Total synthesis of (+)-laurencin: an asymmetric alkylation-ring-closing metathesis approach to medium ring ethers.

Article abstract of DOI:10.1021/ol991201e

[formula: see text] The enantioselective total synthesis of (+)-laurencin 1 is achieved in 18 steps from (S)-(+)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone. The key steps in this synthesis are an asymmetric glycolate alkylation leading to acyl oxazolidinone 2 and a subsequent ring-closing olefin metathesis to construct the oxocene core of 1. The approach to medium ring ethers utilized in this synthesis provides a general and efficient route to the cyclic core of other marine natural products.

Full text of DOI:10.1021/ol991201e

Supporting Information
Total Synthesis of (+)-Laurencin: An Asymmetric Alkylation−Ring-Closing Metathesis
Approach to Medium Ring Ethers
Michael T. Crimmins* and Kyle A. Emmitte
Venable and Kenan Laboratories of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599-3290
cimmins@email.unc.edu
Experimental Section
Materials and Methods: General. Infrared (IR) spectra were obtained using a Perkin-
Elmer 283 infrared spectrometer. Proton and carbon nuclear magnetic resonance (1H and 13C
NMR) spectra were recorded on the following instruments: Bruker model WM-250 (1H at 250
MHz), Bruker model Avance 400 (1H at 400 MHz; 13C at 100 MHz), and Bruker model Avance
500 (1H at 500 MHz; 13C at 125 MHz). Optical rotations were determined using a Perkin-
Elmer 241 polarimeter. Thin layer chromatography (TLC) was conducted on silica gel F254
TLC plates purchased from Scientific Adsorbents, Inc. Flash chromatography was carried out
using silica gel (32 to 63µm) purchased from Scientific Adsorbents, Inc. Diethyl ether,
tetrahydrafuran (THF), and dichloromethane were dried by being passed through a column of
neutral alumina under nitrogen immediately prior to use. Alkylamines and toluene were
distilled from calcium hydride immediately prior to use. Dimethyl sulfoxide (DMSO) was
distilled under reduced pressure from calcium hydride and stored over 4Å molecular sieves.
All air and water sensitive reactions were performed in flasks flame dried under a positive flow
of nitrogen and conducted under a nitrogen atmosphere.

O
O
BnO
H
N
O
Bn
7
(4S)-4-Benzyl-3-[(2R)-2-benzyloxy-pent-4-enoyl]-oxazolidin-2-one (7). Into a flask
fitted with a low-temperature thermometer was added sodium bis(trimethylsilyl)amide (1.0 M
in toluene, 124.0 mL, 124.0 mmol). 200 mL of THF was added and the flask was cooled to –
78 ºC. (S)-(+)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone 6 (28.00 g, 86.0 mmol) in 100 mL
of THF was added via cannula at such a rate so as to maintain the reaction temperature below –
60 ºC. After stirring for 30 minutes at –78 ºC, allyl iodide (39.0 mL, 426.5 mmol) was added
via syringe. After 10 minutes the reaction was warmed to –45 ºC and stirred at that
temperature for 3.5 hours. The reaction was quenched by the addition of saturated NH4Cl and
warmed to room temperature. The THF was removed in vacuo and the remaining solution
extracted twice with 50% ethyl acetate/hexanes. The combined organic extracts were washed
with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash
1
chromatography provided 23.57 g (75%) of acyl oxazolidinone 7: H NMR (400 MHz, CDCl3)
δ 7.37-7.16 (m, 10H), 5.92 (ddt, J = 17.8, 10.1, 6.3 Hz, 1H), 5.19-5.08 (m, 3H), 4.60 (m, 1H),
4.55 (AB, JAB = 12.0 Hz, ∆νAB = 46.6 Hz, 2H), 4.15 (d, J = 11.1 Hz, 2H), 3.25 (dd, J = 13.0,
3.8 Hz, 1H), 2.69-2.50 (m, 2H), 2.67 (dd, J = 13.0, 10.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 37.2, 37.9, 55.0, 66.7, 72.6, 76.7, 118.2, 127.4, 127.8, 128.2, 128.3, 128.9, 129.3, 133.0,
135.0, 137.5, 153.0, 172.2; IR (film) 1775, 1705, 1390, 1210, 1105 cm-1; [α]24D = +94.4º (c
1.79, CH2Cl2).

OH
OBn
8
(2R)-2-Benzyloxy-pent-4-en-1-ol (8). Acyl oxazolidinone 7 (0.555 g, 1.52 mmol) and
anhydrous methanol (0.074 mL, 1.83 mmol) in 15 mL of diethyl ether were cooled to 0 ºC.
Lithium borohydride (2.0 M in THF, 0.91 mL, 1.82 mmol) was added dropwise via syringe.
After stirring 1.5 hours the reaction was quenched by the dropwise addition of 15 mL of 10%
NaOH and warmed to room temperature. After 20 minutes the reaction was extracted twice
with ethyl acetate, and the combined organic layers were dried over Na2SO4. Purification by
1
flash chromatography gave 0.259 g (89%) of primary alcohol 8: H NMR (250 MHz, CDCl3) δ
7.39-7.23 (m, 5H), 5.81 (ddt, J =17.8, 9.6, 7.3 Hz, 1H), 5.18-5.03 (m, 2H), 4.59 (AB, JAB
=
12.3 Hz, ∆νAB = 34.2 Hz, 2H), 3.75-3.48 (m, 3H), 2.47-2.23 (m, 2H), 1.90 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 35.3, 64.0, 71.5, 79.1, 117.5, 127.7, 128.5, 134.0, 138.2; IR (film) 3700-
3100 (br), 2920, 2860, 1090, 910 cm-1; [α]24D = -14.0º (c 0.75, CH2Cl2).
OH
OBn
5
(3R, 4R)-4-Benzyloxy-hept-6-en-3-ol (5). Into a flask equipped with a mechanical
stirrer and low-temperature thermometer was added 150 mL of dichloromethane and oxalyl
chloride (2.0 M in CH2Cl2, 31.6 mL, 63.20 mmol). After cooling to –78 ºC, DMSO (9.00 mL,
126.83 mmol) in 9.0 mL of dichloromethane was added dropwise via addition funnel. After
stirring for 10 minutes, alcohol 8 (11.04 g, 57.44 mmol) in 15.0 mL of CH2Cl2 was added via
addition funnel. After 15 minutes, triethyl amine (40.0 mL, 287.0 mmol) was added dropwise

via addition funnel. The cooling bath was removed and the reaction allowed to warm to room
temperature. The reaction mixture was poured into 600 mL of diethyl ether, and the organic
layer was washed with water, cold 1M HCl, saturated NaHCO3, water, and brine. The organic
layer was dried over Na2SO4 and concentrated in vacuo. The aldehyde was used immediately
without further purification.
Into a flask equipped with a mechanical stirrer was added anhydrous zinc bromide
(14.23 g, 63.19 mmol) and 200 mL of diethyl ether. The reaction was cooled to 0 ºC with
vigorous stirring. The crude aldehyde (10.93 g, 57.44 mmol) in 50 mL of diethyl ether was
added via cannula. After 5 minutes, ethyl magnesium bromide (1.0M in diethyl ether, 345.0
mL, 345.0 mmol) was added rapidly via cannula. After 1 hour, the reaction was quenched by
the careful addition of saturated NH4Cl. 10% HCl was added until all of the salts had dissolved
and the reaction mixture was poured into a separatory funnel. The layers were separated and
the aqueous layer extracted with 50% ethyl acetate/hexanes. The combined organic extracts
were washed with saturated NaHCO3, brine, and dried over Na2SO4. Concentration in vacuo
and purification by flash chromatography provided 10.47 g (83%) of secondary alcohol 5: 1H
NMR (250 MHz, CDCl3) δ 7.38-7.24 (m, 5H), 5.86 (ddt, J = 17.8, 8.7, 7.3 Hz, 1H), 5.18-5.04
(m, 2H), 4.59 (AB, JAB = 11.9 Hz, ∆νAB = 55.2 Hz, 2H), 3.46 (m, 1H), 3.34 (dt, J = 6.2, 5.0 Hz,
1H), 2.53-2.27 (m, 2H), 2.23 (d, J = 5.0 Hz, 1H), 1.64-1.37 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H) ;
13C NMR (100 MHz, CDCl3) δ 10.0, 26.2, 34.8, 72.2, 73.8, 81.2, 117.4, 127.76, 127.83, 128.4,
134.3, 138.2; IR (film) 3630-3160 (br), 2930, 2870, 1060, 905 cm-1; [α]24D = -32.4º (c 5.88,
CH2Cl2).

HO2C
O
OBn
9
[(1R, 2R)-2-Benzyloxy-1-ethyl-pent-4-enyloxy]-acetic acid (9). Sodium hydride
(60% dispersion in mineral oil, 0.978 g, 24.46 mmol) was washed twice with hexanes,
suspended in 4 mL THF, and cooled to 0 ºC. Alcohol 5 (3.59 g, 16.30 mmol) in 2 mL of THF
was added dropwise via syringe, and the reaction allowed to warm to room temperature, where
it was allowed to stir for 1 hour. In a second flask, sodium hydride (60% dispersion in mineral
oil, 0.978 g, 24.46 mmol) was washed twice with hexanes, suspended in 5 mL THF, and cooled
to 0 ºC. Bromoacetic acid (2.49 g, 17.92 mmol) in 3 mL of THF was added via syringe, and
the mixture was stirred for 10 minutes. The sodium alkoxide of alcohol 5 was then transferred
via cannula into the flask containing the sodium carboxylate of bromoacetic acid. The resultant
mixture was allowed to warm to room temperature and stirred for 84 hours. The reaction was
quenched by the slow addition of water, extracted twice with diethyl ether, and dried over
Na2SO4. The aqueous layer was acidified by the addition of 10% H2SO4, extracted three times
with ethyl acetate, and dried over Na2SO4. The diethyl ether extracts were concentrated in
vacuo and purified by flash chromatography to give 0.174g (5%) of recovered alcohol 5. The
ethyl acetate extracts were concentrated in vacuo and purified by flash chromatography to
1
provide 3.99 g (88%) of acid 9: H NMR (250 MHz, CDCl3) δ 7.39-7.22 (m, 5H), 5.83 (m,
1H), 5.17-5.04 (m, 2H), 4.65 (AB, JAB = 10.5 Hz, ∆νAB = 34.2 Hz, 2H), 4.12 (AB, JAB = 17.3
Hz, ∆νAB = 62.4 Hz, 2H), 3.57 (m, 1H), 3.31 (m, 1H), 2.54 (m, 1H), 2.18 (m, 1H), 1.56 (m,
1H), 1.48 (m, 1H), 0.92 (t, J = 7.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 8.6, 22.9, 33.7,

68.2, 72.2, 79.3, 83.4, 118.3, 128.2, 128.3, 128.5, 132.7, 136.6, 172.6; IR (film) 3700-2200
(br), 1735, 1240, 1115, 910 cm-1; [α]24D = -50.0º (c 2.17, CH2Cl2).
Bn
BnO
O
N
O
H
O
O
3
(4S)-4-Benzyl-3-[2-((1R, 2R)-2-benzyloxy-1-ethyl-pent-4-enyloxy)-acetyl]-
oxazolidin-2-one (3). To a solution of carboxylic acid 9 (0.967 g, 3.47 mmol) in 20 mL of
diethyl ether was added triethyl amine (0.53 mL, 3.80 mmol) via syringe, and the mixture was
cooled to –78 ºC. Pivaloyl chloride (0.43 mL, 3.49 mmol) was added dropwise via syringe.
After 5 minutes, the mixture was warmed to 0 ºC, where it was stirred for 1 hour and
subsequently recooled to –78 ºC. In a separate flask, (S)-(+)-4-benzyl-2-oxazolidinone (0.615
g, 3.47 mmol) was dissolved in 7 mL of THF and cooled to –78 ºC. n-Butyl lithium (1.6 M in
hexanes, 2.28 mL, 3.65 mmol) was added dropwise via syringe, and the mixture was stirred for
15 minutes. The lithiated oxazolidinone was added via cannula to the mixed anhydride, and the
reaction stirred for an additional 10 minutes before being warmed to 0 ºC, where stirring
continued for 1 hour. The reaction was quenched by the addition of water and extracted twice
with ethyl acetate. The combined organic layers were washed with brine and dried over
Na2SO4. Concentration in vacuo and purification by flash chromatography gave 1.16 g (76%)
1
of acyl oxazolidinone 3: H NMR (400 MHz, CDCl3) δ 7.38-7.12 (m, 10H), 5.89 (ddt, J = 17.4,
7.8, 6.1 Hz, 1H), 5.16-5.03 (m, 2H), 4.81 (AB, JAB = 18.2, ∆νAB = 24.3 Hz, 2H), 4.64 (m, 1H),
4.62 (AB, JAB = 12.1 Hz, ∆νAB = 20.0 Hz, 2H), 4.23-4.12 (m, 2H), 3.58 (m, 1H), 3.49 (m, 1H),
3.26 (dd, J = 12.5, 3.5 Hz, 1H), 2.67 (dd, J = 12.5, 9.0 Hz, 1H), 2.50 (m, 1H), 2.28 (m, 1H),

1.62 (m, 1H), 1.57 (m, 1H), 0.98 (t, J = 7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 10.1, 23.1,
34.7, 37.6, 54.8, 67.1, 70.7, 72.5, 80.3, 83.4, 117.0, 127.35, 127.44, 127.7, 128.3, 128.9, 129.3,
135.0, 135.1, 138.7, 153.3, 170.4; IR (film) 2940, 1790, 1725, 1400, 1270, 1135 cm-1; [α]24
+47.8º (c 1.99, CH2Cl2).
=
D
Bn
O
N
BnO
O
H
H
O
O
2
(4S)-4-Benzyl-3-[(2R)-2-((1R, 2R)-2-benzyloxy-1-ethyl-pent-4-enyloxy)-pent-4-
enoyl]-oxazolidin-2-one (2). Into a flask fitted with a low-temperature thermometer was
added sodium bis(trimethylsilyl)amide (0.75 M in toluene/THF, 6.70 mL, 5.03 mmol). 8 mL of
THF was added and the flask was cooled to –78 ºC. Acyl oxazolidinone 3 (1.10 g, 2.51 mmol)
in 10 mL of THF was added via cannula at such a rate so as to maintain the reaction
temperature below –60 ºC. After stirring for 30 minutes at –78 ºC, allyl iodide (1.15 mL, 12.58
mmol) was added via syringe. After 10 minutes the reaction was warmed to –45 ºC and stirred
at that temperature for 30 minutes. The reaction was quenched by the addition of saturated
NH4Cl and warmed to room temperature. The solution was extracted twice with 50% ethyl
acetate/hexanes. The combined organic extracts were washed with brine, dried over Na2SO4,
and concentrated in vacuo. Purification by flash chromatography provided 0.848 g (71%) of
1
diene 2: H NMR (400 MHz, CDCl3) δ 7.35-7.16 (m, 10H), 5.95-5.81 (m, 2H), 5.29 (dd, J =
7.0, 4.6 Hz, 1H), 5.16-5.01 (m, 4H), 4.66 (m, 1H), 4.53 (AB, JAB = 12.0 Hz, ∆νAB = 36.4 Hz,
2H), 4.18-4.09 (m, 2H), 3.52 (m, 1H), 3.28-3.21 (m, 2H), 2.64 (dd, J = 13.2, 9.5 Hz, 1H), 2.57-
2.49 (m, 3H), 2.22 (m, 1H), 1.70 (m, 1H), 1.48 (m, 1H), 0.96 (t , J = 7.4 Hz, 3H); 13C NMR

(100 MHz, CDCl3) δ 10.4, 22.8, 34.1, 37.9, 38.0, 55.0, 66.6, 72.4, 76.1, 79.4, 81.7, 116.7,
118.3, 127.4, 127.5, 127.8, 128.2, 128.9, 129. 4, 133.3, 135.0, 135.6, 138.6, 153.1, 172.8; IR
(film) 2940, 1785, 1720, 1395, 1220, 1110 cm-1; [α]24D = +82.5º (c 1.25, CH2Cl2).
Bn
O
N
BnO
O
H
H
O
O
10
(4S)-4-Benzyl-3-[(2R, 7R, 8R)-7-benzyloxy-8-ethyl-3,6,7,8-tetrahydro-2H-oxocine-
2-carbonyl]-oxazolidin-2-one (10). Into a flask equipped with a reflux condenser was added
diene 2 (0.819 g, 1.715 mmol) in 350 mL of dichloromethane. Nitrogen was bubbled through
the stirring solution for 20 minutes. The solution was heated to reflux and
(Cy3P)2Cl2Ru=CHPh (0.071 g, 0.0863 mmol) was added in one portion. The reaction was
stirred at 40 ºC for 3 hours and cooled to room temperature. The solution was stirred open to
air overnight and concentrated in vacuo. Purification by flash chromatography provided 0.726
1
g (94%) of oxocene 10: H NMR (400 MHz, CDCl3) δ 7.39-7.13 (m, 10H), 5.90 (m, 1H), 5.77
(m, 1H), 4.93 (d, J = 8.7 Hz, 1H), 4.68 (m, 1H), 4.56 (AB, JAB = 12.5 Hz, ∆νAB = 101.3 Hz,
2H), 4.27-4.14 (m, 2H), 3.58-3.49 (m, 2H), 3.25 (dd, J = 13.2, 3.7 Hz, 1H), 2.82-2.70 (m, 2H),
2.78 (dd, J = 13.2, 9.1 Hz, 1H), 2.44 (m, 1H), 2.30 (ddd, J = 14.0, 8.2, 1.2 Hz, 1H), 1.77 (m,
1H), 1.53 (m, 1H), 0.77 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 10.4, 24.9, 29.0,
32.0, 37.7, 55.3, 66.6, 71.1, 79.5, 80.3, 84.5, 127.38, 127.43, 127.8, 128.2, 128.7, 128.9, 129.4,
130.0, 135.0, 138.6, 153.1, 170.7; IR (film) 2980, 2950, 1790, 1725, 1400, 1220, 1080 cm-1;
[α]24D = +67.3º (c 1.27, CH2Cl2).

Bn
O
N
HO
O
H
H
O
O
11
(4S)-4-Benzyl-3-[(2R, 7R, 8R)-8-ethyl-7-hydroxy-3,6,7,8-tetrahydro-2H-oxocine-2-
carbonyl]-oxazolidin-2-one (11). To a solution of benzyl ether 10 (0.218 g, 0.485 mmol) in 8
mL of dichloromethane and 0.8 mL of pH 7 buffer solution, was added DDQ (0.440 g, 1.938
mmol) in one portion. The mixture was allowed to stir for 15 hours and was poured into ethyl
acetate and saturated NaHCO3. The layers were separated, and the aqueous layer extracted
twice with ethyl acetate. The combined organic layers were dried over Na2SO4. Concentration
1
in vacuo and purification by flash chromatography gave 0.145 g (83%) of alcohol 11: H NMR
(400 MHz, CDCl3) δ 7.34-7.15 (m, 5H), 5.90-5.78 (m, 2H), 5.03 (dd, J = 8.3, 2.5 Hz, 1H), 4.62
(m, 1H), 4.28 (dd, J = 8.7, 8.3 Hz, 1H), 4.21 (dd, J =8.7, 3.7 Hz, 1H), 3.72 (s, 1H), 3.51 (m,
1H), 3.25 (dd, J = 13.2, 4.1 Hz, 1H), 2.78 (dd, J = 13.2, 9.1 Hz, 1H), 2.67- 2.54 (m, 2H), 2.44-
2.32 (m, 2H), 1.94 (s, 1H), 1.71 (m, 1H), 1.54 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 10.3, 25.2, 31.9, 33.6, 37.9, 55.1, 66.8, 74.1, 78.7, 83.8, 127.5, 128.1, 129.0,
129.4, 130.3, 134.9, 153.0, 171.1; IR (film) 3740-3160 (br), 2980, 1790, 1720, 1400, 1120,
1080 cm-1; [α]24D = +84.5º (c 0.85, CH2Cl2).
Bn
O
N
(i-Pr)3SiO
O
H
H
O
O
12
(4S)-4-Benzyl-3-[(2R, 7R, 8R)-8-ethyl-7-(tri-iso-propylsilanyloxy)-3,6,7,8-
tetrahydro-2H-oxocine-2-carbonyl]-oxazolidin-2-one (12). A solution of alcohol 11 (0.240

g, 0.668 mmol) in 5 mL of dichloromethane was cooled to 0 ºC. 2,6-lutidine (0.23 mL, 1.975
mmol) was added via syringe followed by the dropwise addition of tri-iso-propylsilyl
trifluoromethanesulfonate (0.27 mL, 1.005 mmol). The reaction was warmed to room
temperature and stirred for 2 hours. The mixture was poured into 30% ethyl acetate/hexanes
and washed with 1M HCl, saturated NaHCO3, and brine. The organic layer was dried over
Na2SO4 and concentrated in vacuo. Purification by flash chromatography provided 0.345 g
1
(100%) of silyl ether 12: H NMR (400 MHz, CDCl3) δ 7.35-7.17 (m, 5H), 5.87 (m, 1H), 5.75
(m, 1H), 4.88 (d, J = 10.2 Hz, 1H), 4.72 (m, 1H), 4.26 (dd, J = 9.8, 9.3 Hz, 1H), 4.20 (dd, J =
9.3, 3.3 Hz, 1H), 3.96 (m, 1H), 3.43 (m, 1H), 3.27 (dd, J = 13.3, 3.0 Hz, 1H), 2.84 (q, J = 11.1
Hz, 1H), 2.78 (dd, J = 13.3, 9.2 Hz, 1H), 2.71 (m, 1H), 2.27 (dd, J = 12.6, 7.6 Hz, 1H), 2.25 (m,
1H), 1.75 (m, 1H), 1.46 (m, 1H), 1.07 (s, 21H), 0.84 (t, J = 7.4 Hz, 3H) ; 13C NMR (100 MHz,
CDCl3) δ 10.8, 12.9, 18.3, 18.4, 25.3, 32.6, 33.8, 37.8, 55.2, 66.7, 75.9, 79.9, 85.6, 127.4,
128.3, 128.9, 129.4, 130.1, 135.0, 153.1, 171.4; IR (film) 2950, 1785, 1720, 1390, 1210, 1085
cm-1; [α]24D = +67.4º (c 1.59, CH2Cl2).
OH
(i-Pr)3SiO
O
H
H
[(2R, 3R, 8R)-8-Ethyl-7-(tri-iso-propylsilanyloxy)-3,6,7,8-tetrahydro-2H-oxocin-2-
yl]-methanol. Acyl oxazolidinone 12 (0.345 g, 0.669 mmol) and anhydrous methanol (0.032
mL, 0.790 mmol) in 5 mL of diethyl ether were cooled to 0 ºC. Lithium borohydride (2.0 M in
THF, 0.40 mL, 0.800 mmol) was added dropwise via syringe. After stirring 1 hour the reaction
was quenched by the dropwise addition of 5 mL of 10% NaOH and warmed to room
temperature. After 20 minutes the reaction was extracted with 30% ethyl acetate/hexanes, the

organic layer washed with brine, and the combined aqueous layers extracted with 30% ethyl
acetate/hexanes. The combined organic layers were dried over Na2SO4. Concentration in
1
vacuo and purification by flash chromatography gave 0.207 g (90%) of the primary alcohol: H
NMR (400 MHz, CDCl3) δ 5.76 (m, 1H), 5.67 (m, 1H), 3.88 (ddd, J = 11.2, 5.3, 2.5 Hz, 1H),
3.56-3.48 (m, 2H), 3.42 (m ,1H), 3.35 (m, 1H), 2.73 (q, J = 11.4 Hz, 1H), 2.43-2.32 (m, 2H),
2.19 (ddd, J = 12.0, 6.2, 5.9 Hz, 1H), 1.90 (ddd, J = 13.3, 8.6, 0.9 Hz, 1H), 1.67 (m, 1H), 1.48
(m, 1H), 1.06 (s, 21H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 11.1, 13.0,
18.3, 18.4, 26.0, 31.1, 33.6, 66.3, 76.0, 81.9, 83.7, 129.0,129.4; IR (film) 3700-3120 (br), 2960,
1470, 1250, 1080, 890 cm-1; [α]24D = -27.6º (c 1.82, CH2Cl2).
CHO
(i-Pr)3SiO
O
H
H
4
(2R, 3R, 8R)-8-Ethyl-7-(tri-iso-propylsilanyloxy)-3,6,7,8-tetrahydro-2H-oxocine-2-
carbaldehyde (4). Into a flask was added 3 mL of dichloromethane and oxalyl chloride (2.0 M
in CH2Cl2, 0.12 mL, 0.240 mmol). After cooling to –78 ºC, DMSO (0.035 mL, 0.493 mmol)
was added dropwise via syringe. After stirring for 10 minutes, primary alcohol [(2R, 3R, 8R)-
8-Ethyl-7-(tri-iso-propylsilanyloxy)-3,6,7,8-tetrahydro-2H-oxocin-2-yl]-methanol (0.0523 g,
0.153 mmol) in 2 mL of CH2Cl2 was added dropwise via syringe. After 20 minutes, triethyl
amine (0.11 mL, 0.789 mmol) was added dropwise via syringe. The cooling bath was removed
and the reaction allowed to warm to room temperature. The reaction mixture was poured into
25 mL of ethyl acetate, and the organic layer was washed with water, cold 1M HCl, saturated
NaHCO3, water, and brine. The organic layer was dried over Na2SO4 and concentrated in
1
vacuo. Filtration through a short plug of silica gel gave 0.0504 g (97%) of aldehyde 4: H

NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 5.82-5.69 (m, 2H), 3.94 (ddd, J = 11.8, 5.6, 3.2 Hz,
1H), 3.54 (dd, J = 10.2, 3.2 Hz, 1H), 3.41 (dt, 9.6, 3.2 Hz, 1H), 2.73 (q, J = 10.9 Hz, 1H), 2.48-
2.33 (m, 2H), 2.25 (dt, J = 11.8, 6.4 Hz, 1H), 1.84 (m, 1H), 1.44 (m, 1H), 1.06 (s, 21H), 0.94 (t,
J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 11.1, 12.9, 18.27, 18.33, 25.9, 29.8, 33.8, 76.2,
86.1, 86.6, 128.1, 130.2, 203.4.
i-Bu
S
N
(i-Pr)3SiO
O
H
H
OH O
S
15
(3R)-3-[(2R, 7R, 8R)-8-Ethyl-7-(tri-iso-propylsilanyloxy)-3,6,7,8-tetrahydro-2H-
oxocin-2-yl]-3-hydroxy-1-[(4S)-4-(iso-butyl)-2-thioxo-thiazolidin-3-yl]-propan-1-one (15).
(S)-(+)-3-Acetyl-4-(iso-butyl)-2-thiazolidinethione (0.407 g, 1.872 mmol) in 8 mL of
dichloromethane was cooled to –78 ºC. Titanium tetrachloride (0.18 mL, 1.641 mmol) was
added via syringe. After 5 minutes, di-iso-propylethylamine (0.29 mL, 1.665 mmol) was added
dropwise via syringe. The dark red mixture was allowed to stir for 20 minutes. Aldehyde 4
(0.228 g, 0.669 mmol) in 3 mL of dichloromethane was added via syringe. After 20 minutes,
the reaction was quenched by the addition of half saturated NH4Cl and warmed to room
temperature. The mixture was poured into brine and extracted twice with dichloromethane.
The combined organic layers were dried over Na2SO4. Concentration in vacuo and purification
by flash chromatography provided 0.073 g (19.6%) of the minor aldol product 16 and 0.238 g
1
(63.8%) of the major aldol product 15: H NMR (400 MHz, CDCl3) δ 5.78 (m, 1H), 5.67 (m,
1H), 5.37 (ddd, J = 9.2, 3.7, 3.1 Hz, 1H), 4.13 (m, 1H), 3.88 (ddd, J = 11.2, 5.6, 2.5 Hz, 1H),
3.55 (dd, J = 10.6, 7.2 Hz, 1H), 3.49 (dd, J = 18.0, 3.1 Hz, 1H), 3.43 (m, 1H), 3.37 (dd, J =
18.0, 9.2, Hz, 1H), 3.24 (dd, J = 9.9, 4.4 Hz, 1H), 2.89 (s, 1H), 2.89 (d, J = 10.6 Hz, 1H), 2.61

(q, J = 10.6 Hz, 1H), 2.54 (m, 1H), 2.21 (m, 1H), 2.07 (dd, J = 15.1, 8.6 Hz, 1H), 1.90 (m, 1H),
1.74-1.46 (m, 4H), 1.05 (s, 21H), 0.99 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.2 Hz, 3H), 0.89 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 11.0, 13.1, 18.29, 18.34, 21.3, 23.6, 25.4, 25.7,
30.9, 33.2, 33.5, 39.5, 43.1, 66.2, 70.8, 75.5, 82.7, 83.9, 129.1, 129.5, 172.1, 201.6; IR (film)
3700-3100 (br), 2960, 1700, 1470, 1345, 1275, 1165, 1080 cm-1; [α]24D = +129.4º (c 1.97,
CH2Cl2).
(i-Pr)3SiO
O
H
H
OH
Si(i-Pr)3
20
(E), (1R)-1-[(2R, 7R, 8R)-8-Ethyl-7-(tri-iso-propylsilanyloxy)-3,6,7,8-tetrahydro-2-
H-oxocin-2-yl]-6-(tri-iso-propylsilanyl)-hex-3-en-5-yn-1-ol (20). Alcohol 15 (0.182 g,
0.326mmol) in 5 mL of THF was cooled to –78 ºC. Di-iso-butylaluminum hydride (1.0 M in
hexanes, 0.72 mL, 0.720 mmol) was added dropwise via syringe. After 5 minutes, the reaction
was checked by TLC, and an additional amount of (i-Bu)2AlH (0.10 mL, 0.10 mmol) was
added dropwise via syringe. This process was repeated once more until the reaction was
judged complete by TLC. The reaction was quenched by the dropwise addition of 1 mL of
methanol. After warming to room temperature, 6 mL of saturated sodium potassium tartrate
was added, and the mixture was stirred for 20 minutes. The mixture was poured into brine and
extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4.
Concentration in vacuo and purification by flash chromatography gave an inseparable mixture
of (S)-4-(iso-butyl)-2-thiazolidinethione and the desired aldehyde. The mixture was carried on
the next step.

Phosphonium salt 19 (0.701 g, 1.304 mmol) in 7 mL of THF was cooled to –50 ºC. n-
Butyl lithium (1.42 M in hexanes, 0.87 mL, 1.235 mmol) was added dropwise via syringe.
The bright yellow mixture was stirred for 30 minutes. The aldehyde (0.125 g, 0.326 mmol) in
3 mL of THF was added via syringe. After 10 minutes, the reaction was warmed to 0 ºC,
where it was stirred for 1 hour. The reaction was quenched with saturated NH4Cl and warmed
to room temperature. Enough water to dissolve the salts was added, and the mixture was
poured into brine and extracted twice with 50% ethyl acetate/hexanes. The combined organic
layers were dried over Na2SO4. Concentration in vacuo and purification by flash
1
chromatography provided 0.135 g (74%) of enyne 20: H NMR (400 MHz, CDCl3) δ 6.27 (dt,
J = 15.5, 6.8 Hz, 1H), 5.82-5.63 (m, 2H), 5.60, (d, J = 15.5 Hz, 1H), 3.90 (ddd, J = 11.9, 4.1,
2.1 Hz, 1H), 3.52 (m, 1H), 3.43 (ddd, J = 8.2, 5.3, 2.1 Hz, 1H), 3.10 (dd, J = 10.3, 5.3 Hz, 1H),
2.86 (d, J = 4.1 Hz, 1H), 2.71 (q, J = 10.3 Hz, 1H), 2.51-2.35 (m, 2H), 2.32-2.17 (m, 2H), 2.02
(dd, J = 13.2, 8.2 Hz, 1H), 1.70-1.48 (m, 2H), 1.04 (s, 21H), 1.03 (s, 21H), 0.89 (t, J = 7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 10.9, 11.25, 11.28, 13.1, 18.29, 18.33, 18.6, 25.7, 31.2,
33.5, 37.4, 73.4, 75.4, 83.1, 83.7, 89.4, 105.6, 112.2, 129.0, 129.6, 141.5; IR (film) 3700-3240
(br), 2950, 2140, 1465, 1080, 880 cm-1; [α]24D = -25.9º (c 0.95, CH2Cl2).
(i-Pr)3SiO
O
H
H
OAc
Si(i-Pr)3
(E), (1R)-Acetic acid 1-[(2R, 7R, 8R)-8-Ethyl-7-(tri-iso-propylsilanyloxy)-3,6,7,8-
tetrahydro-2-H-oxocin-2-yl]-6-(tri-iso-propylsilanyl)-hex-3-en-5-ynyl ester. Alcohol 20
(0.091 g, 0.162 mmol) was dissolved in 4 mL of dichloromethane. Pyridine (0.39 mL, 4.827
mmol) was added via syringe followed by DMAP (0.002 g, 0.0164 mmol). Acetic anhydride

(0.23 mL, 2.438 mmol) was added via syringe, and the mixture was stirred for 14 hours at room
temperature. The reaction mixture was poured into 50% ethyl acetate/hexanes and washed with
1M HCl, saturated NaHCO3, and brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo. Purification by flash chromatography provided 0.095 g, (97%) of the
1
acetate: H NMR (400 MHz, CDCl3) δ 6.10 (dt, J = 15.5, 7.2 Hz, 1H), 5.77-5.62 (m ,2H), 5.57
(d, J = 15.5 Hz, 1H), 4.98 (dt, J = 8.7, 4.3 Hz, 1H), 3.88 (ddd, J = 11.2, 4.7, 2.9 Hz, 1H), 3.32
(dd, J = 11.2, 4.7 Hz, 1H), 2.69 (q, J = 11.2 Hz, 1H), 2.57 (dddd, J = 15.1, 6.2, 2.9, 1.5 Hz,
1H), 2.46-2.30 (m, 2H), 2.18 (m, 1H), 2.06-1.97 (m, 2H), 2.04 (s, 3H), 1.62 (m, 1H), 1.45 (m,
1H), 1.06 (s, 21H), 1.05 (s, 21H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 10.9,
11.25, 11.28, 13.1, 18.27, 18.33, 18.6, 21.1, 25.7, 29.4, 33.0, 33.6, 74.6, 75.7, 80.3, 84.6, 89.6,
105.5, 112.6, 129.0, 129.7, 140.8, 170.5; IR (film) 2960, 1750, 1470, 1240, 1090, 890 cm-1;
[α]24D = -17.1º (c 0.95, CH2Cl2).
HO
O
H
OAc
H
21
(E), (1R)-Acetic acid 1-[(2R, 7R, 8R)-8-Ethyl-7-hydroxy-3,6,7,8-tetrahydro-2-H-
oxocin-2-yl]-6-hex-3-en-5-ynyl ester (21). (E), (1R)-Acetic acid 1-[(2R, 7R, 8R)-8-Ethyl-7-
(tri-iso-propylsilanyloxy)-3,6,7,8-tetrahydro-2-H-oxocin-2-yl]-6-(tri-iso-propylsilanyl)-hex-3-
en-5-ynyl ester (0.108 g, 0.178 mmol) in 4 mL of THF was cooled to 0 ºC.
Tetrabutylammonium fluoride (1.0 M in THF, 0.41 mL, 0.410 mmol) was added dropwise via
syringe. The reaction was stirred for 30 minutes at 0 ºC and subsequently warmed to room
temperature, where it was stirred for an additional hour. The mixture was poured into saturated
NH4Cl and extracted three times with dichloromethane. The organic layers were dried over

Na2SO4 and concentrated in vacuo. Purification by flash chromatography provided 0.050 g
1
(96%) of alcohol 21: H NMR (400 MHz, CDCl3) δ 6.13 (dt, J = 15.4, 7.7 Hz, 1H), 5.79-5.67
(m, 2H), 5.51 (ddd, J = 15.4, 2.3, 1.3 Hz, 1H), 4.96 (dt, J = 8.2, 4.6 Hz, 1H), 3.65 (m, 1H), 3.43
(m, 1H), 3.37 (m, 1H), 2.80 (d, J = 2.3 Hz, 1H), 2.55-2.25 (m, 5H), 2.11 (ddd, J = 14.0, 7.8, 2.3
Hz, 1H), 2.04 (s, 3H), 1.70 (m, 1H), 1.67-1.47 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 10.5, 21.0, 25.5, 29.8, 33.5, 34.1, 73.6, 74.3, 76.7, 80.5, 81.9, 83.1, 111.5,
128.8, 129.5, 141.2, 170.4; IR (film) 3720-3100 (br), 3300, 2940, 1740, 1375, 1140, 1070 cm-1;
[α]24D = -20.6º (c 0.93, CH2Cl2).
Br
O
H
OAc
H
1
(+)-Laurencin (1). Alcohol 21 (0.0250 g, 0.0855 mmol) and carbon tetrabromide
(0.142 g, 0.428 mmol) were dissolved in 3 mL of toluene. Trioctyl phosphine (0.38 mL, 0.852
mmol) was added via syringe. After 15 minutes the reaction vessel was lowered into a 70 ºC
oil bath, and the reaction was stirred at that temperature for 3.5 hours. After cooling to room
temperature, the mixture was concentrated in vacuo. Purification by flash chromatography
1
provided 0.0175 g (58%) of (+) Laurencin 1: H NMR (500 MHz, CDCl3) δ 6.14 (dt, J = 16.1,
7.3 Hz, 1H), 5.96-5.83 (m, 2H), 5.51 (dd, J = 16.1, 1.7 Hz, 1H), 4.98 (dt; J = 8.9, 4.5 Hz, 1H),
4.06 (dt, J = 9.9, 3.4 Hz, 1H), 3.41 (ddd, J = 9.9, 7.4, 2.6 Hz, 1H), 3.37 (dd, J = 10.5, 4.5 Hz,
1H), 3.14 (ddd, J = 14.2, 8.6, 3.4 Hz, 1H), 2.80 (d, J = 1.7 Hz, 1H), 2.52-2.28 (m, 4H), 2.06 (m,
1H), 2.06 (s, 3H), 1.93 (ddq, J = 14.5, 7.4, 2.6 Hz, 1H), 1.55 (dqu, J = 14.5, 7.4 Hz, 1H), 0.96
(t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 9.3, 21.0, 25.8, 29.7, 32.3, 33.8, 56.0, 74.0,

76.7, 81.4, 81.8, 84.6, 111.6, 129.0, 129.2, 141.1, 170.3; IR (film) 3300, 2940, 1745, 1375,
1240, 1075, 965 cm-1; [α]24D = +51.7º (c 0.72, CHCl3).