, G. M. Nicholas and A. J. Phillips, Nat. Prod. Rep., 2007, 24,
87; (c) K.-S. Yeung and I. Paterson, Chem. Rev., 2005, 105, 4237 and
references therein.
1
1095, 1063, 755 cm−1; H NMR (500 MHz, CDCl3): d 5.86–5.81
5 T. Irie, M. Suzuki and T. Masamune, Tetrahedron Lett., 1965, 6, 1091.
6 C. P. Falshaw, T. J. King, S. Imre, S. Islimyeli and R. H. Thomson,
Tetrahedron Lett., 1980, 21, 4951.
7 A. Fukuzawa, Y. Takasugi and A. Murai, Tetrahedron Lett., 1991, 32,
5597.
(m, 1H), 5.68–5.63 (m, 1H), 3.89 (dd, 1H, J = 12.5, 7.5), 3.83
(dd, 1H, J = 8, 4.5), 3.69–3.62 (m, 2H), 3.60–3.56 (m, 1H), 2.83
(dd, 1H, J = 12.5, 7.5), 2.36–2.34 (m, 2H), 2.00 (m, 1H), 1.81–
1.74 (m, 1H), 1.73–1.63 (m, 1H), 1.00 (t, 3H, J = 7.5); 13C NMR
(125.77 MHz, CDCl3): d 213.2, 128.3, 126.2, 87.0, 84.3, 66.1, 41.2,
30.2, 26.3, 10.2; [a]D23 = +610 (c 1, CHCl3) (lit.8h [a]D25 = +568 (c
0.81, CHCl3); MS (APCI): 183.1 (M − 1, 100).
8 (a) Total synthesis of racemic laurencin: K. Tsushima and A. Murai,
Tetrahedron Lett., 1992, 33, 4345; (b) Enantioselective total syntheses:
K. Fujiwara, S. Yoshimoto, A. Takizawa, S. Souma, H. Mishima, A.
Murai, H. Kawai and T. Suzuki, Tetrahedron Lett., 2005, 46, 6819; (c) S.
Baek, H. Jo, H. Kim, H. Kim, S. Kim and D. Kim, Org. Lett., 2005, 7,
75; (d) M. T. Crimmins and K. A. Emmitte, Org. Lett., 1999, 1, 2029;
(e) J. W. Burton, J. S. Clark, S. Derrer, T. C. Stork, J. G. Bendall and
A. B. Holmes, J. Am. Chem. Soc., 1997, 119, 7483; (f) M. Bratz, W. H.
Bullock, L. E. Overman and T. Takemoto, J. Am. Chem. Soc., 1995,
117, 5958; (g) Enantioselective formal syntheses: J. W. Burton, J. S.
Clark, J. Bendall, S. Derrer, T. Stork and A. B. Holmes, J. Am. Chem.
Soc., 1996, 118, 6806; (h) M. T. Mujica, M. M. Afonso, A. Galindo
and J. A. Palenzuela, J. Org. Chem., 1998, 63, 9728; (i) M. T. Crimmins
and A. L. Choy, J. Am. Chem. Soc., 1999, 121, 5653; (j) J. Krueger and
R. W. Hoffmann, J. Am. Chem. Soc., 1997, 119, 7499; (k) M. T. Mujica,
M. M. Afonso, A. Galindo and J. A. Palenzuela, Synlett, 1996, 983;
(l) Review on the synthesis of laurencin and prelaureatin: N. T. Patil
and Y. Yamamoto, Recent Res. Dev. Org. Chem., 2005, 9, 131.
9 (a) S. V. Pansare and V. A. Adsool, Org. Lett., 2006, 8, 5897; (b) S. V.
Pansare, R. G. Ravi and R. P. Jain, J. Org. Chem., 1998, 63, 4120.
10 (a) V. F. Rudchenko, V. G. Shtamburg, A. P. Pleshkova and R. G.
Kostyanovskii, Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.),
1981, 30, 825; (b) S. V. Pansare, B. A. Shinkre and A. Bhattacharyya,
Tetrahedron, 2002, 58, 8985.
11 Alternatively, 6 may also be prepared by dehydration of the hemiac-
etal obtained by reaction of (1R,2S)-ephedrine and 2-oxopentanoyl
chloride, see ref. 9b.
12 For regioselective ring opening of glucose-derived spiro epoxides under
acidic or basic conditions, see: L. Lay, F. Nicotra, L. Panza and
G. Russo, Synlett, 1995, 167. For a recent review on the chemistry
of epoxides see:; L. I. Kas’yan, A. O. Kas’yan and S. I. Okovityi,
Russ. J. Org. Chem., 2006, 42, 307.
13 Alcohol 8 was prepared from commercially available (R)-benzylglycidyl
ether according to the literature procedure: M. T. Crimmins and E. A.
Tabet, J. Am. Chem. Soc., 2000, 122, 5473.
14 Prepared from commercially available (R)-glycidol by adapting the
literature procedure: J. Cossy, F. Pradaux and S. BouzBouz, Org. Lett.,
2001, 3, 2233.
Acknowledgements
These investigations were supported by the Natural Sciences
and Engineering Research Council of Canada and the Canada
Foundation for Innovation.
References
1 (a) For reviews see: K. Fujiwara, Top. Heterocycl. Chem., 2006, 5,
97; (b) I. Nakamura and Y. Yamamoto, Chem. Rev., 2004, 104, 2127;
(c) M. C. Elliot, J. Chem. Soc., Perkin Trans. 1, 2002, 2301; (d) M. C.
Elliot and E. Williams, J. Chem. Soc., Perkin Trans. 1, 2001, 2303.
2 (a) Recent reports: N. Miyakoshi, Y. Ohgaki, K. Masui and C. Mukai,
Heterocycles, 2007, 74, 185; (b) N. Ortega, T. Martin and V. S. Martin,
Org. Lett., 2006, 8, 871; (c) C. M. Carreno, R. Des Mazery, A. Urbano,
F. Colobert and G. Solladie, Org. Lett., 2005, 7, 2039; (d) H. Lee,
H. Kim, T. Yoon, B. Kim, S. Kim, H.-D. Kim and D. Kim, J. Org.
Chem., 2005, 70, 8723; (e) G. H. Posner, M. A. Hatcher and W. A.
Maio, Org. Lett., 2005, 7, 4301; (f) I. Kadota, H. Uyehara and Y.
Yamamoto, Tetrahedron, 2004, 60, 7361; (g) R. Batchelor and J. O.
Hoberg, Tetrahedron Lett., 2003, 44, 9043; (h) S. E. Denmark and
S. M. Yang, J. Am. Chem. Soc., 2002, 124, 15196.
3 (a) Recent reports: J. W. Burton, E. A. Anderson, P. T. O’Sullivan,
I. Collins, J. E. Davies, A. D. Bond, N. Feeder and A. B. Holmes,
Org. Biomol. Chem., 2008, 6, 693; (b) S. K. Mandal and S. C. Roy,
Tetrahedron, 2007, 63, 11341; (c) S. Basu and H. Waldmann, J. Org.
Chem., 2006, 71, 3977; (d) T. K. M. Shing and Y.-L. Zhong, Synlett,
2006, 1205; (e) M. Perez, P. Canoa, G. Gomez, M. Teijeira and Y. Fall,
Synthesis, 2005, 411; (f) K. Fujiwara, A. Goto, D. Sato, H. Kawai and
T. Suzuki, Tetrahedron Lett., 2005, 46, 3465; (g) C. Mukai, M. Ohta,
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2011–2015 | 2015
©