Total synthesis of RK-397

Article abstract of DOI:10.1021/ja052226d

An enantioselective synthesis of the polyene macrolide RK-397 is described. The use of the same eight-carbon building block twice for the construction of the polyol chain allowed for a highly convergent synthesis. The synthesis highlights stereoselective vinylogous aldol addition using a chiral bisphosphoramide as well as a sequential palladium-catalyzed cross-coupling reaction for the preparation of key fragments. Copyright

Full text of DOI:10.1021/ja052226d

Denmark and Fujimori
S1
Total Synthesis of RK-397
Scott E. Denmark and Shinji Fujimori
Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
SUPPORTING INFORMATION
Table of Contents
Page
S1
General Experimental
Literature Preparations
S3
Synthesis Scheme
S3
Experimental Procedures and Configurational Assignments
Comparison of Natural and Synthetic RK-397
References
S5
S44
S50
General Experimental
1
13
31
1
H, C and P NMR spectra were recorded on Varian Unity-400 (400 MHz H, 100
13
MHz C, 162 MHz P), Unity-500 (500 MHz H, 125 MHz C, 202 MHz P) and Varian
31
1
13
31
1
Unity Inova 500 (500 MHz H) spectrometers in deuterochloroform unless otherwise stated.
Data are reported in the following order: chemical shift in ppm (δ); multiplicities are indicated
(br (broadened), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet)); coupling constants,
1
13
J, are reported in hertz (Hz); integration is provided; and assignment is indicated. H and C
NMR assignments are corroborated by 2D experiments (HETCOR and COSY). Spectra are
available on request from denmark@scs.uiuc.edu. Mass spectrometry was performed by the
University of Illinois Mass Spectrometry Center. Electron impact (EI) spectra were performed
on a Micromass 70-VSE spectrometer, chemical ionization (CI) spectra were obtained on a
Micromass 70-VSE spectrometer using methane as the carrier gas, field ionization (FI) spectra
were obtained from Micromass 70-VSE spectrometer, electrospray ionization (ESI) spectra were
obtained from Micromass Q-TOF spectrometer. Data are reported in the form of m/z (intensity
relative to base peak = 100). Infrared spectra (IR) were recorded on a Mattson Galaxy 5020

Denmark and Fujimori
S2
spectrophotometer. Peaks are reported in cm-1 with indicated intensities: s (strong, 67 – 100%
absorption), m (medium, 34 – 66%), w (weak, 0 – 33%). UV/Vis spectrum was obtained from
HP8453 spectrophotometer. Optical rotations were measured on a Jasco DIP-360 digital
polarimeter and are reported in the standard format for [α]. The CD spectrum was obtained with
Jasco J-720 spectropolarimeter. Elemental analyses were performed by the University of Illinois
Microanalytical Service Laboratory.
Analytical thin-layer chromatography was performed on Merck silica gel plates with F-
254 indicator. Visualization was accomplished by UV light, iodine, potassium permanganate
solution (KMnO4), phosphomolybdic acid stain(PMA), p-anisaldehyde stain or
dinitrophenylhydrazine (DNP) solution. Column chromatography was performed by the method
of Still1 with 32-63 mm silica gel (Merck). Bulb-to-bulb distillations were performed on a Büchi
GKR-50 Kugelrohr and boiling points (bp) correspond to uncorrected, air bath temperatures.
Analytical supercritical fluid chromatography (SFC) was performed on a Berger Instruments
packed-column SFC with built in photometric detector. Analytical columns used were Daicel
Chiralpak AD and AS, Chiralcel OJ and OD and Regis (R,R)-Welk-01. Analytical and
preparative HPLC were performed on Rainin Model SD 200 equipped with UV absorbance
detector (Model UV 1) at a wavelength of 360 nm. The products were analyzed and purified on
Vydac C-18 (analytical column, 250 x 4.6 mm; preparative column, 250 x 22 mm). Products
were eluted with 40/60 to 20/80 water/methanol with flow rates of 1 mL/min for analytical and 8
mL/min for preparative runs. Melting points (mp) were determined in sealed capillary tubes on a
Thomas-Hoover melting point apparatus and are corrected.
All reactions were performed in oven (140 °C) and/or flame-dried glassware under an
atmosphere of dry argon, unless otherwise stated. All reaction temperatures correspond to
internal temperatures measured by Teflon-coated thermocouples unless otherwise noted.
Solvents for extraction and chromatography were technical grade and distilled from the indicated
drying agents: dichloromethane (CH Cl ), pentane, hexane: CaCl ; ethyl acetate (EtOAc):
2
2
2
K CO ; acetone and methanol (MeOH) were reagent grade. n-Butyllithium was titrated
2
3
according to the method of Gilman.2 “Brine” refers to a saturated solution of NaCl. Polymer-
bound piperidine (200 – 400 mesh, 3.0 mmol/g loading, 1% cross-lined with divinylbenzene)
was purchased from Aldrich and used as received.

Denmark and Fujimori
S3
Literature Preparations
The following compounds were prepared by literature methods: 3-benzyldimethylsilyl-
propargyl alcohol (7)3, 1-tert-butylsilyloxy-1-ethoxy-1,3-butadiene (6)4, (2R,3R)-3-p-
methoxybenzyloxy-2,4-dimethylpentanal (10)5, 1-dimethylhydroxylsilyl-4-benzyldimethylsilyl-
1,3-butadiene (17)6, 3-iodo-1-tetrahydropyranyloxy-2-propene (18)7, ethyl 3-iodoacrylate8.
Tetraenephosphonate 1 was prepared from THP ether 20 according to the procedure
described by Mori et al.9
Scheme 1. Synthesis of RK-397. Characterized compounds not appearing in the text are shown
in bold italic type.
O
OH
O
BnMe2Si
BnMe2Si
OH
OH
BnMe2Si
Ph
H
BnMe2Si
BnMe2Si
OEt
7
22
5
4
Ph
Ph
O
O
O
O
O
O
O
O
O
OMe
BnMe2Si
N
BnMe2Si
Me
OEt
Me
2
23
8
PMBO
O
PMBO
PMBO
Me
PMBO
Me
Me
Me
COOMe
CHO
H
OH
Me Me
10
Me Me
Me Me
Me Me
24
25
3
SiMe2Bn
HOMe2Si
I
17
+
THPO
SiMe2Bn
THPO
COOEt
COOEt
OTHP
19
20
1
18
(EtO)2OP

Denmark and Fujimori
S4
Scheme 2. Synthesis of RK-397 (continued).
Me
Ph
OPMB
Me
Me
PMBO
Me
OH
O
O
O
SiMe2Bn
SiMe2Bn
O
O
O
O
26
Me Me
12
BnMe2Si
Ph
Ph
O
Ph
Me
Me
OPMB
OPMB
O
Me
Me
14
Me
Me
H
O
O
O
O
O
O
O
O
O
OH
O
15
Ph
Ph
Ph
Ph
BnMe2Si
O
Ph
O
O
O
Ph
Me
Me
OPMB
O
OPMB
H
Me
Me
Me
Me
O
O
O
O
O
O
O
O
O
O
O
O
27
28
Me Me
Me Me
Ph
Ph
Ph
Ph
O
Ph
O
O
Ph
EtOOC
i-Pr
OH
Me
O
OH
H
O
Me
Me
Me
O
O
O
O
O
O
O
O
O
O
O
O
21
16
Me Me
Me Me
Ph
Ph
Ph
Ph
O
O
Ph
Me
O
Me
OH
OH
O
O
Me
Me
O
Me
Me
O
O
O
O
O
O
29
OH OH OH OH OH OH
Me Me
Ph
Ph
RK-397

Denmark and Fujimori
S5
Experimental Procedures
(E)-3-Benzyldimethylsilyl-2-propen-1-ol (22)
3
1
7
5
2
BnMe2Si
SMEAH
Et2O
6
8
Si
Me Me
OH
OH
9
4
7
22
To a 500-mL 3-neck flask equipped with a 250-mL, pressure-equalized addition funnel, a
septum (pierced with thermocouple probe), a gas inlet and a magnetic stir bar were placed
sodium methoxyethoxyaluminium hydride (40.8 mL, 136 mmol, 1.25 equiv) and ether (100 mL).
The solution was cooled to 0 oC using an ice bath. To the solution was added solution of 7 (22.3
g, 109 mmol) in 30 mL of ether dropwise over 1 h maintaining the internal temperature below 5
oC. After the addition, the reaction mixture was warmed to rt and was stirred for 1 h. The
o
reaction mixture was cooled to 0 C using an ice bath. The reaction mixture was carefully
o
quenched with 1.8 M H2SO4 (200 mL) maintaining the internal temperature below 10 C. The
biphasic mixture was transferred to a 1-L separatory funnel, and the phases were separated. The
aqueous layer was extracted with pentane (2 x 200 mL). The combined organic layers were
washed with saturated NaHCO3 (2 x 100 mL) and with brine (100 mL). The solution was dried
over Na2SO4 and was concentrated under reduced pressure. The residue was distilled to afford
16.6 g (80.6 mmol, 74%) of 22 as a clear, colorless oil.
Data for 22:
bp:
1H NMR:
125 oC (0.5 mmHg)
(500 MHz, CDCl3)
7.22 (t, J = 7.5, 2 H, 2 x HC(8)); 7.07 (t, J = 7.5, 1 H, HC(9)); 6.99 (d, J = 7.0, 2
H, 2 x HC(7)); 6.16 (dt, J = 18.5, 4.3, 1 H, HC(2)); 5.92 (dt, J = 18.5, 1.8, 1 H,
HC(3)); 4.18 (m, 2 H, H2C(1)), 2.14 (s, 2 H, H2C(5)); 1.36 (t, J = 6.0, 1 H, HO);
0.06 (s, 6 H, 2 x H3C(4))
13C NMR:
(126 MHz, CDCl3)
146.02 (C(2)); 139.83 (C(6)); 128.22 (2 x C(8)); 128.11 (2 x C(7)); 127.30 (C(3));

Denmark and Fujimori
S6
124.00 (C9)); 65.42 (C(1)); 25.37 C(5)); -3.50 (C4))
(neat)
IR:
3368 (br, s); 3081 (m); 3024 (m); 2955(s); 2917(s); 1618 (m); 1600 (m); 1492 (s);
1451(m); 1407 (w); 1248 (m); 1207 (m); 1154 (m); 1057 (m)
(FI)
MS:
206 (100, M+); 170 (12); 156 (10); 126 (10); 115 (10); 114 (13); 60 (17)
Rf 0.28 (hexane/EtOAc, 1/1) [silica gel, KMnO4]
C12H18OSi (206.36)
TLC:
Analysis:
Calcd:
Found:
C, 69.84%; H, 8.39%
C, 69.67%; H, 8.54%
(E)-3-Dimethylsilyl-2-propenal (5)
DMSO, (COCl2)
Et3N
O
3
7
5
2
6
8
1
Si
H
BnMe2Si
OH
CH2Cl2
Me Me
9
4
22
5
In a 500-mL, Schlenk flask were placed oxalyl chloride (10.2 mL, 117 mmol, 1.5 equiv)
o
and dichloromethane (200 mL). The solution was cooled to –70 C (internal temperature) using
an isopropanol/dry ice bath. To the solution was added dimethyl sulfoxide (13.8 mL, 194 mmol,
o
2.5 equiv) dropwise maintaining internal temperature below –50 C over 20 min. The reaction
mixture was stirred for 10 min. To the reaction mixture was added solution of 22 (16.0 g, 77.7
mmol) in 50 mL of dichloromethane dropwise over 20 min maintaining internal temperature
o
below –50 C. The reaction mixture was stirred for 20 min. To the reaction mixture was added
triethylamine (38.0 mL, 272 mmol, 3.5 equiv) dropwise over 30 min maintaining internal
o
temperature below –30 C. The reaction mixture was stirred for 30 min at –70 C and for 1 h
O
o
after warming to 0 C. To the reaction mixture was added 100 mL of water and 100 mL of
pentane. The biphasic solution was transferred to a 1-L separatory funnel. The organic layer
was successively washed with 1 M HCl (100 mL), water (100 mL), saturated NaHCO3 (100 mL)
and brine (100 mL). The solution was dried over Na2SO4 and concentrated under reduced

Denmark and Fujimori
S7
pressure. The resulting oil was distilled under vacuum to afford 13.1 g (64.1 mmol, 83%) of 5 as
a clear, pale-yellow oil.
Data for 5:
bp:
108 °C (0.5 mm Hg)
1H NMR:
(500 MHz, CDCl3)
9.49 (d, J = 8.0, 1 H, HC(1)); 7.23 (t, J = 7.5, 2 H, 2 x HC(8)); 7.11 (t, J = 7.0, 1
H, HC(9)); 6.99 (d, J = 7.0, 2 H, 2 x HC(7)); )); 7.14 (d, J = 19.0, 1 H, HC(3));
6.48 (dd, J = 18.5, 7.5, 1 H, HC(2); 2.23 (s, 2 H, H2C(5)); 0.16 (s, 6 H, 2 x
H3C(4))
13C NMR:
(126 MHz, CDCl3)
194.53 (C(1)); 156.63 (C(3)); 144.87 (C(2)); 138.44 (C(6)); 128.38 (2 x C(8));
128.13 (2 x C(7)); 124.53 (C(9)); 24.90 (C(5)); -4.01 (2 x C(4))
IR:
(neat)
3059 (w); 3024 (m); 2958(m); 2798(m); 1692 (s); 1599 (m); 1493 (m); 1452(m);
1407 (w); 1251 (m); 1206 (m); 1157 (m); 1085 (m)
MS:
(FI)
204 (100, M+)
TLC:
Rf 0.25 (hexane/EtOAc, 5/1) [silica gel, KMnO4]
C12H16OSi (204.34)
Analysis:
Calcd:
Found:
C, 70.53%; H ,7.89%
C, 70.25%; H, 8.04%

Denmark and Fujimori
S8
(5R)-Ethyl 7-benzyldimethylsilyl-5-hydroxy-hepta-2,6-dienoate (4)
Me
N
O
P
(R,R)-9
CH
2
N
N
Me
Me
2
8
O
OH
7
11
OTBS
OEt
O
13
9
SiCl4
12
14
+
3
5
1
Me
O
Si
Me Me
4
2
6
BnMe2Si
H
CH2Cl2
15
6
5
4
10
In a 100-mL Schlenk flask were placed phosphoramide (R,R)-9 (220 mg, 0.26 mmol,
0.015 equiv), dichloromethane (50 mL), aldehyde 5 (3.72 g, 18.2 mmol) and
o
diisopropylethylamine (0.65 mL, 3.64 mmol, 0.20 equiv). The solution was cooled to –70 C
(internal temperature measured by thermocouple) using an isopropanol/dry ice bath. To the
reaction mixture was added silicon tetrachloride (2.29 mL, 20.0 mmol, 1.1 equiv) followed by
ketene acetal 6 (5.00 g, 21.8 mmol, 1.2 equiv) dropwise over 20 min maintaining the internal
o
o
temperature below –68 C. The reaction mixture was stirred at –70 C for 3 hrs. Then the
reaction mixture was transferred via cannula into a vigorously stirring saturated aqueous
o
NaHCO3 solution (200 mL) at 0 C (bath temperature). The resulting mixture was stirred
vigorously for 3 h at rt. The solution was filtered through a layer of Celite, and the filtrate was
transferred into a 500-mL separatory funnel. The aqueous layer was extracted with
dichloromethane (2 x 100 mL), and the combined organic layers were washed with brine (100
mL). The organic solution was dried over Na2SO4 and concentrated under reduced pressure to
give 8.7 g of a crude oil. The crude product was chromatographed (silica gel, hexane/EtOAc 3/1,
60 mm) to afford 4.35 g (13.7 mmol, 75%) of 4 as a clear, colorless oil.
Data for 4:
1H NMR:
(500 MHz, CDCl3)
7.20 (t, J = 7.7, 2 H, 2 x HC(14)); 7.06 (t, J = 7.3, 1 H, HC(15)); 6.98 (d, J = 7.1,
2 H, 2 x HC(13)); 6.94 (dd, J = 15.6, 7.5, 1 H, HC(3)); 6.01 (dd, J = 18.8, 5.2, 1
H, HC(6)); 5.90 (dd, J = 15.8, 1.5, 1 H, HC(2); 5.87 (dd, J = 18.9, 1.2, 1 H,
HC(7)); 4.22 (qd, J = 5.6, 1.1, 1 H, HC(5)); 4.19 (q, J = 7.2, 2 H, H2C(8)); 2.34-

Denmark and Fujimori
S9
2.46 (m, 2 H, H2C(4)); 2.14 (s, 2 H, H2C(11)); 1.60 (d, J = 4.5, 1 H, HO); 1.28 (t,
J = 7.1, 3 H, H3C(9)); 0.06 (s, 6 H, 2 x H3C(10))
13C NMR:
(126 MHz, CDCl3)
166.24 (C(1)); 148.18 (C(6)); 144.54 (C(3)); 139.58 (C(12)); 128.12 (2 x C(13));
128.08 (C(7)); 128.03 (2 x C(14)); 123.97 (C(15)); 123.87 (C(2)); 72.74 (C(5));
60.23 (C(8)); 39.54 (C(4)); 25.78 (C(11)); 14.16 (C(9)); -3.53 (2 x C(10))
(neat)
IR:
3437 (br, m); 3060 (w); 3024 (m); 2982 (m); 2956(m); 2898(m); 1720 (s); 1655
(m); 1619 (w); 1600 (m); 1493 (m); 1452(m); 1396 (w); 1369 (m); 1316 (m);
1249 (m); 1207 (m); 1157 (m); 1096 (m); 1042 (m)
(FI)
MS:
319 (100, M+); 227 (55)
24
Opt. Rot.:
[
!
]
–5.79 (c = 0.36, EtOH)
D
TLC:
SFC:
Rf 0.08 (hexane/EtOAc, 5/1) [silica gel, KMnO4]
(Chiralpak-AD, 3.0 mL/min, 4.0% MeOH, 125 bar);
(5R)-4: 5.31 min (98.1%); (5S)-4: 5.74 min (1.9%)
C18H26O3Si (318.48)
Analysis:
Calcd:
Found:
C, 67.88%; H, 8.23%
C, 67.59%; H, 8.41%
(2’R, 4’S, 6’R)-Ethyl (2’-phenyl-6’-(2-benzyldimethylsilylethenyl)-[1,3]dioxan-4’-yl)-acetate
(8)
14
13
12
11
PhCHO
OH
O
KHMDS
O
O
10 O
7
16
8
18
9
17
BnMe2Si
OEt
THF
19
20
3
5
4
1
Me
O
Si
Me Me
15
2
6
4
8
In a 500-mL Schlenk flask were placed 4 (3.41 g, 10.7 mmol), benzaldehyde (1.23 mL,

Denmark and Fujimori
S10
11.8 mmol, 1.1 equiv) and THF (100 mL). The solution was cooled to 0 oC (internal temperature
monitored by thermocouple) using ice bath. To the solution was added 0.5 M KHMDS in THF
(2.13 mL, 1.07 mmol, 0.1 equiv) in one portion. The reaction mixture turned dark yellow and
the internal temperature rose to 5 oC. The reaction mixture was stirred for 20 min at 0 oC. To the
reaction mixture were added benzaldehyde (1.23 mL, 11.8 mmol, 1.1 equiv) and 0.5 M KHMDS
in THF (2.13 mL, 1.07 mmol, 0.1 equiv). The reaction mixture was stirred for 20min at 0oC.
The addition and stirring sequence was repeated one more time before the reaction mixture was
o
quenched with cold (0 C, bath temperature) pH 7 phosphate buffer (100 mL). The biphasic
mixture was poured into a 500-mL separatory funnel and was extracted with pentane (200 mL).
The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under
reduced pressure. Most of the remaining benzaldehyde was removed under vacuum with
stirring. The resulting crude oil was chromatographed (silica gel, hexanes/EtOAc 9/1, 60 mm) to
afford 3.38 g (7.96 mmol, 74%) of 8 as a pale-yellow oil.
Data for 8:
1H NMR:
(500 MHz, CDCl3)
7.52 (d, J = 6.7, 2 H, 2 x HC(12)); 7.33 – 7.38 (m, 3 H, HC(14), 2 x HC(13));
7.20 (t, J = 7.6, 2 H, 2 x HC(19)); 7.07 (t, J = 7.4, 1 H, HC(20)); 6.98 (d, J = 7.2,
2 H, 2 x HC(18)); 6.07 (dd, J = 19.0, 4.6, 1 H, HC(6)); 5.94 (dd, J = 19.1, 1.2, 1
H, HC(7); 5.62 (s, 1 H, HC(10));4.32 – 4.40 (m, 2 H, HC(3), HC(5)); 4.18 (q, J =
7.2, 2 H, H2C(8)); 2.64 (ABX, JAB = 5.7, 2 H, H2C(2)); 2.13 (s, 2 H, H2C(16));
1.78 (dt, J = 13.0, 7.3, 1 H, HeqC(4)); 1.53 (q, J = 11.4, 1 H, HaxC(4)); 1.28 (t, J =
7.1, 3 H, H3C(9)); 0.05 (s, 6 H, 2 x H3C(15))
13C NMR:
(126 MHz, CDCl3)
170.61 (C(1)); 145.69 (C(6)); 139.62 (C(17)); 138.19 (C(11)); 128.64 (C(14));
128.14 (C7)); 128.08 (2 x C(13)); 128.05 (2 x (C(18)); 128.00 (2 x C(19)); 126.10
(C(12)); 123.91 (C(20)); 100.42 (C(10)); 78.22 (C(5)); 72.97 (C(3)); 60.50 (C(8));
40.75 (C(2)); 36.00 (C(4)); 25.71 (C(16)); 14.06 (C(9)); -3.71, -3.66 (2 x C(15))
(neat)
IR:
3061 (w); 3024 (m); 2981 (m); 2957(m); 2897(m); 1736 (s); 1623 (m); 1600 (m);
1493 (m); 1452(m); 1401 (m); 1373 (m); 1339 (m); 1314 (m); 1250(m); 1206

Denmark and Fujimori
S11
(m); 1158 (m); 1112 (m); 1097 (m); 1056 (m)
(FI)
MS:
425 (52, M+); 424 (27); 423 (31); 422 (18); 351 (19); 335 (88); 333 (47); 317
(43); 316 (35); 291 (38); 290 (97); 243 (38); 220 (92); 219 (29); 190 (67); 128
(27); 106 (100); 91 (45)
Opt. Rot.:
TLC:
[α]24D + 15.3 (c = 0.57, EtOH)
Rf 0.33 (pentane /ether 9/1) [silica gel, KMnO4]
Calc for C25H32O4Si (424.60)
Analysis:
Calcd:
Found:
C, 70.72%; H, 7.60%
C, 70.73%; H, 7.52%
(2’R, 4’S, 6’R)-N,O-Dimethyl (2’-phenyl-6’-(2-benzyldimethylsilylethenyl)-[1,3]dioxan-4’-
yl)-acetamide (23)
14
13
Ph
12
11
HN(OMe)Me
O
O
O
i-PrMgCl
O
O
10 O
7
16
18
9
BnMe2Si
OEt
THF
17
O
19
20
3
5
4
1
Me
N
Si
Me Me
15
2
6
Me
8
8
23
In a 50-mL Schlenk flask were placed 8 (2.20 g, 5.18 mmol), N,O-
dimethylhydroxylamine hydrochloride (758 mg, 7.77 mmol, 1.5 equiv) and THF (11 mL). The
o
reaction mixture was cooled to –20 C (internal temperature monitored by thermocouple) using
NaCl/ice bath. To the reaction mixture was added 2 M solution of isopropylmagnesium chloride
in THF (7.77 mL, 15.5, 3 equiv) dropwise over 30 min maintaining internal temperature below –
o
o
10 C. The reaction mixture was stirred at –20 C for 20 min and was quenched with saturated
aqueous NH4Cl solution (20 mL). The reaction mixture was poured into a 250-mL separatory
funnel and extracted with pentane (100 mL). The organic phase was washed with brine (25 mL),
dried over Na2SO4 and concentrated. The resulting oil was chromatographed (silica gel,
hexane/EtOAc 2/1, 50 mm) to afford 1.98 g (4.50 mmol, 87%) of 23 as a clear, colorless oil.

Denmark and Fujimori
S12
Data for 23:
1H NMR:
(500 MHz, CDCl3)
7.53 (dd, J = 8.0, 1.4, 2 H, 2 x HC(12)); 7.32 – 7.38 (m, 3 H, HC(14), 2 x
HC(13)); 7.21 (t, J = 7.7, 2 H, 2 x HC(19)); 7.07 (t, J = 7.5, 1 H, HC(20)); 6.99
(d, J = 7.1, 2 H, 2 x HC(18)); 6.09 (dd, J = 19.1, 4.7, 1 H, HC(6)); 5.95 (dd, J =
18.9, 1.3, 1 H, HC(7)); 5.64 (s, 1 H, HC(10)); 4.38 – 4.46 (m, 2 H, HC(3),
HC(5)); 3.68 (s, 3 H, H3C(9)); 3.20 (s, 3 H, H3C(8)); 2.79 (ABX, JAB = 15.6, 2 H,
H2C(2)); 2.14 (s, 2 H, H2C(16)); 1.90 (dt, J = 13.2, 2.4, 1 H, HeqC(4)); 1.52 (q, J =
12.4, 1 H, HaxC(4)); 0.05, 0.04 (s, 6 H, 2 x H3C(15))
13C NMR:
(126 MHz, CDCl3)
171.24 (C(1)); 145.90 (C(6)); 139.78 (C(17)); 138.43 (C(11)); 128.73 (C(7));
128.24 (2 x C(18)); 128.17 (2 x C(13), 2 x C(19)); 128.09 (C(14)); 126.24 (2 x
C(12)); 123.97 (C(20)); 100.70 (C(10)); 78.46 (C(5)); 73.40 (C(3)); 61.37 (C(9));
38.08 (C(2)); 36.53 (C(4)); 31.93 (C(8)); 25.81 (C(16)); -3.63, -3.60 (2 x C(15))
(neat)
IR:
3060 (w); 3024 (m); 2998 (m); 2956(m); 2916 (m); 2894(m); 1664 (s); 1623 (s);
1600 (m); 1493 (m); 1452(m); 1413 (m); 1388 (m); 1336 (m); 1313 (w); 1248(m);
1208 (m); 1176 (m); 1128 (m); 1097 (m); 1056 (m); 1027 (m)
(FI)
MS:
440 (3, M+); 437 (14); 436 (43); 434 (11); 423 (22); 422 (67); 420 (13); 409 (31);
408 (100); 381 (23); 380 (77); 366 (28)
24
Opt. Rot.:
[
!
]
+ 12.5 (c = 0.50, EtOH)
D
TLC:
Rf 0.08 (hexane/EtOAc 2/1) [silica gel, KMnO4]
Analysis:
Calc for C25H33NO4Si (439.62)
Calcd:
Found:
C, 68.30%; H, 7.57%;
C, 68.28%; H, 7.61%;
N, 3.19%
N, 3.29%

Denmark and Fujimori
S13
(2’R, 4’S, 6’R)-3-(2’-Phenyl-6’-(2-benzyldimethylsilylethenyl)-[1,3]dioxan-4’-yl)-propan-2-
one (2)
13
12
Ph
11
10
O
O
O
MeMgBr
Et2O
9
O
O
O
OMe
8
15
17
BnMe2Si
N
16
18
19
4
6
2
Me
1
Si
Me Me
14
Me
5
3
7
23
2
In a 100-mL Schlenk flask were placed 23 (1.49 g, 3.39 mmol) and ether (20 mL). The
o
reaction mixture was cooled to 0 C in an ice bath. To the solution was added a 3 M solution of
methylmagnesium bromide in ether (1.69 mL, 5.08 mmol, 1.5 equiv) dropwise over 1 min. The
reaction mixture was allowed to warm to rt and was stirred for 10 h. The reaction was quenched
with saturated aqueous NH4Cl solution (10 mL) and was poured into a 125-mL separatory
funnel, and the biphasic mixture was extracted with pentane (80 mL). The organic phase was
washed with brine (20 mL), dried over Na2SO4 and concentrated. The resulting oil was
chromatographed (silica gel, hexanes/EtOAc 3/1, 50 mm) to afford 1.20 g (3.04 mmol, 90%) of 2
as a clear, colorless oil.
Data for 2:
1H NMR:
(500 MHz, CDCl3)
7.51 (dd, J = 7.8, 1.5, 2 H, 2 x HC(11)); 7.32 – 7.38 (m, 3 H, HC(13), 2 x
HC(12)); 7.20 (t, J = 7.7, 2 H, 2 x HC(18)); 7.07 (t, J = 7.3, 1 H, HC(19)); 6.99
(d, J = 7.3, 2 H, 2 x HC(17)); 6.07 (dd, J = 18.9, 4.5, 1 H, HC(7)); 5.94 (dd, J =
18.8, 12, 1 H, HC(8)); 5.61 (s, 1 H, HC(9)); 4.32 – 4.40 (m, 2 H, HC(4), HC(6));
2.75 (ABX, JAB = 16.4, JAX = 7.0, JBX = 5.7, 2 H, H2C(3)); 2.22 (s, 3 H, H3C(1));
2.13 (s, 2 H, H2C(15)); 1.78 (dt, J = 13.1, 2.5, 1 H, HeqC(5)); 1.47 (dt, J = 13.0,
11.3, 1 H, HaxC(5)); 0.05, 0.04 (s, 6 H, 2 x H3C(14))
13C NMR:
(126 MHz, CDCl3)
206.25 (C(2)); 145.67 (C(8)); 139.59 (C(16)); 138.19 (C(10)); 128.63 (C(13));

Denmark and Fujimori
S14
128.18 (C(7)); 128.11 (2 x C(17)); 128.05 (2 x C(12)); 127.97 (2 x C(18)); 126.02
(2 x C(11)); 123.89 (C(19)); 100.39 (C(9)); 78.38 (C(6)); 76.26 (C(4)); 49.15
(C(3)); 36.15 (C(5)); 31.00 (C(1)); 25.68 (C(15)); -3.72, -3.68 (2 x C(14))
(neat)
IR:
3060 (w); 3025 (m); 2999 (m); 2958(m); 2916 (m); 1716 (s); 1623 (m); 1600 (m);
1494 (m); 1452(m); 1403 (m); 1337 (m); 1316 (w); 1248(m); 1208 (m); 1159 (m);
1133 (m); 1099 (m); 1055 (m); 1027 (m)
MS:
(FI)
394 (100, M+); 306 (15); 305 (50); 304 (21); 303 (80); 270 (17); 204 (11); 161
(17); 152 (12); 115 (12); 114 13), 113 (14); 106 (11)
24
Opt. Rot.:
[
!
]
+ 4.9 (c = 0.85, EtOH)
D
TLC:
Rf 0.28 (hexanes/EtOAc 3/1) [silica gel, KMnO4]
Analysis:
Calc for C24H30O3Si (394.58)
Calcd:
Found:
C, 73.05%; H, 7.66%
C, 72.96%; H, 7.87%
(4S, 5S)-Methyl 4,6-dimethyl-5-(4-methoxyphenylmethoxy)-2-heptenoate (24)
Me
15
O
14
13
12
PMBO
Me
O
11
Ph3PCHCO2Me
MeCN, reflux
10
H
O
O
3
Me Me
10
4
6
Me
7
Me
8
5
1
O
2
Me Me
24
9
7'
In
a
250-mL flask were placed 10 (4.43 g, 17.7 mmol), methyl
triphenylphosphanylideneacetate (8.88 g, 26.6, 1.5 equiv) and acetonitrile (100 mL). The flask
was fitted with a reflux condenser and was immersed into an oil bath. The mixture was heated to
90 oC (bath temperature) for 24 hrs. The reaction mixture was cooled to rt and was placed under
reduced pressure (20 mmHg) to remove most of the acetonitrile. The resulting solid/oil mixture
was chromatographed (silica gel, hexanes/EtOAc 9/1, 60 mm) to afford 4.86 g (15.9 mmol, 90%)

Denmark and Fujimori
of 24 as a clear, colorless oil.
Data for 24:
S15
1H NMR:
(500 MHz, CDCl3)
7.27 (d, J = 8.5, 2 H, 2 x HC(12)); 7.02 (dd, J = 15.9, 8.1, 1 H, HC(3)); 6.88 (d, J
= 8.6, 2 H, 2 x HC(13)); 5.86 (dd, J = 15.6, 1.2, 1 H, HC(2)); 4.48 (s, 2 H,
H2C(10)); 3.84 (s, 3 H, H3C(15)); 3.74 (s, 3 H, H3C(8)); 3.08 (t, J = 5.6, 1 H,
HC(5)); 2.62 (sextd, J = 6.6, 1.0, 1 H, HC(4)); 1.82 (sext, J = 6.8, 1 H, HC(6));
1.12 (d, J = 6.6, 3 H, H3C(9)); 0.96 (d, J = 6.9, 3 H, H3C(7)); 0.95 (d, J = 6.6, 3 H,
H3C(7’))
13C NMR:
(126 MHz, CDCl3)
167.11 (C(1)); 159.08 (C(14)); 152.69 (C(3)); 130.72 (C(11)); 129.29 (C(12));
119.93 (C(2)); 113.64 (C(13)); 87.35 (C(5)); 74.77 (C(10)); 55.14 (C(15)); 51.36
(C(8)); 39.70 (C(4)); 31.19 (C(6)); 20.17 (C(7)); 17.48 (C(7’)); 14.58 (C(9))
(neat)
IR:
2961 (m); 2909(m); 2874 (m); 2838 (m); 1723 (s); 1655 (m); 1613 (m); 1586 (m);
1514 (m); 1464(m); 1436 (m); 1383 (w); 1364 (w); 1336 (m); 1301 (m); 1249 (s);
1194 (m); 1175 (m); 1137 (w); 1110 (m); 1063 (m); 1036 (m); 1012 (m)
(FI)
MS:
307 (20); 306 (100, M+); 276 (15)
24
Opt. Rot.:
[
!
]
+ 5.0 (c = 0.90, EtOH)
D
TLC:
Rf 0.18 (hexanes/EtOAc 9/1) [silica gel, KMnO4]
Analysis:
Calc for C14H26O4 (306.40)
Calcd:
Found:
C, 70.56%; H, 8.55%
C, 70.57%; H, 8.52%

Denmark and Fujimori
S16
(4S, 5S)-4,6-Dimethyl-5-(4-methoxy-phenylmethoxy)-2-hepten-1-ol (25)
Me
14
O
13
12
11
10
9
O
PMBO
Me
Dibal-H
Et2O
3
4
6
Me
7
COOMe
5
1
OH
2
Me Me
8
Me Me
24
7'
25
In a 250-mL, three-neck flask equipped with a 50-mL pressure-equalizing addition
funnel, a septum pierced with thermocouple temperature probe and a gas inlet were placed 24
(4.33 g, 14.1 mmol) and ether (90 mL). The solution was cooled to –74 oC (internal temperature)
using isopropanol/dry ice bath. The addition funnel was charged with 1 M solution of
diisobutylaluminum hydride in hexanes (42.3 mL, 42.3 mmol, 3 equiv). The solution of
diisobutylaluminum hydride was added dropwise over 30 min maintaining temperature below
-65 oC. The reaction mixture was stirred for 30 min at –74 oC, allowed to warm to 0 oC and was
o
stirred for 1 h at 0 C. At this temperature, the reaction mixture was carefully quenched with
o
10% v/v aqueous acetic acid (100 mL) maintaining internal temperature below 10 C. The
resulting clear solution was poured into a 500-mL separatory funnel. The aqueous layer was
extracted with ether (2 x 100 mL), and the combined organic layers were washed with water (50
mL), saturated aqueous NaHCO3 solution (2 x 50 mL) and brine (50 mL). The extracts were
dried over Na2SO4 and concentrated under reduced pressure. The resulting clear oil was
chromatographed (silica gel, hexanes/EtOAc 2/1, 60 mm) to afford 25 (3.80 g, 13.6 mmol, 97%)
as clear colorless oil.
Data for 25:
1H NMR:
(500 MHz, CDCl3)
7.28 (d, J = 8.5, 2 H, 2 x HC(11)); 6.87 (d, J = 8.6, 2 H, 2 x HC(12)); 5.64 – 5.68
(m, 2 H, HC(2), HC(3)); 4.50 (s, 2 H, H2C(9)); 4.09 (td, J = 4.9, 2.2, 2 H,
H2C(1)); 3.80 (s, 3 H, H3C(14)); 2.98 (t, J = 5.8, 1 H, HC(5)); 2.46 (sext, J = 6.5,

Denmark and Fujimori
S17
1 H, HC(4)); 1.84 (sext, J = 6.7, 1 H, HC(6)); 1.23 (t, J = 7.5, 1 H, HO); 1.07 (d, J
= 6.8, 3 H, H3C(8)); 0.96 (d, J = 6.8, 3 H, H3C(7)); 0.95 (d, J = 6.8, 3 H, H3C(7’))
(126 MHz, CDCl3)
13C NMR:
159.05 (C(13)); 136.61 (C(3)); 130.21 (C(10)); 129.23 (2 x C(11)); 128.10 (C(2));
113.67 (2 x C(12)); 88.34 (C(5)); 74.86 (C(9)); 63.77 (C(1)); 55.24 (C(14)); 39.59
(C(4)); 30.95 (C(6)); 20.41 (C(7)); 17.51 (C(7’)); 15.68 (C(9))
(neat)
IR:
3392 (br, m); 2961 (s); 2871 (m); 1723 (s); 1689 (w); 1613 (m); 1587 (m); 1514
(s); 1464 (m); 1422 (m); 1383 (m); 1364 (m); 1351 (m); 1302 (m); 1249 (s); 1173
(m); 1110 (m); 1037 (m); 1012 (m)
MS:
(EI, 70eV, 170oC)
278 (0.3, M+); 206 (2); 122 (10); 121 (100); 91 (3); 78 (5); 77 (4)
24
Opt. Rot.:
[
!
]
+ 4.9 (c = 0.85, EtOH)
D
TLC:
Rf 0.18 (hexanes/EtOAc 2/1) [silica gel, short UV]
Analysis:
Calc for C17H26O3 (278.39)
Calcd:
Found:
C, 73.34%; H, 9.41%
C, 73.27%; H, 9.26%
(4S, 5S)-4,6-Dimethyl-5-(4-methoxyphenylmethoxy)-2-heptenal (3)
Me
O
14
13
12
11
10
PMBO
Me
MnO2
9
O
O
3
OH
4
6
CH2Cl2, reflux
Me
5
1
H
7
2
Me Me
Me Me
8
7'
25
3
In a 250-mL round bottom flask were placed 25 (8.07 g, 28.7 mmol), dichloromethane
(80 mL) and manganese (IV) oxide (22.5 g, 259 mmol, 9.0 equiv). The flask was fitted with a
reflux condenser and the reaction mixture was heated to reflux under argon for 36 h. The

Denmark and Fujimori
S18
reaction mixture was cooled to rt and was filtered through a pad of silica gel (60 mm x 2 cm).
The silica gel was washed with dichloromethane (200 mL) and ethyl acetate (200 mL). The
combined filtrates were concentrated under reduced pressure. The resulting brown oil was
chromatographed (silica gel, hexanes/EtOAc 5/1, 60 mm) to afford 5.58 g (20.2 mmol, 70%) of 3
as a pale yellow oil along with 2.30 g (8.27 mmol, 29%) of recovered 25.
Data for 3:
1H NMR:
(500 MHz, CDCl3)
9.47 (d, J = 8.0, 1 H, HC(1)); 7.25 (d, J = 8.5, 2 H, 2 x HC(11)); 6.88 (d, J = 8.6,
2 H, 2 x HC(12)); 6.83 (dd, J = 15.8, 7.8, 1 H, HC(3)); 6.12 (dd, J = 15.5, 8.0, 1
H, HC(2)); 4.50 (AB, 2 H, H2C(9)); 3.81 (s, 3 H, H3C(14)); 3.13 (t, J = 5.5, 1 H,
HC(5)); 2.74 (sext, J = 6.2, 1 H, HC(4)); 1.84 (sext, J = 6.8, 1 H, HC(6)); 1.15 (d,
J = 6.5, 3 H, H3C(9)); 0.97 (d, J = 6.5, 3 H, H3C(7)); 0.97 (d, J = 6.6, 3 H, H3C(7’)
(126 MHz, CDCl3)
13C NMR:
194.45 (C(1)); 162.28 (C(3)); 159.49 (C(13)); 132.02 (C(2)); 130.82 (C(10));
129.61 (2 x C(11)); 114.02 (2 x C(12)); 87.39 (C(5)); 74.93 (C(9)); 55.48 (C(14));
40.26 (C(4)); 31.56 (C(6)); 20.44 (C(7)); 18.16 (C(7’)); 14.41 (C(9)
(neat)
IR:
2962 (m); 2873 (m); 2837 (m); 2731 (w); 1686 (s); 1612 (m); 1586 (m); 1514
(m); 1466(m); 1421 (w); 1384 (m); 1364 (m); 1350 (m); 1302 (m); 1248 (m);
1173 (m); 1112 (m); 1059 (m); 1036 (m)
MS:
(FI)
277 (20); 276 (100, M+)
24
Opt. Rot.:
[
!
]
+ 19.6 (c = 0.45, EtOH)
D
TLC:
Rf 0.18 (hexanes/EtOAc 5/1) [silica gel, p-anisaldehyde]
Analysis:
Calc for C17H26O3 (276.37)
Calcd:
Found:
C, 73.88%; H, 8.75%
C, 73.52%; H, 8.72%

Denmark and Fujimori
S19
(7S, 9S, 2’R, 4’S, 6’R) 1-(6’-(2-benzyldimethylsilyl-ethenyl)-2’-phenyl-[1,3]-dioxan-4’-yl)-
7,9-dimethyl-6-hydroxy-8-(4-methoxy-phenylmethoxy)-5-nonen-2-one (12)
Me
33
O
32
26
25
24
31
30
Ph
Bu2BOTf
DIPEA
23
29
PMBO
Me
O
O
O
28
22 O
+
O
OH
O
O
CHO
1
Et2O, -78 oC
11
17
19
BnMe2Si
Me
12
14
18
Me
15
20
13
5
3
4
9
7
Si
Me Me
16
Me Me
10
6
2
8
Me Me
27
2
3
12
21
15'
In a 50-mL Schlenk flask were placed 2 (592 mg, 1.50 mmol, 1.2 equiv) and ether (7
mL). The solution was cooled to –72 oC (internal temperature) using a dry ice/isopropanol bath.
To the solution was added diisopropylethylamine (0.32 mL, 1.80 mmol, 1.44 equiv) followed by
a 1.0 M solution of dibutylboron triflate in dichloromethane (1.65 mL, 1.65 mmol, 1.32 equiv).
o
The reaction mixture was stirred at –72 C for 15 min before the addition of 3 (345 mg, 1.25
mmol) whereupon the reaction mixture was stirred for 7 h. To the reaction mixture was added a
o
6/1 MeOH/pH 7 phosphate buffer solution (10 mL). The reaction mixture was warmed to 0 C
using an ice bath. To the reaction mixture was added a 3/1 MeOH/30% H2O2 solution (10 mL)
dropwise. The resulting emulsion was stirred for 1 h and was poured into a 125-mL separatory
funnel. The whole mixture was extracted with ethyl acetate (3 x 50 mL). The combined extracts
were washed with saturated aqueous NaHCO3 solution (25 mL) and brine (25 mL). The extracts
were dried over Na2SO4 and were concentrated under reduced pressure. The resulting clear oil
was chromatographed (silica gel, hexanes/EtOAc 5/1 to 3/1, 40 mm) to afford 715 mg (1.07
mmol, 85%) of 12 as a clear, colorless oil.
Data for 12:
1H NMR:
(500 MHz, CDCl3)
7.49 (dd, J = 7.7, 1.8, 2 H, 2 x HC(24)); 7.32 – 7.38 (m, 3 H, HC(26), 2 x
HC(25)); 7.27 (d, J = 7.5, 2 H, 2 x HC(30)); 7.20 (t, J = 7.6, 2 H, 2 x HC(20));
7.07 (t, J = 7.3, 1 H, HC(21)); 6.99 (dd, J = 7.3, 1.3, 2 H, 2 x HC(19)); 6.86 (d, J
= 8.5, 2 H, 2 x HC(31)) ; 6.06 (dd, J = 18.9, 4.5, 1 H, HC(2)); 5.92 (dd, J = 19.1,
1.3, 1 H, HC(1)); 5.67 (ddd, J =15.5, 8.0, 1.0, 1 H, HC(11)); 5.59 (s, 1 H,

Denmark and Fujimori
S20
HC(22)); 5.46 (ddd, J = 15.5, 6.3, 0.8, 1 H, HC(10)); 4.52 – 4.57 (m, 1 H, HC(9));
4.48 (s, 2 H, H2C(28)); 4.35 – 4.41 (m, 2 H, HC(3), HC(5)); 3.79 (s, 3 H,
H3C(33)); 2.95 (t, J = 5.8, HC(13)); 2.75 (d, J = 3.7, HO); 2.73 (ABX, JAB = 16.3,
JAX = 7.3, J BX = 5.4, 2 H, H2C(6)); 2.67 (ABX, JAB = 11.5, JAX = 5.9, J BX = 3.1, 2
H, H2C(8)); 2.41 (sext, J = 6.9, 1 H, HC(12)); 2.13 (s, 2 H, H3C(17)); 1.79 (sext, J
= 6.8, 1 H, HC(14)); 1.75 (dt, J = 12.9, 2.4, 1 H, HeqC(4)); 1.47 (dt, J = 13.2, 11.2,
1 H, HaxC(4)); 1.05 (d, J = 6.8, 3 H, H3C(27)); 0.94 (d, J = 8.3, 3 H, H3C(15));
0.92 (d, J = 8.3, 3 H, H3C(15’)); 0.04, 0.04 (s, 6 H, 2 x H3C(14))
(126 MHz, CDCl3)
13C NMR:
208.73 (C(7)); 159.00 (C(32)); 145.56 (C(2)); 139.71 (C(18)); 138.13 (C(23));
135.63 (C(11)); 131.17 (C(29)); 129.73 (C(10)); 129.17 (C(30)); 128.55 (C(26));
128.31 (C(1)); 128.22 (2 x C(19), 2 x C(25)); 128.09 (2 x C(20)); 126.12 (2 x
C(24)); 123.99 (C(21)); 113.65 (C(31)); 100.59 (C(22)); 88.25 (C(13)); 78.37
(C(3)); 74.86 (C(9)); 72.72 (C(5)); 68.33 (C(28)); 55.24 (C(33)); 50.50 (C(8));
49.30 (C(6)); 39.61 (C(12)); 36.28 (C(4)); 30.97 (C(14)); 25.81 (C(17)); 20.41,
17.44 (C(15), C(15’)); 15.70 (C(27)); -3.57, -3.60 (2 x C(16))
(neat)
IR:
3480 (br, m); 3061 (m); 3025 (m); 2959(s); 2872 (m); 1714 (s); 1614 (m); 1601
(m); 1589 (m); 1514 (s); 1494 (m); 1454(m); 1384 (m); 1338 (m); 1302 (s); 1248
(m); 1209 (m); 1174 (m); 1030 (m)
MS:
(HR ESI)
Calcd: 693.3587 (for C41H54O6Si + Na)
Found: 693.3603
24
Opt. Rot.:
[
!
]
+8.5 (c = 0.45, EtOH)
D
TLC:
Rf 0.09 (hexane/EtOAc 3/1) [silica gel, p-anisaldehyde]
Analysis:
Calc for C41H54O6Si (670.95)
Calcd:
Found:
C, 73.39%; H, 8.11%
C, 73.33%; H, 7.97%

Denmark and Fujimori
S21
Determination of Configuration at C(9) in Aldol Adduct 12, (C(27) in RK-397).
Ph
(R)- or (S)-MTPA-chloride
Pyridine
PMBO
Me
OH
O
O
O
CDCl3
SiMe2Bn
9
Me Me
Ph
12
(S)- or (R)-MTPA
PMBO
Me
O
O
O
O
SiMe2Bn
9
Me Me
30
In an NMR tube was placed a solution of 12 (5.0 mg, 0.0075 mmol) in CDCl3 (0.75 mL). To the
solution was added sequentially pyridine (0.02 mL) and (R)- or (S)-α-methoxy-α-
trifluoromethylphenylacetyl chloride (2.8 µL, 0.015 mmol, 2.0 equiv). The reaction mixture was
thoroughly mixed and was let stand for 2 h at rt. The crude Mosher ester 30 was analyzed by
NMR and found to be of R configuration.
From (R)-MTPA-30:
From (S)-MTPA-30:
Ph
Ph
(R)-MTPA
(S)-MTPA
PMBO
H
O
O
O
O
PMBO
H
O
O
O
O
10
8
10
8
Me
Me
SiMe2Bn
SiMe2Bn
9
9
Me Me
H
Me Me
H
δ H2C(8) = 2.70 ppm
δ HC(10) = 5.48 ppm
δ H2C(8) = 2.77 ppm
δ HC(10) = 5.35 ppm
Difference in chemical shifts:
ΔδSR H2C(8) = + 0.07 ppm
ΔδSR HC(9) = - 0.13 ppm

Denmark and Fujimori
S22
Bisbenzylidene Silane 26
Me
O
38
31
26
37
30
29
25
24
36
35
1. Et2BOMe,
NaBH4
Ph
23
34
28
2. PhCH(OMe)2
CSA
33
27
8
PMBO
Me
OH
O
O
O
O
O
O
O
22 O
1
11
17
19
12
14
18
Me
15
20
13
5
3
4
SiMe2Bn
9
7
Si
Me Me
16
10
6
2
Me Me
Me Me
32
21
15'
12
26
In a 50-mL Schlenk flask were placed 12 (2.85 g, 4.25 mmol), tetrahydrofuran (20 mL)
and methanol (4.3 mL). The reaction mixture was cooled to –72 oC (internal temperature) using
dry ice/isopropanol bath. To the solution was added dropwise diethylmethoxyborane (0.693 mL,
5.10 mmol, 1.2 equiv), and the reaction mixture was stirred for 15 min at –72 oC. To the solution
was added sodium borohydride (193 mg, 5.10 mmol, 1.2 equiv) and the mixture was stirred for
4 h at –72 oC. The reaction mixture was quenched with acetic acid (6 mL) in one portion and the
mixture was allowed to warm to rt and then was transferred to a 125-mL separatory funnel. The
solution was extracted with ethyl acetate (2 x 25 mL) and the combined organic layers were
washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). The extracts were
dried over Na2SO4 and were concentrated under reduced pressure to afford a crude diol (3.10 g).
In a 100-mL round bottom flask were placed the crude diol (3.10 g), dichloromethane (25 mL),
benzaldehyde dimethyl acetal (2.54 mL, 17.0 mmol, 4.0 equiv) and dl-camphorsulfonic acid
(148 mg, 0.64 mmol, 0.15 equiv). The reaction mixture was stirred at rt for 16 h and was
quenched with saturated aqueous NaHCO3 solution (30 mL). The biphasic mixture was
transferred to a 125-mL separatory funnel and the aqueous layer was extracted with
dichloromethane (20 mL). The combined organic layers were washed with saturated aqueous
NaHCO3 solution (20 mL) and brine (20 mL). The solution was dried over Na2SO4 and
concentrated under reduced pressure. The resulting crude oil was chromatographed (silica gel,
hexanes/ether 9/1, 60 mm) to afford 2.79 g (3.80 mmol, 86%) of 26 as a clear, colorless oil.
Data for 26:
1H NMR:
(500 MHz, CDCl3)
7.55 (dd, J = 8.3, 1.5, 2 H, 2 x HC(24) or HC(29)); 7.53 (dd, J = 8.1, 1.3, 2 H, 2 x

Denmark and Fujimori
S23
HC(24) or HC(29)); 7.34 – 7.40 (m, 6 H, HC(26), 2 x HC(25), HC(31), 2 x
HC(30)); 7.27 (d, J = 7.3, 2 H, 2 x HC(35)); 7.19 (t, J = 7.6, 2 H, 2 x HC(20));
7.06 (t, J = 7.4, 1 H, HC(21)); 6.98 (d, J = 6.8, 2 H, 2 x HC(19)); 6.83 (d, J = 8.6,
2 H, 2 x HC(36)) ; 6.07 (dd, J = 19.0, 4.8, 1 H, HC(2)); 5.91 (dd, J = 19.0, 1.4, 1
H, HC(1)); 5.76 (dd, 15.7, 7.9, 1 H, HC(11)); 5.61 (s, 1 H, HC(22) or HC(27));
5.61 (s, 1 H, HC(22) or HC(27)); 5.59 (dd, J = 16.7, 6.9,, 1 H, HC(10)); 4.48 (AB,
Jab = 10.8, 2 H, H2C(33)); 4.31 – 4.36 (m, 2 H, HC(3), HC(9)); 4.20 – 4.23 (m, 2
H, HC(5), HC(7)); 3.78 (s, 3 H, H3C(38)); 2.98 (t, J = 5.8, HC(13)); 2.45 (sext, J
= 6.7, 1 H, HC(12)); 2.13 (s, 2 H, H3C(17)); 1.83 (sext, J = 6.7, 1 H, HC(14));
1.81 (m, 2 H, H2C(6)) 1.66 (dt, J = 13.2, 2.5, 1 H, HeqC(4) or HeqC(8)); 1.63 (dt, J
= 13.2, 2.6, 1 H, HeqC(4) or HeqC(8)); 1.54 (dt, J = 13.5, 11.2, 1 H, HaxC(4) or
HaxC(8)); 1.49 (dt, J = 13.5, 11.2, 1 H, HaxC(4) or HaxC(8)); 1.07 (d, J = 6.8, 3 H,
H3C(32)); 0.95 (d, J = 6.6, 3 H, H3C(15)); 0.94 (d, J = 6.9, 3 H, H3C(15’)); 0.04
(s, 6 H, 2 x H3C(14))
13C NMR:
(126 MHz, CDCl3)
158.94 (C(37)); 146.08 (C(2)); 139.67 (C(18)); 138.76, 138.66 (C(23), C(27));
135.93 (C(11)); 131.07 (C(34)); 129.20 (2 x C(35)); 128.81 (C(10)); 128.62,
128.55 (C(26), C(31)); 128.15 (2 x C(25) or C(30)); 128.11 (2 x C(19)); 128.10 (2
x C(25) or C(30)); 128.01 (2 x C(20)); 127.97 (C(1)); 126.15 (2 x C(24), 2 x
C(29)); 123.92 (C(21)); 113.57 (2 x C(31)); 100.38, 100.33 (C(22), C(27)); 88.23
(C(13)); 78.47 (C(3)); 77.15 (C(9)); 74.78 (C(33)); 72.36, 72.33 (C(5), C(7));
55.09 (C(38)); 42.42 (C(6)); 39.44 (C(12)); 37.49, 36.94 (C(4), C(8)); 30.91
(C(14)); 25.77 (C(17)); 20.20, 17.78 (C(15), C(15’)); 15.04 (C(32)); -3.61, -3.66
(2 x C(16))
IR:
(CHCl3)
3154 (w); 3066 (m); 3027 (m); 2959(s); 2916 (m); 2873 (m); 2838 (m); 2250 (m);
1794 (w); 1613 (m); 1600 (m); 1587 (w); 1514 (s); 1493 (m); 1453 (m); 1429 (w);
1408 (m); 1386 (m); 1339 (m); 1302 (m); 1248(s); 1210 (m); 1174 (m); 1121 (m);
1095 (m); 1057 (m); 1029 (s); 1010 (s)

Denmark and Fujimori
S24
MS:
(HR ESI)
Calcd: 783.4057 (for C48H60O6Si + Na)
Found: 783.4059
24
Opt. Rot.:
[
!
]
+ 62.4 (c = 1.05, EtOH)
D
TLC:
Rf 0.07 (hexane/EtOAc 9/1) [silica gel, p-anisaldehyde]
Analysis:
Calc for C48H60O6Si
Calcd:
Found:
C, 75.75%; H, 7.95%
C, 75.79%; H, 8.02%
Bisbenzylidene Aldehyde 14
Me
O
32
25
20
31
24
23
19
18
30
29
Me
17
28
22
OPMB
Me
TBAF;
H2O2, KHCO3
SiMe2Bn
THF/MeOH
O
27
16 O
O
21
O
O
O
O
11
Me
12
14
Me
15
13
5
3
4
1
9
7
H
O
O
O
10
6
2
8
Me Me
26
26
14
15'
Ph
Ph
In a 100-mL round bottom flask were placed 26 (751 mg, 0.99 mmol) and
o
tetrahydrofuran (14 mL). The solution was cooled to 0 C (bath temperature) using an ice bath.
To the solution was added a 1.0 M solution of TBAF (1.08 mL, 1.08 mmol, 1.1 equiv) dropwise
over 10 min. The reaction mixture was stirred for 15 min at 0 oC. To the reaction mixture were
added 30% H2O2 solution (4.24 mL, 23.8 mmol, 24 equiv), methanol (10 mL) and KHCO3 (495
mg, 4.95 mmol, 5.0 equiv). The reaction mixture was warmed to rt and stirred for 18 h. To the
reaction mixture was added water (40 mL) and the resulting emulsion was stirred for 30 min.
The reaction mixture was diluted with ethyl acetate (20 mL) and transferred to a 250-mL
separatory funnel. The aqueous layer was extracted with ethyl acetate (2 x 50 mL) and the
combined organic extracts were washed with 30% aqueous Na2S2O3 solution (3 x 30 mL) and
with brine (30 mL). The combined extracts were dried over MgSO4 and concentrated. The
resulting clear oil was chromatographed (silica gel, hexanes/ether 1/1, 30 mm) to afford 14 (457
mg, 0.73 mmol, 73%) as white foamy solid.

Denmark and Fujimori
S25
Data for 14:
mp:
101 – 103 oC
(500 MHz, CDCl3)
1H NMR:
9.85 (t, J = 1.9, 1 H, HC(1)); 7.52 (dd, J = 8.0, 1.6, 2 H, 2 x HC(18) or HC(23));
7.49 (dd, J = 7.9, 1.5, 2 H, 2 x HC(18) or HC(23)); 7.39 – 7.27 (m, 6 H, HC(20),
2 x HC(19), HC(25), 2 x HC(24)); 7.26 (d, J = 8.3, 2 H, 2 x HC(29)); 6.84 (d, J =
8.8, 2 H, 2 x HC(30)) ; 5.76 (dd, J = 15.6, 8.0, 1 H, HC(11)); 5.61 (s, 1 H, HC(16)
or HC(21)); 5.60 (s, 1 H, HC(16) or HC(21)); 5.59 (dd, J = 16.4, 6.9,, 1 H,
HC(10)); 4.48 (AB, Jab = 10.6, 2 H, H2C(27)); 4.45 – 4.41 (m, 1 H, HC(9)); 4.34 –
4.31 (m, 1 H, HC(3) or HC(5) or HC(7)); 4.26 – 4.18 (m, 2 H, HC(3) or HC(5) or
HC(7)); 3.78 (s, 3 H, H3C(32)); 2.98 (t, J = 5.8, HC(13)); 2.71 (ABXd, Jax = 7.4,
Jbx = 5.1, Jab = 16.9, J = 2.0, 2 H, H2C(2)); 2.44 (sext, J = 6.8, 1 H, HC(12)); 1.83
(sext, J = 6.6, 1 H, HC(14)); 1.82 – 1.80 (m, 2 H, H2C(6)) 1.71 (dt, J = 13.0, 2.5, 1
H, HeqC(4) or HeqC(8)); 1.62 (dt, J = 13.2, 2.6, 1 H, HeqC(4) or HeqC(8)); 1.57 –
1.43 (m, 2 H, HaxC(4), HaxC(8)); 1.06 (d, J = 6.9, 3 H, H3C(26)); 0.95 (d, J = 6.6,
3 H, H3C(15)); 0.94 (d, J = 6.8, 3 H, H3C(15’))
13C NMR:
(126 MHz, CDCl3)
200.37 (C(1)); 159.03 (C(31)); 138.74, 138.31 (C(22), C(17)); 136.11 (C(11));
131.18 (C(28)); 129.30 (2 x C(29)); 128.82 (C(10)); 128.67 (C(20), C(25));
128.24, 128.20 (2 x C(19), 2 x C(24)); 126.19, 126.02 (2 x C(18), 2 x C(23));
113.66 (2 x C(30)); 100.59, 100.46 (C(16), C(21)); 88.35 (C(13)); 77.25 (C(9));
74.87 (C(27)); 72.45, 72.33, 71.81 (C(3), C(5), C(7)); 55.23 (C(32)); 49.30
(C(2)); 42.37 (C(6)); 39.54 (C(12)); 37.53, 37.00 (C(4), C(8)); 30.99 (C(14));
20.26, 17.81 (C(15), C(15’)); 15.12 (C(32))
IR:
MS:
(CH2Cl2)
3051 (m); 2960(s); 2911 (m); 2869 (m); 1726 (w); 1612 (m); 1600 (m); 1514 (m);
1458 (m); 1344 (m); 1266 (m); 1244(m); 1110 (m); 1058 (m); 1028 (m); 1007 (m)
(FD)
630 (15); 629 (47); 628 (100, M+); 627 (12); 556 (17); 435 (14); 122 (10); 121
(69); 105 (22)
24
Opt. Rot.:
[
!
]
+ 81.3 (c =0.45 , EtOH)
D

Denmark and Fujimori
S26
TLC:
Rf 0.12 (hexane/Ether 1/1) [silica gel, p-anisaldehyde]
Calc for C39H48O7 (628.79)
Analysis:
Calcd:
Found:
C, 74.49%; H, 7.69%
C, 74.55%; H, 7.67%
Aldol Product 15
Ph
O
O
O
Me
50
O
49
44
BnMe2Si
Me
39
34
33
32
43
42
38
37
48
2
47
+
Me
36
46
Bu2BOTf
DIPEA
41
40
31
OPMB
45
30
O
O
O
O
35 O
OH
O
O
O
Me
Me
1
19
27
25
26
20
22
Me
23
28
29
H
Et2O, -78 oC
21
13
11
9
17
15
Si
Me Me
7
5
3
12
4
18
8
14
10
16
2
6
Me Me
51
O
O
O
O
O
15
24
24'
23'
14
Ph
Ph
In a 100-mL Schlenk flask were placed 2 (1.07 g, 2.71 mmol, 1.2 equiv) and ether (10
mL). The solution was cooled to –72 oC (internal temperature) using a dry ice/isopropanol bath.
To the reaction mixture were added diisopropylethylamine (0.583 mL, 3.25 mmol, 1.44 equiv)
followed by a 1.0 M solution of dibutylboron triflate (2.98 mL, 2.98 mmol, 1.32 equiv)
dropwise. The reaction mixture was stirred for 20 min before the addition of solution of 14 (1.42
g, 2.26 mmol) in dichloromethane (7 mL + 2 mL rinse) dropwise over 1 h whereupon the
reaction mixture was stirred for 8 h. To the reaction mixture was added a 6/1 mixture MeOH/pH
7 phosphate buffer solution (35 mL). The resulting emulsion was allowed to warm to 0 oC using
an ice bath. To the reaction mixture was added dropwise a 3/1 mixture of MeOH/30% H2O2
solution (32 mL). The reaction mixture was stirred for 30 min and was poured into a 250-mL
separatory funnel. The solution was diluted with ethyl acetate (100 mL) and was washed with
water (20 mL), saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). The solution
was dried over Na2SO4 and was concentrated under reduced pressure. The resulting clear oil was
chromatographed (silica gel, hexanes/EtOAc 5/1 to 2/1, 50 mm) to afford 2.03 g (1.98 mmol,
88%) of 15 as white foam.ꢀ

Denmark and Fujimori
S27
Data for 15:
mp:
52 – 53 oC
1H NMR:
(500 MHz, CDCl3)
7.53 – 7.46 (m, 6 H, 2 x HC(32), 2 x HC(37), 2 x HC(42)); 7.38 – 7.30 (m, 9 H,
HC(34), 2 x HC(33), HC(39), 2 x HC(38), HC(44), 2 x HC(43)); 7.26 (d, J = 7.3,
2 H, 2 x HC(47)); 7.20 (t, J = 7.7, 2 H, 2 x HC(28)); 7.07 (t, J = 7.3, 1 H,
HC(29)); 6.98 (d, J = 7.6, 2 H, 2 x HC(27)); 6.84 (d, J = 8.6, 2 H, 2 x HC(48) ;
6.05 (dd, J = 18.9, 4.5, 1 H, HC(2)); 5.93 (d, J = 18.8, 1 H, HC(1)); 5.77 (dd,
15.7, 8.1, 1 H, HC(19)); 5.60, 5.58, 5.54 (3 x s, 3 x 1 H, HC(30), HC35),
HC(40)); 5.59 (dd, J = 15.4, 6.4,, 1 H, HC(18)); 4.48 (AB, Jab = 10.7, 2 H,
H2C(45)); 4.44 – 4.30 (m, 4 H, HC(3), HC(5), HC(9), HC(17)); 4.19 – 4.17 (m, 2
H, HC(11), HC(13) or HC(15)); 4.11 – 4.08 (m, 1 H, HC(11) or HC(13) or
HC(15)); 3.78 (s, 3 H, H3C(50)); 3.17 (d, J = 3.9, 1 H, OH); 2.98 (t, J = 5.8,
HC(21)); 2.72 (ABX, Jax = 7.5, Jbx = 5.2, Jab = 16.2, 2 H, H2C(6)); 2.66 (ABX, Jax
= 3.2, Jbx = 9.0, Jab = 17.3, 2 H, H2C(8)) 2.45 (sext, J = 6.8, 1 H, HC(20)); 2.13 (s,
2 H, H3C(25)); 1.82 (sext, J = 6.5, 1 H, HC(22)); 1.82 – 1.67 (m, 7 H, H2C(10),
H2C(14), HeqC(4), HeqC(12), HeqC(16)); 1.57 – 1.43 (m, 3 H, HaxC(4), HaxC(12),
HaxC(16)); 1.06 (d, J = 6.6, 3 H, H3C(51)); 0.95 (d, J = 6.3, 3 H, H3C(23)); 0.94
(d, J = 6.6, 3 H, H3C(23’)); 0.04 (s, 6 H, 2 x H3C(24))
13C NMR:
(126 MHz, CDCl3)
208.27 (C(7)); 158.97 (C(49)); 145.55 (C(2)); 139.69 (C(26)); 138.73, 138.66,
138.06 (C(31), C(36), C(41)); 136.02 (C(19)); 131.12 (C(46)); 129.26 (2 x
C(47)); 128.85 (C(18)); 128.63, 128.58, 128.51, 128.19, 128.16, 128.14 (C(34),
C(39), HC(44),2 x C(33), 2 x C(38), 2 x C(43), 2 x C(27), 2 x C(28), C(1));
126.13, 126.11, 125.97 (2 x C(32), 2 x C(37), 2 x C(42)); 123.98 (C(29)); 113.62
(2 x C(48)); 100.62, 100.37 (C(30), C(35), C(40)); 88.33 (C(21)); 78.34 (C(3));
77.24 (C(17)); 74.85 (C(45)); 73.50, 72.83, 72.55, 72.42 (C(5), C(11), C(13),
C(15)); 64.15 (C(9)); 55.21 (C(50)); 50.86 (C(8)); 49.13 (C(6)); 42.44, 42.04
(C(10), C(14)); 39.52 (C(20)); 37.57, 37.35, 36.25 (C(4), C(12), C(16)); 30.98
(C(22)); 25.80 (C(25)); 20.27, 17.81 (C(23), C(23’)); 15.13 (C(51)); -3.57, -3.61
(2 x C(24))

Denmark and Fujimori
S28
IR:
(CH2Cl2)
3522 (br, m); 3034 (m); 2955(s); 2914 (m); 2872 (m); 1712 (m); 1613 (m); 1514
(m); 1494 (m); 1453 (m); 1408 (m); 1338 (m); 1248 (m); 1212(m); 1174 (m);
1111 (m); 1057 (m); 1012 (m)
MS:
(FD)
1024 (23); 1023 (54, M+); 1022 (77); 1021 (21); 931 (11); 122 (12); 121 (100);
106 (14)
24
Opt. Rot.:
[
!
]
+ 45.3 (c =0.40 , EtOH)
D
TLC:
Rf 0.30 (hexane/EtOAc 1/1) [silica gel, p-anisaldehyde]
Analysis:
Calc for C63H78O10Si (1023.37)
Calcd:
Found:
C, 73.94%; H, 7.68%
C, 73.92%; H, 7.86%
Determination of Configuration at C(9) in Aldol Adduct 15, (C(19) in RK-397).
BnMe2Si
O
Ph
Me
OPMB
O
(R)- or (S)- MTPA chloride
Pyridine
Me
Me
9
CDCl3
24 hrs
O
O
O
O
OH O
Ph
Ph
Ph
Ph
Ph
(R)-MTPA
15
O
O
O
PMBO
Me
O
O
O
O
O
SiMe2Bn
9
Me Me
31
In an NMR tube was placed a solution of 15 (4.1 mg, 0.0039 mmol) in CDCl3 (0.75 mL). To the
solution was added sequentially pyridine (0.02 mL) and (R)- or (S)-α-mehoxy-α-trifluoromethyl-
phenylacetyl chloride (5.6 µL, 0.031 mmol, 8.0 equiv). The reaction mixture was thoroughly
mixed and was let stand for 24 h at rt. The crude Mosher ester 31 was analyzed by NMR and
found to be of S configuration.

Denmark and Fujimori
S29
From (R)-MTPA-31
Ph
Ph
Ph
(R)-MTPA
O
O
O
PMBO
Me
O
O
O
O
O
SiMe2Bn
11
9
8
10
Me Me
δ H2C(8) = 2.86 ppm
δ H2C(11) = 3.80 ppm
From (S)-MTPA-31
Ph
Ph
Ph
(S)-MTPA
O
O
O
PMBO
Me
O
O
O
O
O
SiMe2Bn
11
9
8
10
Me Me
δ H2C(8) = 2.90 ppm
δ H2C(11) = 3.62 ppm
Difference in chemical shifts:
ΔδSR H2C(18) = + 0.04 ppm
ΔδSR HC(21) = - 0.18 ppm

Denmark and Fujimori
S30
Acetonide 27
Me
O
53
46
41
34
52
33
32
45
44
40
39
51
50
BnMe2Si
O
Ph
36
Me
38
49
Me Me
43
42
31
1. Me4NHB(OAc)3
2. Me2C(OMe)2
CSA
OPMB
Me
O
48
30
37 O
O
O
O
O
35
O
O
O
O
1
19
27
28
25
26
20
22
Me
23
Me
21
13
11
9
17
15
Si
Me Me
7
5
3
12
4
18
8
14
10
2
16
6
O
O
O
O
OH
O
2
9
Me Me
24
24'
47
23'
Ph
Ph
15
27
In a 100-mL, round-bottom flask were placed 15 (1.34 g, 1.31 mmol), acetonitrile (7 mL)
o
and acetic acid (7 mL). The solution was cooled to 0 C (bath temperature) using an ice bath.
To the solution was added tetramethylammonium triacetoxyborohydride (1.72 g, 6.55 mmol, 5.0
o
equiv), and the reaction mixture was stirred at 0 C for 10 h. The reaction was quenched with
saturated aqueous sodium potassium tartrate (50 mL) and the mixture was transferred to a 125-
mL separatory funnel and then was extracted with dichloromethane (2 x 30 mL). The combined
organic extracts were washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20
mL), then was dried over Na2SO4 and concentrated under reduced pressure to afford a crude diol
(1.89 g). In a 100-mL, round-bottom flask were placed the crude diol (1.89 g), dichloromethane
(60 mL), 2,2-dimethoxypropane (1.59 mL, 13.1 mmol, 10.0 equiv) and dl-camphorsulfonic acid
(5 mg). The solution was stirred at rt for 6 h. The reaction was quenched with saturated
aqueous NaHCO3 solution (30 mL) and the biphasic mixture was transferred to a 250-mL
separatory funnel. The aqueous layer was extracted with dichloromethane (30 mL) and the
combined organic extracts were washed with saturated aqueous NaHCO3 solution (30 mL) and
brine (30 mL). The extracts were dried over Na2SO4 and concentrated under reduced pressure.
The resulting crude oil was chromatographed (silica gel, hexane/EtOAc 9/1 to 5/1, 50 mm) to
afford 1.21 g (1.14 mmol, 87%) of 27 as white foam.
Data for 27:
mp:
61 - 62 oC
1H NMR:
(500 MHz, CDCl3)
7.53 – 7.50 (m, 6 H, 2 x HC(32), 2 x HC(39), 2 x HC(44)); 7.39 – 7.30 (m, 9 H,
HC(34), 2 x HC(33), HC(41), 2 x HC(40), HC(46), 2 x HC(45)); 7.27 (d, J = 7.1,