Phormidolides B and C, cytotoxic agents from the sea: Enantioselective synthesis of the macrocyclic core

Article abstract of DOI:10.1002/chem.201404341

New cytotoxic polyketide macrolides named phormidolides B and C were isolated from a marine sponge of the Petrosiidae family collected off the coast of Pemba (Tanzania). The isolation, structure elucidation, and enantioselective synthesis of three diastereomers of the macrocyclic core is described herein. The described synthetic methodology started from 2-deoxy-d-ribose or 2-deoxy-l-ribose and afforded the desired macrocycles with high enantiomeric purity. The key step of the synthesis is the formation of the Z-trisubstituted double bond using a Julia-Kocienski olefination. The versatility of the synthetic methodology may provide access to other enantiopure macrocycles by making changes in the starting materials or chiral inductors.

Full text of DOI:10.1002/chem.201404341

Supporting Information
ꢀ
Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2014
Phormidolides B and C, Cytotoxic Agents from the Sea:
Enantioselective Synthesis of the Macrocyclic Core
[
a, b]
[a, b]
[f]
[f]
Adriana Lorente,
Fernando Albericio,
Alejandro Gil,
Rogelio Fernꢀndez, Carmen Cuevas,
[
a, b, c, d]
[a, b, e]
and Mercedes ꢁlvarez*
chem_201404341_sm_miscellaneous_information.pdf

TABLE OF CONTENTS
1
2
3
4
5
6
7
8
. General Procedures
SI 1
. Isolation of phormidolides B and C
. NMR data table and characterization of phormidolides B and C
. J-based configuration analysis
SI 2
SI 3
SI 5
. Experimental procedures and characterization
. NMR data table of macrocycles 1a-c
. NMR spectra of compounds
SI 7
SI 26
SI 27
SI 165
. References
1
. General Procedures
Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) were dried using a PureSolv
solvent purification system. All other solvents and reagents were used as purchased without further
purification, unless otherwise indicated. Flash column chromatography was performed on silica gel
(
60A 35-70 µm) as stationary phase. Analytical TLC was performed on pre-coated silica gel 60 F254
plates (0.2 mm thick, 20x20 cm) and visualized under UV light (254 and 360 nm), with anisaldehyde in
conc. H SO or with phosphomolybdic acid in ethanol. Polarimetry studies were performed on a Perkin-
2
4
Elmer 241 or JascoP-2000 polarimeter equipped with a Na-lamp. IR spectra were recorded on a
Thermo Nicolet FT-IR Nexus spectrometer. For the isolation H and 13C-NMR were recorded on a
Varian Unity 300MHz or a Varian Unity 500MHz; for the synthesis were recorded on a Varian
Mercury 400MHz or a Varian VNMRS500 500MHz. Chemical shifts are reported in ppm referenced to
1
3
the appropriate residual solvent peaks (CDCl ) and coupling constants are reported in Hz. Multiplicity
of the carbons was assigned with gHSQC experiments. Standard abbreviations for off-resonance
decoupling were employed: s = singlet, d = doublet, t = triplet, q = quadruplet, bs = broad singlet, bd =
broad doublet, m = multiplet. The same abbreviations were also used for the multiplicity of signals in
1H-NMR. High Resolution Mass Spectroscopy (HRMS) was performed an Agilent LC/MSD-TOF
2
006 system using the ESI-MS technique.

2
. Isolation of Phormidolides B and C
Phormidolides B and C
Scheme 1. Isolation of phormidolides B and C.
The frozen sponge (146 g, ORMA 41004) was triturated and extracted with a mixture of
MeOH-CH
reduced pressure to yield a crude of 6.7 g. This material was chromatographed (VLC) on Lichroprep
RP-18 with a stepped gradient from H O to MeOH and then to CH Cl . The fraction eluted with MeOH
340 mg) was subjected to flash Silica gel CC eluting with a gradient of hexane:EtOAc:MeOH to yield
2 2
Cl (50:50, 3 × 500 mL) at 23 ºC (Scheme 1). The organic extract was evaporated under
2
2
2
(
4
fractions (S1 to S4). Fraction S3 (hexane:EtOAc 20:80) was subjected to semipreparative reversed
CN in 30 min, UV detection, flow 3.8 mL/min) to
phase HPLC (SunFire, 10 ×150 mm, 100% of CH
3
yield phormidolide B (34.7 mg) and phormidolide C (8.3 mg).
Table 1. GI50 values for Phormidolides B and C.
SI 1

Compound
Phormidolide B
Phormidolide C
A-549
1.4 µM
1.3 µM
HT-29
1.3 µM
0.8 µM
MDA-MB-231
1.0 µM
0.5 µM
Lung (A-549), colon (HT-29) and breast (MDA-MB-231) cancer cell lines.
3
. NMR data table of phormidolides B and C. Spectra recorded in CDCl
3
(
500MHz)
Phormidolide B
H, mult, J (Hz)
Phormidolide C
H, mult, J (Hz)
C, mult
171.1, s
39.5, t
C, mult
1
2
3
4
5
6
7
8
9
-
-
171.1, s
39.5, t
2
.72, dd, 13.5, 11.9
2.73, dd, 13.5, 12.2
2.36, dd, 13.5, 3.0
2.34, dd 13.5, 3.0
4.74, brd, 11.8
71.9, d
121.6, d
133.1, s
36.4, t
4.75, brd, 12.2
71.9, d
121.5, d
133.2, s
36.4, t
5.36, brs
-
5.37, brs
-
1
1
.91, dd, 16.8, 10.9
.76, dd, 16.8, 2.5
1.90, brd, 16.1, 11.2
1.78, dd, 16.1, 2.9
3.86, m
63.3, d
43.2, t
3.85, m
63.3, d
43.2, t
1
1
.45, ddd, 13.2, 13.2, 3.6
.30, ddd, 13.2, 13.2, 3.5
1.46, dd, 13.5, 13.5
1.31, dd, 13.5, 13.5
1.71, m
24.9, d
39.6, t
1.72, m
24.9, d
39.6, t
1
.94, dd, 12.4, 12.4
.15, ddd, 12.4, 12.4, 4.9
1.95, dd, 12.4, 12.4
1.17, ddd, 12.4, 12.4, 4.9
1
1
1
1
0
1
1
2
3
4.34, ddd, 12.4, 8.4, 4.9
77.6, d
34.3, t
4.36, ddd, 12.4, 8.3, 4.9
77.6, d
34.3, t
2.41, d, 14.4
2.43, d, 14.4
2.11, ddd 13.7, 7.8, 3.9
2
.09, ddd 13.4, 8.0, 4.0
5.22, dd, 3.4, 3.4
75.2, d
5.24, dd, 3.9, 3.9
75.3, d
SI 2

1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3.81,dd, 8.6, 3.4
4.59, dd, 8.6, 8.6
5.36, d, 8.6
-
83.9, d
66.6, d
129.0, d
137.6, s
42.0, t
3.84, dd, 8.3, 3.4
4.64, dd, 8.3, 8.3
5.37, d, 8.3
-
83.8, d
66.8, d
128.9, d
137.8, s
41.9, t
2.30, brd, 13.4
2.32, d, 13.2
2.06, dd, 13.2, 10.8
2.05, dd, 13.4, 10.9
3.67, dd, 10.9, 2.0
77.3, d
40.3, s
81.6, d
35.1, t
3.68, brd, 10.8
77.2, d
40.4, s
81.6, d
35.1, t
-
-
3.83, brd, 10.9
3.83, d, 10.7
1
1
.63, m
.44, m
1.62, m
1.43, m
4.06, brd, 10.4
1.47, m
77.8, d
41.5, d
74.0, d
39.3, t
4.07, brd, 9.8
1.44, m
77.8, d
41.5, d
74.0, d
39.4, t
3.95, ddd, 6.5, 6.5, 1.0
3.97, dd, 8.5, 8.5
1
1
.80, m
.74, m
1.80, m
1.74, m
4.95, dddd, 6.8, 6.8, 6.8, 6.8
70.6, d
39.3, t
4.96, dddd, 6.8, 6.8, 6.8, 6.8
70.6, t
2
2
.57, dd, 14.4, 6.8
.53, dd, 14.4, 6.8
2.58, dd, 14.2, 7.3
2.53, dd, 14.2, 5.9
39.4, t
-
138.2, s
158.3, s
78.9, d
23.0, q
20.6, q
17.0, q
21.7, q
13.8, q
5.0, q
-
138.2, s
158.3, s
78.6, d
23.0, q
20.6, q
17.2, q
21.6, q
13.8, q
4.9, q
-
-
5.33, s
1.69, s
0.83, d, 6.4
1.77, s
0.73, s
0.88, s
0.91, d, 7.0
5.33, s
1.70, s
0.84, d, 6.9
1.79, s
0.74, s
0.90, s
0.93, d, 7.5
5
5
.41, d, 1.0
.36, d, 1.0
5.42, d, 0.9
5.37, d, 0.9
122.1, d
173.7, s
34.6, t
122.2, t
173.8, s
34.6, t
-
-
2.27, t, 7.0
1.58, m
2.27, dd, 7.8, 7.3
1.58, m
24.8, t
24.9, t
SI 3

4
4
2-
6
1
.27, m
28.5, t
29.1-29.0, t
33.0, t
1.27, m
1.27, m
1.39, m
1.62, m
2.91, dd, 7.8, 6.8
-
28.6, t
29.4-28.4, t
28.4, t
4
7
1.40, m
2.14, ddd, 6.7, 6.7, 6.7
6.01, ddd, 15.4, 6.7, 6.7
6.06, d, 15.4
-
4
4
5
5
5
8
9
0
1
2
140.4, d
116.7, d
129.7, s
116.5, d
55.6, q
29.5, t
33.3, t
131.3, s
105.7, d
55.6, q
6.36, s
6.53, s
OMe
3.58, s
3.59, s
Phormidolide B: [α]
D
= 6.4 (c 0.4, CHCl
3
). IR (KBr film)  3397 (br), 2930, 2855, 1732, 1607,
457, 1377, 1277, 1179, 1150 cm . MS (API-ES) 1103 (M+Na, 100), 1105 (M+Na, 45), 1102 (M+Na,
7), 1107 (M+Na, 8).
-
1
1
3
Phormidolide C: [α]
D
=  (c 0.1, CHCl ). IR (KBr film)  3377 (br), 2925, 2854, 1732, 1679,
3
-
1
1
607, 1440, 1378, 1277, 1200, 1121 cm . MS (API-ES) 1149 (M+Na, 100), 1150 (M+Na, 58), 1152
(
M+Na, 40) 1148 (M+Na, 25), 1154 (M+Na, 9)
1
Fatty acid of phormidolide B: . H NMR (400 MHz, CDCl
3
) δ 1.271.37 (m, 10H); 1.391.45 (m,
2
6
2
H); 1.591.67 (m, 2H); 2.132.18 (m, 2H); 2.35 (t, J = 7.4 Hz, 2H); 6.02 (dt, J = 14.9, 6.0 Hz, 1H);
1
3
.07 (d, J = 14.9 Hz, 1H); 6.37 (s) . C NMR (100.6 MHz, CDCl
9,3 (t); 33.1 (t); 34.1 (t); 116.7 (d); 116.9 (d); 129.9 (s); 140.6 (d); 179.9 (s). MS (API-ES) 311
O+H, 100), 313 (M+H O+H, 65), 312 (M+H O+H, 15).
3
) δ 24.8 (t); 28.7 (t); 29.0 (t); 29,1 (t);
(
M+H
2
2
2
4
. J-based configuration analysis
Determination of the relative stereochemistry of C9 and C7 to C11:
Protons 10CH
and CH
8
are systems with the characteristic of having two large J-coupling
2
2
constants and one small, meaning each one has a proton in an anti-relationship[1] (J-coupling constants
were determined based on 1D-TOCSY experiments).
L H
As an example, assuming that H10 has H11 in an anti-relationship, and H10 has H9 in an
anti-relationship, for those two cases, two dispositions are possible. With the aid of ROESY
experiments, the right relative disposition is revealed for each case. Combination of the two relative
dispositions C11-C10 and C10-C9 provides the relative disposition of C11-C9 (Figure 1). Same
procedure is followed to obtain the relative stereochemistry of C9-C7 (Figure 2).
SI 4

Figure 1. Determination of relative stereochemistry of C9-C11.
Figure 2. Determination of relative stereochemistry of C7-C9.
SI 5

Determination of the relative stereochemistry of C14-C15:
Protons H14 and H15 exist on a conformation where their coupling constant value is that of
J
(H14,H15) = 8.6 Hz, indicating a dominant anti disposition for those protons.[2] A single conformer with a
correct configuration can be deduced based on the lack of observation of correlation signal in the
ROESY spectra, given that in the case of the H/H-anti and C/C-gauche conformation, if present, H-13
and H-16 should come within the range of NOE.[2]
Figure 3. Determination of relative stereochemistry of C14-C15.
5
. Experimental procedures and characterization
General procedure for the preparation of triol S1: [3]
Ethyl (triphenylphosphoranylidene)acetate (1.1 eq.) was added to a solution of sugar (1 eq.) in
THF. The solution was stirred at reflux temperature for 5 h and the solvent was removed under reduced
2 2
pressure. Purification by silica gel column chromatography with CH Cl -MeOH (95:5 to 90:10) yielded
the corresponding triol S1 as a colorless oil.
Ethyl (5S,6R,E)-5,6,7-trihydroxyhept-2-enoate (S1a).
2
-Deoxy-D-ribose (3.40 g, 25.5 mmol) led to triol S1a (4.9 g, 94%). IR
-
1 1
(
KBr film)  3380, 2981, 2936, 1701, 1654, 1370, 1270, 1173 cm . H
NMR (400 MHz, CDCl ) δ 1.26 (t, J = 7.1 Hz, 3H); 2.332.52 (m, 2H);
.553.61 (m, 1H); 3.663.72 (m, 2H); 3.743.82 (m, 1H); 3.934.13 (m, 3H, OH); 4.15 (q, J = 7.1,
3
3
2
3
13
H); 5.91 (d, J = 15.7, 1H); 6.98 (dt, J = 15.7, 7.5 Hz, 1H). C NMR (100.6 MHz, CDCl
5.8 (t); 60.5 (t); 63.1 (t); 71.5 (d); 74.0 (d); 123.6 (d); 145.8 (d); 166.9 (s). HRMS (+ESI): m/z calcd.
(M+H) 205.1076, found 205.1068.
3
) δ 14.2 (q);
9 17 5
for C H O
Ethyl (5R,6S,E)-5,6,7-trihydroxyhept-2-enoate (S1b).
2
-Deoxy-L-ribose (627 mg, 4.67 mmol) led to triol 1b (875 mg, 92%).
1H NMR (400 MHz, CDCl
3
) δ 1.26 (t, J = 7.1 Hz, 3H); 2.332.52 (m,
2
H); 3.553.61 (m, 1H); 3.663.72 (m, 2H); 3.743.82 (m, 1H);
3
.934.13(m, 3H, OH); 4.15 (q, J = 7.1, 2H); 5.91 (d, J = 15.7, 1H); 6.98 (dt, J = 15.7, 7.5 Hz, 1H).
SI 6

General procedure for the preparation of the tetrahydrofuran ring: [3]
NaEtO (0.1 eq.) was added to a solution of S1 (1 eq.) in EtOH. The reaction mixture was
stirred at r.t. for 24 h. The solvent was removed under reduced pressure and the residue was filtered
through a pad of silica with CH
2 2
Cl -MeOH (90:10) to yield the corresponding tetrahydrofuran 4 as a
mixture of diastereomers A:B (60:40).
Ethyl 2-[(2RS,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]acetate (4a).
Triol S1a (13.50 g, 64.4 mmol) led to tetrahydrofuran 4a (10.56 g, 80%) as a
mixture of diastereomers A:B (60:40). IR (KBr film)  3409, 2981, 2935,
-
1 1
1
731, 1370, 1303, 1197 cm . H NMR (400 MHz, CDCl
3
) δ 1.26 (t, J = 7.1
Hz, 3HA+B); 1.80 and 1.92 (ddd, J = 13.1, 6.5, 5.4 Hz and ddd, J = 13.1, 9.4, 6.4 Hz, 1HA+B); 2.04 and
2
3
4
.44 (ddd, J = 13.1, 5.8, 2.6 Hz and dt, J = 13.1, 7.1 Hz, 1HB+A); 2.592.66 and 2.712.78 (2m, 2HA+B);
.583.57 (m, 2HA+B); 3.853.96 (m, 1HA+B); 4.16 (q, J = 7.1 Hz, 2HA+B); 4.314.40 (m, 1HA+B);
1
3
.454.57 (m, 1HA+B). C NMR (100.6 MHz, CDCl
); 60.7 (t ); 60.8 (t ); 62.3 (t ); 62.9 (t ); 72.6 (d
); 171.3 (s ); 171.6 (s ). HRMS (+ESI): m/z calcd. for C
3
) δ 14.1 (q
A
+q
); 74.4 (d
(M+H) 205.1076, found 205.1065.
B
); 39.9 (t
B
); 40.0 (t
A
); 40.6(t
B
); 40.8
(
(
t
A
A
B
A
B
A
); 73.1 (d
B
A
); 74.5(d
B
); 85.4 (d
A
); 87.1
d
B
B
A
9
H
17
O
5
Ethyl 2-[(2RS,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]acetate (4b).
Triol S1b (280 mg, 2.8 mmol) led to tetrahydrofuran 4b (517 mg, 89%) as a
mixture of diastereomers A:B (60:40). IR (KBr film)  3340 (bs), 2980,
-
1 1
2
935, 1730, 1304, 1094 cm . H NMR (400 MHz, CDCl
3
) δ 1.26 (t, J = 7.1
Hz, 3HA+B); 1.80 and 1.92 (ddd, J = 13.1, 6.5, 5.4 Hz and ddd, J = 13.1, 9.4, 6.4 Hz, 1HA+B); 2.04 and
2
3
4
4
.44 (ddd, J = 13.1, 5.8, 2.6 Hz and dt, J = 13.1, 7.1 Hz, 1HB+A); 2.592.66 and 2.712.78 (2m, 2HA+B);
.583.67 (m, 2HA+B); 3.853.96 (m, 1HA+B); 4.16 (q, J = 7.1 Hz, 2HA+B); 4.314.40 (m, 1HA+B);
.454.57 (m, 1HA+B). 13C NMR (100.6 MHz, CDCl
0.9 (t ); 60.8 (t +t ); 62.4 (t ); 63.0 (t ); 72.7 (d ); 73.2 (d
); 171.4 (s ); 171.7 (s ). HRMS (+ESI): m/z calcd. for C
+q
); 40.0 (t
); 40.2 (t
); 40.7 (t
);
3
) δ 14.2 (q
A
B
B
A
B
A
A
B
A
B
A
B
); 74.5 (d
A
); 74.6 (d
B
); 85.5 (d
A
); 87.2
(
d
B
B
A
9
H
17
O
5
(M+H) 205.1076, found 205.1065.
General procedure for TBDPS protection:
TBDPSCl (0.95 eq) was added to a solution of diol 4a or 4b (1 eq.), Et
0.1 eq.) in CH Cl . The reaction mixture was stirred at r.t. for 48 h. After this time, the reaction
mixture was washed with 1M aqueous HCl, dried over MgSO , filtered and the solvent was removed
under reduced pressure. Purification by silica gel column chromatography with hexane-CH Cl -Et
50:30:20) yielded 5a (45%) and 5b (28%) or 5c (28%) and 5d (48%) respectively as colorless oils.
3
N (2 eq.) and DMAP
(
2
2
4
2
2
2
O
(
Ethyl 2-[(2S,4S,5R)-5-(tert-butyldiphenylsilyloxymethyl)-4-hydroxytetrahydrofuran-2-yl]acetate
5a).
(
[
α]
D
= +14.0 (c 1.0, CHCl
3
). IR (KBr film)  3450, 2931, 2857, 1735,
) δ 1.06 (s, 9H); 1.25 (t, J
-
1 1
1
427, 1112 cm . H NMR (400 MHz, CDCl
3
SI 7

=
7.1 Hz, 3H); 1.79 (ddd, J = 13.2, 6.3, 4.6 Hz, 1H); 2.47 (dt, J = 13.2, 7.2 Hz, 1H); 2.63 (dd, J = 15.7,
6
1
7
.0 Hz, 1H); 2.72 (dd, J = 15.7, 6.4 Hz, 1H); 3.62 (dd, J = 10.6, 6.0 Hz, 1H); 3.75 (dd, J = 10.6, 3.9 Hz,
H); 3.98 (dt, J = 6.0, 3.9 Hz, 1H); 4.15 (q, J = 7.1 Hz, 2H); 4.424.53 (m, 2H); 7.357.45 (m, 6H);
1
3
3
.637.69 (m, 4H). C NMR (100.6 MHz, CDCl ) δ 14.2 (q); 19.2 (s); 26.8 (q); 39.9 (t); 40.9 (t); 60.5
(
(
t); 64.8 (t); 74.5 (d); 75.0 (d); 85.7 (d); 127.7 (d); 129.8 (d); 133.1 (s); 135.5 (d); 171.4 (s). HRMS
+ESI): m/z calcd. for C25 NaSi (M+Na) 465.2073, found 465.2083.
34 5
H O
Ethyl 2-[(2R,4S,5R)-5-(tert-butyldiphenylsilyloxymethyl)-4-hydroxytetrahydrofuran-2-yl]acetate
5b).
(
[
α]
D
= +12.1 (c 1.0, CHCl
3
). IR (KBr film)  3450, 2931, 2857, 1735,
427, 1112 cm . H NMR (400 MHz, CDCl ) δ 1.05 (s, 9H); 1.25 (t, J
7.1 Hz, 3H); 1.84 (ddd, J = 13.1, 9.6, 6.2 Hz, 1H); 2.06 (ddd, J =
-
1 1
1
3
=
1
1
4
3.1, 5.7, 2.3 Hz, 1H); 2.48 (dd, J = 15.4, 6.0 Hz, 1H); 2.64 (dd, J = 15.4, 7.1 Hz, 1H); 3.58 (dd, J =
0.6, 6.0 Hz, 1H); 3.76 (dd, J = 10.6, 3.9 Hz, 1H); 3.863.90 (m, 1H); 4.14 (q, J = 7.1 Hz, 2H); 4.43-
.48 (m, 1H); 4.514.60 (m, 1H); 7.357.45 (m, 6H); 7.637.69 (m, 4H). 13C NMR (100.6 MHz,
CDCl
27.7 (d); 129.7 (d); 133.1 (s); 135.5 (d); 171.0 (s). HRMS (+ESI): m/z calcd. for C25
M+Na) 465.2073, found 465.2083.
3
) δ 14.2 (q); 19.2 (s); 26.8 (q); 40.5 (t); 40.6 (t); 60.5 (t); 64.6 (t); 74.3 (d); 74.6 (d); 86.9 (d);
1
34 5
H O
NaSi
(
Ethyl 2-[(2S,4R,5S)-5-(tert-butyldiphenylsilyloxymethyl)-4-hydroxytetrahydrofuran-2-yl]acetate
(
5c).
[
α]
D
= 11.2 (c 1.0, CHCl
3
). IR (KBr film)  3449 (br), 2931, 2857,
736, 1428, 1113 cm . 1H NMR (400 MHz, CDCl
) δ 1.06 (s, 9H);
.25 (t, J = 7.1 Hz, 3H); 1.84 (ddd, J = 13.1, 9.6, 6.2 Hz, 1H); 2.07
-
1
1
1
3
(
(
ddd, J = 13.1, 5.8, 2.3 Hz, 1H); 2.48 (dd, J = 15.4, 5.8 Hz, 1H); 2.64 (dd, J = 15.4, 7.1 Hz, 1H); 3.59
dd, J = 10.6, 6.0 Hz, 1H); 3.76 (dd, J = 10.6, 3.8 Hz, 1H); 3.863.90 (m, 1H); 4.14 (q, J = 7.1 Hz, 2H);
4
.434.47 (m, 1H); 4.55 (ddt, J = 9.6, 7.1, 5.8 Hz, 1H); 7.357.45 (m, 6H); 7.637.69 (m, 4H). 13C
NMR (100.6 MHz, CDCl ) δ 14.2 (q); 19.2 (s); 26.8 (q); 40.6 (t); 40.6 (t); 60.5 (t); 64.6 (t); 74.3 (d);
4.6 (d); 86.9 (d); 127.7 (d); 129.7 (d); 133.1 (s); 133.2 (s); 135.5 (d); 135.6 (d); 171.0 (s). HRMS
+ESI): m/z calcd. for C25 NaSi (M+Na) 465.2073, found 465.2067.
3
7
(
34 5
H O
Ethyl 2-[(2R,4R,5S)-5-(tert-butyldiphenylsilyloxymethyl)-4-hydroxytetrahydrofuran-2-yl]acetate
5d).
(
[
α]
D
= 15.1 (c 1.0, CH
2
Cl
2
). IR (KBr film)  3449 (br), 2931, 2857,
736, 1428, 1113 cm . H NMR (400 MHz, CDCl ) δ 1.06 (s, 9H);
.25 (t, J = 7.1, 3H); 1.70 (ddd, J = 13.5, 6.2, 4.7 Hz, 1H); 2.48 (dt, J =
-
1
1
1
1
3
1
6
2
3.5, 7.2 Hz, 1H); 2.55 (dd, J = 15.6, 6.0 Hz, 1H); 2.75 (dd, J = 15.6, 7.6 Hz, 1H); 3.62 (dd, J = 10.5,
.1 Hz, 1H); 3.76 (dd, J = 10.5, 4.1 Hz, 1H); 3.97 (m, 1H); 4.15 (q, J = 7.1 Hz, 2H); 4.454.52 (m,
13
3
H); 7.357.45 (m, 6H); 7.637.69 (m, 4H). C NMR (100.6 MHz, CDCl ) δ 14.3 (q); 19.3 (s); 27.0
SI 8

(
(
q); 40.0 (t); 41.0 (t); 60.7 (t); 65.0 (t); 74.8 (d); 75.1 (d); 85.9 (d); 127.9 (d); 129.9 (d); 133.2 (s); 135.7
d); 171.6 (s). HRMS (+ESI): m/z calcd. for C25 Si (M+NH ) 460.2514, found 460.2511.
H
38NO
5
4
Ethyl 2-[(2S,5S)-5-(tert-butyldiphenylsilyloxymethyl)-4-oxotetrahydrofuran-2-yl]acetate (S2).
DMP (10.4 g, 24.5 mmol) was added to a solution of alcohol 5c (8.35
g, 18.8 mmol) in CH
reaction mixture was dissolved with sat. Na
the residue was extracted with Et O. The organic extracts were dried over MgSO
concentrated under reduced pressure. Purification by silica gel column chromatography with hexane-
EtOAc (80:20) yielded S2 (7.45 g, 90%) as a colorless oil. [α] = 94.4 (c 1.0, CHCl ). IR (KBr film) 
931, 2858, 1762, 1737, 1472, 1428, 1194, 1113 cm . H NMR (400 MHz, CDCl ) δ 1.03 (s, 9H); 1.29
t, J = 7.1 Hz, 3H); 2.32 (dd, J = 17.7, 10.3 Hz, 1H); 2.692.77 (m, 2H); 2.94 (dd, J = 15.8, 6.7 Hz,
2
Cl
2
(100 mL) and was stirred for 2 h. The
and sat. NaHCO and
, filtered and
2
S
2
O
3
3
2
4
D
3
-
1 1
2
3
(
1
1
H); 3.87 (dd, J = 11.6, 2.8 Hz, 1H); 3.903.94 (m, 2H); 4.21 (qd, J = 7.1, 1.8 Hz, 2H); 4.65 (dtd, J =
0.3, 6.7, 5.8 Hz, 1H); 7.367.45 (m, 6H); 7.657.74 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 14.2
3
(
(
q); 19.2 (s); 26.7 (q); 40.9 (t); 43.5 (t); 60.8 (t); 63.0 (t); 72.2 (d); 82.2 (d); 127.7 (d); 129.7 (d); 132.7
s); 132.9 (s); 135.6 (d); 170.3 (s); 213.7 (s). HRMS (+ESI): m/z calcd. for C25 NaSi (M+Na)
63.1911, found 463.1910.
32 5
H O
4
Ethyl 2-[(2S,4S,5S)-5-(tert-butyldiphenylsilyloxymethyl)-4-hydroxytetrahydrofuran-2-yl]acetate
5e).
(
NaBH
4
(953 mg, 25.2 mmol) was added to a solution of ketone S2
5.56 g, 12.6 mmol) and CeCl ·7H O (5.16 g, 13.9 mmol) in EtOH
200 mL) at 20 ºC. The reaction mixture was stirred at this
Cl was added and the solvent was removed under reduced
pressure. The residue was extracted with EtOAc, and the organic layer was dried over MgSO , filtered
and the solvent was removed under reduced pressure. Purification by silica gel column chromatography
with hexane-EtOAc (80:20) yielded 5e (4.8 g, 86%) as a colorless oil. [α] = 5.0 (c 1.0, CHCl ). IR
KBr film)  3469, 2932, 2858, 1735, 1472, 1428, 1112 cm . H NMR (400 MHz, CDCl ) δ 1.06 (s,
H); 1.24 (t, J = 7.1 Hz, 3H); 1.80 (ddd, J = 13.4, 6.0, 3.1 Hz, 1H); 2.42 (ddd, J = 13.4, 7.9, 6.2 Hz,
(
(
3
2
temperature for 40 min. After this time, NH
4
4
D
3
-
1 1
(
3
9
1
3
7
H); 2.65 (dd, J = 16.0, 6.0 Hz, 1H); 2.77 (dd, J = 16.0, 6.9 Hz, 1H); 3.81 (dt, J = 5.7, 4.2 Hz, 1H);
.96 (dd, J = 10.9, 4.2 Hz, 1H); 4.00 (dd, J = 10.9, 5.7 Hz, 1H); 4.14 (q, J = 7.1 Hz, 2H); 4.34 (ddt, J =
.9, 6.9, 6.0 Hz, 1H); 4.484.53 (m, 1H); 7.367.45 (m, 6H); 7.657.73 (m, 4H). 13C NMR (100.6
MHz, CDCl
d); 127.8 (d); 129.9 (d); 133.5 (s); 133.8 (s); 135.5 (d); 135.6 (d); 171.4 (s). HRMS (+ESI): m/z calcd.
Si (M+H) 443.2248, found 443.2251.
3
) δ 14.2 (q); 19.1 (s); 26.8 (q); 40.5 (t); 40.8 (t); 60.5 (t); 63.1 (t); 73.6 (d); 74.0 (d); 81.5
(
35 5
for C25H O
General procedure for TBS protection:
2 2
TBSCl (1.2 eq.) was added to a solution of alcohol 5 (1 eq.) and imidazole (1 eq.) in CH Cl
(
180 mL). The reaction mixture was stirred at r.t. for 6 or 48 h. After this time, the mixture was washed
with water, dried over MgSO
4
, filtered and the solvent was removed under reduced pressure.
SI 9

Purification by silica gel column chromatography with hexane-EtOAc (90:10) yielded the
corresponding protected adduct S3 as a colorless oil.
Ethyl 2-[(2S,4S,5R)-4-(tert-butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]acetate (S3a).
Alcohol 5a (8.8 g, 20 mmol) led to S3a (9.99 g, 90%). [α]
D
= +26.0 (c
1
1
.0, CHCl
3
). IR (KBr film)  2955, 2930, 2857, 1737, 1471, 1428,
-
1 1
256, 1112 cm . H NMR (400 MHz, CDCl
3
) δ 0.05 (s, 3H); 0.06 (s,
3
1
5
H); 0.88 (s, 9H); 1.05 (s, 9H); 1.25 (t, J = 7.1 Hz, 3H); 1.71 (dt, J = 13.0, 4.4 Hz, 1H); 2.29 (dt, J =
3.0, 6.7 Hz, 1H); 2.60 (dd, J = 15.3, 6.7 Hz, 1H); 2.78 (dd, J = 15.3, 7.1 Hz, 1H); 3.57 (dd, J = 11.0,
.2 Hz, 1H); 3.64 (dd, J = 11.0, 3.8 Hz, 1H); 3.943.98 (m, 1H); 4.15 (q, J = 7.1 Hz, 2H); 4.454.49
(
m, 1H); 4.57–4.50 (m, 1H); 7.347.45 (m, 6H); 7.647.69 (m, 4H). 13C NMR (100.6 MHz, CDCl
3
) δ

4.7 (q); 4.8 (q); 14.2 (q); 17.9 (s); 19.2 (s); 25.7 (q); 26.8 (q); 40.2 (t); 41.6 (t); 60.3 (t); 64.2 (t); 73.6
(
(
d); 75.4 (d); 86.8 (d); 127.7 (d); 129.6 (d); 129.7 (d); 133.2 (s); 133.4 (s); 135.6 (d); 171.5 (s). HRMS
+ESI): m/z calcd. for C31 NaSi (M+Na) 579.2938, found 579.2922.
H
48
O
5
2
Ethyl 2-[(2S,4S,5S)-4-(tert-butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]acetate (S3b).
Alcohol 5e (9.14 g, 20.6 mmol) led to S3b (10.7 g, 94%). [α]
D
= +17.2
(
c 1.0, CHCl ). IR (KBr film)  2950, 2931, 2857, 1735, 1471, 1428,
3
-
1 1
1
255, 1112 cm . H NMR (400 MHz, CDCl
H); 0.83 (s, 9H); 1.07 (s, 9H); 1.24 (t, J = 7.1 Hz, 3H); 1.73 (ddd, J = 13.2, 4.7, 2.7 Hz, 1H); 2.28
ddd, J = 13.2, 8.0, 5.4 Hz, 1H); 2.58 (dd, J = 15.5, 7.4 Hz, 1H); 2.77 (dd, J = 15.5, 6.6 Hz, 1H);
3
) δ 0.01 (s, 3H); 0.04 (s,
3
(
3
7
.733.81 (m, 1H); 3.833.90 (m, 2H); 4.094.17 (m, 2H); 4.334.52 (m, 2H); 7.347.45 (m, 6H);
1
3
.647.69 (m, 4H). C NMR (100.6 MHz, CDCl ) δ 5.2 (q); 4.7 (q); 14.2 (q); 17.9 (s); 19.2 (s); 25.7
3
(
(
q); 26.9 (q); 40.1 (t); 41.8 (t); 60.2 (t); 63.3 (t); 72.4 (d); 74.1 (d); 83.9 (d); 127.6 (d); 129.5 (d); 133.6
s); 133.8 (s); 135.6 (d); 135.7 (d); 171.5 (s). HRMS (+ESI): m/z calcd. for C31 NaSi (M+Na)
79.2938, found 579.2932.
H
48
O
5
2
5
General procedure for ester reduction:
A 1 M solution of DIBALH in heptane (1 eq.) was added to a solution of ester S3 (1 eq.) in
2 2
CH Cl at 78 ºC. The reaction mixture was stirred at this temperature for 15 min and MeOH and a
saturated solution of NaK tartrate were added, the mixture was stirred at r.t. for further 2 h. After this
time, water was added and the residue was extracted with CH Cl . The organic solution was dried over
MgSO , filtered and the solvent was removed under reduced pressure. Purification by silica gel column
2
2
4
chromatography with hexane-EtOAc (90:10) yielded the corresponding aldehyde 6 as a colorless oil.
SI 10

2
2
-[(2S,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetrahydrofuran-
-yl]acetaldehyde (6a).
Ester S3a (1.65 g, 2.96 mmol) led to aldehyde 6a (1.43 g, 94%). [α]
D
=
+
28.9 (c 1.0, CHCl ). IR (KBr film)  2955, 2930, 2857, 1726, 1471,
3
-
1 1
1
428, 1256, 1113 cm . H NMR (400 MHz, CDCl
s, 3H); 0.89 (s, 9H); 1.07 (s, 9H); 1.69 (ddd, J = 13.0, 5.3, 4.0 Hz, 1H);
.34 (ddd, J = 13.0, 7.4, 6.2 Hz, 1H); 2.66 (ddd, J = 16.7, 5.3, 2.0 Hz, 1H); 2.90 (ddd, J = 16.7, 7.4, 2.0
3
) δ 0.06 (s, 3H); 0.07
(
2
Hz, 1H); 3.61 (dd, J = 11.0, 5.0 Hz, 1H); 3.66 (dd, J = 11.0, 3.8 Hz, 1H); 3.953.99 (m, 1H); 4.484.52
13
(
m, 1H); 4.60 (tt, J = 7.4, 5.3 Hz, 1H); 7.367.46 (m, 6H); 7.667.70 (m, 4H); 9.82 (t, J = 2.0, 1H). C
NMR (100.6 MHz, CDCl ) δ 4.7 (q); 4.8 (q); 17.9 (s); 19.2 (s); 25.7 (q); 26.8 (q); 40.5 (t); 50.5 (t);
4.1 (t); 73.5 (d); 73.9 (d); 86.8 (d); 127.7 (d); 129.7 (d); 133.2 (s); 133.3 (s); 135.6 (d); 201.6 (s).
HRMS (+ESI): m/z calcd. for C29 NaSi (M+Na) 535.2670, found 535.2672.
3
6
H
44
O
4
2
2
2
-[(2S,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetrahydrofuran-
-yl]acetaldehyde (6b).
Ester S3b (7.0 g, 12.6 mmol) led to aldehyde 6b (6.43 g, 99%). [α]
D
=
+
22.9 (c 1.0, CHCl ). IR (KBr film)  2955, 2930, 2857, 1726, 1472,
3
-
1 1
1
428, 1256, 1112 cm . H NMR (400 MHz, CDCl
s, 3H); 0.81 (s, 9H); 1.07 (s, 9H); 1.66 (ddd, J = 13.4, 4.9, 2.5 Hz, 1H);
.33 (ddd, J = 13.4, 8.2, 5.5 Hz, 1H); 2.63 (ddd, J = 16.8, 5.6, 1.8 Hz, 1H); 2.85 (ddd, J = 16.8, 7.1, 2.1
3
) δ 0.02 (s, 3H); 0.02
(
2
Hz, 1H); 3.743.82 (m, 1H); 3.833.90 (m, 2H); 4.334.37 (m, 1H); 4.384.47 (m, 1H); 7.367.46
(
(
m, 6H); 7.667.70 (m, 4H); 9.78 (t, J = 1.9 Hz, 1H). 13C NMR (100.6 MHz, CDCl
q); 17.9 (s); 19.2 (s); 25.7 (q); 26.9 (q); 41.0 (t); 50.7 (t); 63.4 (t); 72.4 (d); 72.6 (d); 84.1(d); 127.6 (d);
29.5 (d); 129.6 (d); 133.5 (s); 133.8 (s); 135.6 (d); 135.7 (d); 201.7 (s). HRMS (+ESI): m/z calcd. for
NaSi (M+Na) 535.2670, found 535.2673.
3
) δ 5.2 (q); 4.7
1
C
29
H
44
O
4
2
Diethyl (R)-2-oxo-2-(2-oxo-4-phenyloxazolidin-3-yl)ethylphosphonate (7). [4]
A 50% solution of T3P in EtOAc (13 mL, 21.8 mmol) was added to a solution
of (R)-4-phenyl-2-oxazolidinone (2.45 g, 15 mmol) and
diethylphosphonoacetic acid (2.65 mL, 16.5 mmol) in EtOAc (100 mL) and
the mixture was stirred at reflux temperature for 48 h. After this time, water
was added, and the solution was treated with a 20% solution of NaOH until pH = 6. The organic phase
4
was washed with water, dried over MgSO , filtered and the solvent was removed under reduced
pressure. Purification by silica gel column chromatography with hexane-EtOAc (50:50 to 30:70)
1
yielded 7 (4.78 g, 94%) as a colorless oil. H NMR (400 MHz, CDCl
3
) δ 1.28 (dt, J = 10.3, 7.0 Hz,
6
2
H); 3.76 (dd, J = 22.2, 13.9 Hz, 1H); 3.81 (dd, J = 22.6, 13.9 Hz, 1H); 3.713.86 (m, 4H); 4.11 (m,
H); 4.28 (dd, J = 8.8, 3.9 Hz, 1H); 4.70 (t, J = 8.8 Hz, 1H); 5.46 (dd, J = 8.8, 3.9 Hz, 1H); 7.307.41
(
m, 5H).
SI 11

General procedure for HWE reaction:
A 1 M solution of NaHMDS in THF (1.3 eq.) was added to a solution of phosphonate 7 (1.4
eq.) in THF. After 10 min, a solution of aldehyde 6 (1 eq.) in THF was added dropwise, and the
mixture was stirred at r.t. for 2 h. After this time, KH
solvent was removed under reduced pressure. The residue was disolved in water and extracted with
EtOAc. The organic layer was dried over MgSO , filtered and the solvent was removed under reduced
2 4
PO -NaOH pH =7 buffer was added and the
4
pressure. Purification by silica gel column chromatography with hexane-EtOAc (90:10 to 80:20)
yielded the corresponding olefin S3 as a colorless oil.
(
R)-3-[(E)-4-((2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl)but-2-enoyl]-4-phenyloxazolidin-2-one (S4a).
Aldehyde 6a (4.18g, 8.15 mmol) led to olefin S4a (4.46 g,
7
2
1
8%). [α]
D
= 14.1 (c 1.0, CHCl ). IR (KBr film)  2954,
3
929, 2857, 1781, 1689, 1636, 1383, 1347, 1196, 1256,
-
1 1
3
252, 1112 cm . H NMR (400 MHz, CDCl ) δ 0.03 (s, 3H);
0
1
1
6
1
.05 (s, 3H); 0.87 (s, 9H); 1.04 (s, 9H); 1.66 (ddd, J = 12.8, 5.9, 4.7 Hz, 1H); 2.21 (dt, J = 12.8, 6.4 Hz,
H); 2.49–2.59 (m, 1H); 2.642.73 (m, 1H); 3.59 (dd, J = 11.0, 4.3 Hz, 1H); 3.63 (dd, J = 11.0, 3.8 Hz,
H); 3.91 (dt, J = 4.3, 3.8 Hz, 1H); 4.144.20 (m, 1H); 4.28 (dd, J = 8.8, 3.9 Hz, 1H); 4.46 (ddd, J =
.4, 4.7, 3.8 Hz, 1H); 4.69 (t, J = 8.8 Hz, 1H); 5.49 (dd, J = 8.8, 3.9 Hz, 1H); 7.09 (dt, J = 15.4, 7.3,
H); 7.307.45 (m, 12H); 7.647.68 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 4.8 (q); 17.9 (s); 19.2
3
(
(
(
s); 25.8 (q); 26.8 (q); 39.7 (t); 40.2 (t); 57.7 (d); 64.1 (t); 69.9 (t); 73.3 (d); 77.5 (d); 86.5 (d); 121.9
d); 126.0 (d); 127.6 (d); 128.6 (d); 129.1 (d); 129.6 (d); 133.2 (s); 133.4 (s); 135.6 (d); 139.0 (s); 148.2
d); 153.6 (s); 164.3 (s). HRMS (+ESI): m/z calcd. for C40
22.3309.
53 6 2
H O NNaSi (M+Na) 722.3304, found
7
(
R)-3-[(E)-4-((2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl)but-2-enoyl]-4-phenyloxazolidin-2-one (S4b).
Aldehyde 6b (5.0 g, 9.8 mmol) led to S4b (6.66 g, 95%).
α] = 14.8 (c 1.0, CHCl ). IR (KBr film)  2954, 2930,
857, 1781, 1689, 1637, 1384, 1346, 1197, 1112 cm . H
NMR (400 MHz, CDCl ) δ 0.03 (s, 3H); 0.02 (s, 3H); 0.81
s, 9H); 1.07 (s, 9H); 1.65 (ddd, J = 13.2, 5.1, 2.7 Hz, 1H); 2.20 (ddd, J = 13.2, 7.9, 5.6 Hz, 1H); 2.47–
[
D
3
-
1
1
2
3
(
2
4
2
1
.56 (m, 1H); 2.642.73 (m, 1H); 3.77 (dd, J = 9.8, 5.6 Hz, 1H); 3.803.84 (m, 1H); 3.88 (dd, J = 9.8,
.4 Hz, 1H); 4.04 (dtd, J = 7.9, 6.6, 5.1 Hz, 1H); 4.28 (dd, J = 8.8, 3.9 Hz, 1H); 4.33 (ddd, J = 5.6, 3.9,
.7 Hz, 1H); 4.68 (t, J = 8.8 Hz, 1H); 5.48 (dd, J = 8.7, 3.9 Hz, 1H); 7.08 (ddd, J = 15.4, 7.7, 6.6 Hz,
H); 7.307.45 (m, 12H); 7.647.68 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 5.3 (q); 4.7 (q); 17.9
3
(
s); 19.2 (s); 25.7 (q); 26.9 (q); 39.9 (t); 40.5 (t); 57.7 (d); 63.4 (t); 69.9 (t); 73.4 (d); 76.4 (d); 83.9 (d);
1
1
7
21.8 (d); 126.0 (d); 127.5 (d); 128.6 (d); 129.1 (d); 129.5 (d); 133.6 (s); 133.9 (s); 135.6 (d); 139.0 (s);
53 6 2
48.2 (d); 153.6 (s); 164.3 (s). HRMS (+ESI): m/z calcd. for C40H O NNaSi (M+Na) 722.3304, found
22.3300.
SI 12

General procedure for 1,4-addition:
2
A 1.4 M solution of MeMgBr in THF (1.1 eq.) was added to a solution of CuBr·Me S (1.1 eq.)
in THF at 40 ºC, and the mixture was stirred at 40 ºC for 1 h. The solution was cooled to 78 ºC and
BF ·Et O (1.1 eq.) was added, followed by a solution of oxazolidinone S4 (1 eq.) in THF. The reaction
mixture was stirred at -78 ºC for 1 h, slowly warmed to r.t. during 2 h and stirred at r.t. for further 1
hour. After this time, sat. NH Cl was added and the solvent was removed under reduced pressure. The
residue was diluted in sat. NH Cl and extracted with Et O. The organic solution was dried over MgSO
3
2
4
4
2
4
,
filtered and the solvent was removed under reduced pressure. Purification by silica gel column
chromatography with hexane-EtOAc (90:10 to 80:20) yielded the corresponding methylated 8a as a
colorless oil.
(
R)-3-[(S)-4-((2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl)-3-methylbutanoyl]-4-phenyloxazolidin-2-one (8a).
Olefin S4a (4.27 g, 6.1 mmol) led to methylated 8a (3.67 g,
8
2
1
4%). [α]
D
= 40.0 (c 1.0, CHCl ). IR (KBr film)  2956,
3
930, 2857, 1784, 1707, 1471, 1428, 1384, 1322, 1252, 1196,
-
1 1
3
112 cm . H NMR (400 MHz, CDCl ) δ 0.04 (s, 3H); 0.06
(
s, 3H); 0.88 (s, 9H); 0.94 (d, J = 6.7 Hz, 3H); 1.05 (s, 9H); 1.461.69 (m, 3H); 2.092.25 (m, 2H);
.85 (dd, J = 16.7, 7.4 Hz, 1H); 2.96 (dd, J = 16.7, 6.2 Hz, 1H); 3.64 (dd, J = 11.0, 3.9 Hz, 1H); 3.69
dd, J = 11.0, 3.9 Hz, 1H); 3.81 (dt, J = 4.5, 3.9 Hz, 1H); 4.074.16 (m, 1H); 4.24 (dd, J = 8.8, 3.6 Hz,
H); 4.47 (td, J = 6.4, 4.5 Hz, 1H); 4.62 (t, J = 8.8 Hz, 1H); 5.40 (dd, J = 8.8, 3.6 Hz, 1H); 7.277.45
m, 11H); 7.667.72 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 4.8 (q); 4.6 (q); 17.9 (s); 19.2 (s);
0.1 (q); 25.8 (q); 26.8 (q); 27.5 (d); 41.4 (t); 42.3 (t); 42.9 (t); 57.6 (d); 64.0 (t); 69.8 (t); 72.9 (d); 76.8
2
(
1
(
3
2
(
(
d); 85.5 (d); 125.8 (d); 127.6 (d); 129.1 (d); 128.6 (d); 129.1 (d); 129.5 (d); 129.6 (d); 133.4 (s); 133.5
s); 135.6 (d); 139.3 (s); 153.6 (s); 171.9 (s). HRMS (+ESI): m/z calcd. for C41 NNaSi (M+Na)
38.3617, found 738.3614.
H
57
O
6
2
7
(
R)-3-[(S)-4-((2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl)-3-methylbutanoyl]-4-phenyloxazolidin-2-one (8b).
Olefin S4b (8.0 g, 11.4 mmol) led to methylated 8b (7.73 g,
8
2
1
1%). [α]
D
= 11.1 (c 1.0, CHCl ). IR (KBr film)  2956,
3
930, 2857, 1783, 1707, 1471, 1428, 1384, 1325, 1252,
-
1
1
198, 1112 cm . H NMR (400 MHz, CDCl ) δ 0.04 (s,
3
3
1
1
H); 0.01 (s, 3H); 0.80 (s, 9H); 0.92 (d, J = 6.7 Hz, 3H); 1.06 (s, 9H); 1.49 (dt, J = 13.6, 5.9 Hz, 1H);
.53 (ddd, J = 16.6, 6.3, 3.8 Hz, 1H); 1.67 (dt, J = 13.6, 7.5 Hz, 1H); 2.102.22 (m, 2H); 2.80 (dd, J =
6.7, 7.6 Hz, 1H); 2.96 (dd, J = 16.7, 6.1 Hz, 1H); 3.713.79 (m, 2H); 3.813.94 (m, 2H); 4.23 (dd, J
=
8.8, 3.6 Hz, 1H); 4.31 (dt, J = 6.0, 3.8 Hz, 1H); 4.61 (t, J = 8.8 Hz, 1H) 5.39 (dd, J = 8.8, 3.6 Hz,
H); 7.277.46 (m, 11H); 7.667.72 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 5.2 (q); 4.6 (q); 18.0
s); 19.2 (s); 20.2 (q); 25.8 (q); 26.9 (q); 27.4 (d); 41.5 (t); 42.2 (t); 43.2 (t); 57.6 (d); 63.6 (t); 69.8 (t);
1
3
(
7
2.5 (d); 75.8 (d); 83.3 (d); 125.9 (d); 127.5 (d); 128.6 (d); 129.1 (d); 129.4 (d); 133.7 (s); 134.0 (s);
SI 13

1
35.6 (d); 135.7 (d); 139.2 (s); 153.7 (s); 171.9 (s). HRMS (+ESI): m/z calcd. for C41
57 6 2
H O NNaSi
(
M+Na) 738.3617, found 738.3612.
General procedure for oxazolidinone removal:
A 2 M solution of LiBH in THF (2 eq.) was added to a solution of olefin 8 (1 eq.) in Et
10 ºC and the reaction mixture was stirred at 0 ºC for 1 h. After this time, a 1 M solution of NaOH
was added and the mixture was extracted with EtOAc, dried over MgSO , filtered and the solvent was
4
2
O at

4
removed under reduced pressure. Purification by silica gel column chromatography with hexane-
EtOAc (90:10 to 85:15) yielded the corresponding alcohol S5 as a colorless oil.
(
R)-4-[(2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetrahydro-
furan-2-yl]-3-methylbutan-1-ol (S5a).
Oxazolidinone 8a (3.67 g, 5.12 mmol) led to alcohol S5a (2.25 g,
7
2
9%). [α]
D
= 25.8 (c 1.0, CHCl ). IR (KBr film)  3395 (br)
3
-
1 1
955, 2929, 2857, 1472, 1428, 1252, 1112 cm . H NMR (400
MHz, CDCl
.381.69 (m, 5H); 1.701.78 (m, 1H); 2.192.26 (m, 1H); 3.613.73 (m, 4H); 3.85 (dt, J = 4.2, 4.0
Hz, 1H); 4.164.23 (m, 1H); 4.49 (td, J = 6.3, 4.4 Hz, 1H); 7.347.44 (m, 6H); 7.667.72 (m, 4H). 13
NMR (100.6 MHz, CDCl ) δ 4.8 (q); 4.7 (q); 17.9 (s); 19.2 (s); 20.4 (q); 25.8 (q); 26.8 (q); 27.2 (d);
9.7 (t); 41.3 (t); 43.3 (t); 61.0 (t); 64.1 (t); 73.0 (d); 76.8 (d); 85.7 (d); 127.6 (d); 129.6 (d); 133.4 (s);
33.5 (s); 135.6 (d). HRMS (+ESI): m/z calcd. for C32 NaSi (M+Na) 579.3296, found 579.3296.
3
) δ 0.04 (s, 3H); 0.05 (s, 3H); 0.87 (s, 9H); 0.95 (d, J = 6.6 Hz, 3H); 1.05 (s, 9H);
1
C
3
3
1
H
52
O
4
2
(
R)-4-[(2R,4S,5S)-4-(tert-butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetrahydro-
furan-2-yl]-3-methylbutan-1-ol (S5b).
Oxazolidinone 8b (2.3 g, 3.21 mmol) led to alcohol S5b (1.50 g,
8
2
4%). [α]
D
= +12.8 (c 1.0, CHCl ). IR (KBr film)  3408 (br),
3
-
1 1
955, 2930, 2857, 1471, 1428, 1254, 1113 cm . H NMR (400
MHz, CDCl
3
) δ 0.04 (s, 3H); 0.01 (s, 3H); 0.80 (s, 9H); 0.93 (d, J = 6.6 Hz, 3H); 1.06 (s, 9H); 1.41
(
td, J = 13.6, 6.8 Hz, 1H); 1.461.57 (m, 2H); 1.611.69 (m, 2H); 1.721.80 (m, 1H); 2.21 (ddd, J =
1
4
2.7, 7.2, 6.2 Hz, 1H); 3.603.73 (m, 2H); 3.743.80 (m, 2H); 3.833.89 (m, 1H); 3.944.02 (m, 1H);
13
.33 (dt, J = 6.2, 3.9 Hz, 1H); 7.337.43 (m, 6H); 7.667.72 (m, 4H). C NMR (100.6 MHz, CDCl
5.2 (q); 4.6 (q); 18.0 (s); 19.2 (s); 20.6 (q); 25.7 (q); 26.9 (q); 27.0 (d); 39.8 (t); 41.5 (t); 43.5 (t);
1.1 (t); 63.6 (t); 72.6 (d); 75.9 (d); 83.3 (d); 127.5 (d); 129.4 (d); 129.5 (d); 133.7 (s); 133.9 (s); 135.6
d); 135.7 (d). HRMS (+ESI): m/z calcd. for C32 NaSi (M+Na) 579.3296, found 579.3272.
3
) δ

6
(
H
52
O
4
2
General procedure for alcohol oxidation:
Dess-Martin Periodinane (DMP, 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-
one) (1.2 eq.) was added to a solution of alcohol S5 (1 eq.) in CH Cl and was stirred for 2 h. The
reaction mixture was diluted with sat. Na and sat. NaHCO and the residue was extracted with
CH Cl . The organic extracts were dried over MgSO , filtered and concentrated under reduced
2
2
2
S
2
O
3
3
2
2
4
SI 14

pressure. Purification by silica gel column chromatography with hexane-EtOAc (95:5) yielded the
corresponding aldehyde 9 as a colorless oil.
(
S)-4-[(2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetrahydro-
furan-2-yl]-3-methylbutanal (9a).
Alcohol S5a (2.25 g, 4 mmol) led to aldehyde 9a (2.04 g, 92%).
α] = +22.2 (c 1.0, CHCl ). IR (KBr film)  2956, 2930, 2857,
727, 1472, 1428, 1252, 1112 cm . H NMR (400 MHz, CDCl
.05 (s, 3H); 0.06 (s, 3H); 0.88 (s, 9H); 1.01 (d, J = 6.5 Hz, 3H); 1.06 (s, 9H); 1.50 (ddd, J = 14.1, 6.6,
[
D
3
-
1 1
1
3
) δ
0
5
3
4
.1 Hz, 1H); 1.61 (ddd, J = 12.8, 7.3, 5.8 Hz, 1H); 1.73 (ddd, J = 14.1, 8.3, 6.4 Hz, 1H); 2.182.29 (m,
H); 2.452.55 (m, 1H); 3.66 (dd, J = 11.1, 3.9 Hz, 1H); 3.70 (dd, J = 11.1, 4.1 Hz, 1H); 3.85 (dt, J =
.1, 3.9 Hz, 1H); 4.114.19 (m, 1H); 4.474.53 (m, 1H); 7.347.44 (m, 6H); 7.667.72 (m, 4H); 9.74
(
(
(
t, J = 2.0 Hz, 1H). 13C NMR (100.6 MHz, CDCl
q); 25.8 (d); 26.8 (q); 41.4 (t); 43.2 (t); 50.6 (t); 64.1 (t); 73.0 (d); 76.4 (d); 85.8 (d); 127.6 (d); 129.6
d); 133.4 (s); 133.5 (s); 135.6 (d); 202.9 (d). HRMS (+ESI): m/z calcd. for C32 NaSi (M+Na)
77.3140, found 577.3142.
3
) δ 4.8 (q); 4.7 (q); 17.9 (s); 19.2 (s); 20.5 (q); 25.8
H
50
O
4
2
5
(
S)-4-[(2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetrahydro-
furan-2-yl]-3-methylbutanal (9b)
Alcohol S5b (5.70 g, 10.24 mmol) led to aldehyde 9b (5.2 g,
9
2
2%). [α]
D
= +11.9 (c 1.0, CHCl ). IR (KBr film)  2955, 2930,
3
-
1
1
857, 1726, 1472, 1428, 1255, 1113 cm . H NMR (400 MHz,
CDCl ) δ 0.04 (s, 3H); 0.01 (s, 3H); 0.80 (s, 9H); 0.99 (d, J = 6.5 Hz, 3H); 1.06 (s, 9H); 1.48 (ddd, J =
3
1
2
4
3.9, 6.7, 5.3 Hz, 1H); 1.56 (ddd, J = 12.9, 6.4, 3.4 Hz, 1H); 1.73 (ddd, J = 13.9, 8.0, 6.3 Hz, 1H);
.152.30 (m, 3H); 2.422.53 (m, 1H); 3.743.82 (m, 2H); 3.833.88 (m, 1H); 3.913.98 (m, 1H);
.304.35 (m, 1H); 7.347.44 (m, 6H); 7.667.72 (m, 4H); 9.73 (t, J = 2.1 Hz, 1H). 13C NMR (100.6
MHz, CDCl
3
) δ 5.2 (q); 4.6 (q); 18.0 (s); 19.2 (s); 20.6 (q); 25.7 (q); 25.8 (d); 26.9 (q); 41.6 (t); 43.4
(
t); 50.6 (t); 63.7 (t); 72.5 (d); 75.4 (d); 83.5 (d); 127.5 (d); 129.5 (d); 133.7 (s); 133.9 (s); 135.6 (d);
1
50 4 2
35.7 (d); 203.1 (d). HRMS (+ESI): m/z calcd. for C32H O NaSi (M+Na) 577.3140, found 577.3147.
General procedure for stereoselective aldol addition:
Acetone (5.5 eq.) and Et (5 eq.) were added to
chlorodiisopinocampheylborane (5 eq.) in Et O at 0 ºC and the solution was stirred at 0 ºC for 45 min.
The solution was cooled to 78 ºC, a solution of aldehyde 9 (1 eq.) was added and the reaction mixture
was stirred at 78 ºC for 1 h and at 20 ºC for 16 h. After this time, H , KH PO -NaOH pH = 7
buffer and MeOH were added and stirring continued for further 1 h. The reaction mixture was diluted
with water and extracted with Et O and EtOAc. The organic extracts were dried over MgSO , filtered
3
N
a
solution of ()-B-
2
2
O
2
2
4
2
4
and the solvent was removed under reduced pressure. Purification by silica gel column chromatography
with hexane-EtOAc (90:10 to 80:20) yielded the corresponding aldol 10 as a colorless oil.
SI 15

(
4S,6R)-7-[(2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]-4-hydroxy-6-methylheptan-2-one (10a).
Aldehyde 9a (2.04 g, 3.7 mmol) led to aldol 10a (1.51 g, 67%)
(
dr = 8:1). [α]
br), 2955, 2929, 2857, 1711, 1478, 1428, 1361, 1257, 1113 cm-
H NMR (400 MHz, CDCl ) δ 0.03 (s, 3H); 0.05 (s, 3H); 0.87
s, 9H); 0.95 (d, J = 6.7 Hz, 3H); 1.05 (s, 9H); 1.361.41 (m, 2H); 1.501.64 (m, 3H); 1.711.81 (m,
D
= 36.1 (c 1.0, CHCl ). IR (KBr film)  3454
3
(
1. 1
3
(
1
3
2
H); 2.12 (s, 3H); 2.192.26 (m, 1H); 2.46 (dd, J = 17.6, 9.0 Hz, 1H); 2.56 (dd, J = 17.6, 2.7 Hz, 1H);
.64 (dd, J = 10.9, 3.9 Hz, 1H); 3.69 (dd, J = 10.9, 3.9 Hz, 1H); 3.833.87 (m, 1H); 4.104.22 (m,
H); 4.434.49 (m, 1H); 7.347.44 (m, 6H); 7.667.72 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 4.8
3
(
q); 4.6 (q); 17.9 (s); 19.2 (s); 21.0 (q); 25.8 (q); 26.8 (q); 26.9 (d); 30.7 (q); 41.2 (t); 42.8 (t); 43.6 (t);
0.2 (t); 64.1 (t); 65.6 (d); 73.0 (d); 76.9 (d); 85.8 (d); 127.6 (d); 129.6 (d); 133.4 (s); 133.5 (s); 135.6
d); 210.0 (s). HRMS (+ESI): m/z calcd. for C35 Si (M+H) 613.3739, found 613.3743.
5
(
H
57
O
5
2
(
4S,6R)-7-[(2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]-4-hydroxy-6-methylheptan-2-one (10b).
Aldehyde 9b (1.2 g, 2.16 mmol) led to aldol 10b (1.06 g, 80%)
dr = 6:1). [α] = 19.8 (c 1.0, CHCl ). IR (KBr film)  3462 (br),
955, 2930, 2857, 1711, 1472, 1428, 1361, 1255, 1112 cm . H
NMR (400 MHz, CDCl ) δ 0.05 (s, 3H); 0.01 (s, 3H); 0.80 (s,
H); 0.94 (d, J = 6.7 Hz, 3H); 1.06 (s, 9H); 1.38 (t, J = 6.8 Hz, 2H); 1.501.70 (m, 3H); 1.78 (h, J = 6.7
Hz, 1H); 2.12 (s, 3H); 2.21 (ddd, J = 13.2, 7.5, 6.1 Hz, 1H); 2.48 (dd, J = 17.5, 8.9 Hz, 1H); 2.58 (dd, J
17.5, 3.0 Hz, 1H); 3.16 (bs, 1H); 3.733.80 (m, 2H); 3.823.88 (m, 1H); 3.944.01 (m, 1H);
.104.18 (m, 1H); 4.32 (dt, J = 6.1, 3.6 Hz, 1H); 7.337.43 (m, 6H); 7.667.72 (m, 4H). 13C NMR
100.6 MHz, CDCl ) δ 5.2 (q); 4.6 (q); 18.0 (s); 19.2 (s); 21.2 (q); 25.7 (q); 26.6 (d); 26.9 (q); 30.8
q); 41.6 (t); 43.0 (t); 43.6 (t); 50.1 (t); 64.6 (t); 65.6 (d); 72.5 (d); 75.8 (d); 83.4 (d); 127.5 (d); 129.5
(
D
3
-
1 1
2
3
9
=
4
(
(
(
(
3
57 5 2
d); 133.7 (s); 133.9 (s); 135.6 (d); 135.7 (d); 210.1 (s). HRMS (+ESI): m/z calcd. for C35H O Si
M+H) 613.3739, found 613.3729.
General procedure for MPA derivatization:
α-Methoxyphenylacetic acid (3 or 6 eq.) and DCC (3 or 6 eq.) were added to a solution of
alcohol 10 (1 eq.) in THF, then DMAP (0.1 eq.) was added and the solution was stirred for 30 min. The
solution was filtered, poured into Et
2
O and washed with 0.2 M aqueous HCl and sat. NaHCO
3
. The
organic residue was dried over MgSO
4
, filtered and the solvent was removed under reduced pressure.
Purification by silica gel column chromatography with hexane-EtOAc (90:10) yielded the
corresponding ester S6 as a colorless oil.
SI 16

(
2S,4S)-1-[(2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]-2-methyl-6-oxoheptan-4-yl (S)-2-methoxy-2-phenylacetate (S6a).
S-α-Methoxyphenylacetic acid (25 mg, 0.15 mmol) and
alcohol 10a (30 mg, 0.05 mmol) led to ester S6a (30 mg,
1
7
9%). H NMR (400 MHz, CDCl
3
) δ 0.03 (s, 3H); 0.05
(
s, 3H); 0.87 (s, 9H); 0.94 (d, J = 5.6 Hz, 3H); 1.05 (s,
H); 1.451.60 (m, 6H); 1.81 (s, 3H); 2.17 (dt, J = 12.6,
9
6
1
4
.4 Hz, 1H); 2.45 (dd, J = 16.1, 4.9 Hz, 1H); 2.52 (dd, J = 16.1, 7.6 Hz, 1H); 3.37 (s, 3H); 3.64 (dd, J =
1.0, 3.9 Hz, 1H); 3.68 (dd, J = 11.0, 3.9 Hz, 1H); 3.81 (q, J = 3.9 Hz, 1H); 4.034.11 (m, 1H);
.424.47 (m, 1H); 4.68 (s, 1H); 5.335.41 (m, 1H); 7.307.47 (m, 11H); 7.657.72 (m, 4H).
(
2S,4S)-1-[(2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]-2-methyl-6-oxoheptan-4-yl (R)-2-methoxy-2-phenyl-acetate (S6b).
R-α-Methoxyphenylacetic acid (25 mg, 0.15 mmol) and
alcohol 10a (30 mg, 0.05 mmol) led to ester S6b (26 mg,
1
6
8%). H NMR (400 MHz, CDCl
3
) δ 0.03 (s, 3H); 0.05
(
s, 3H); 0.78 (d, J = 6.5 Hz, 3H); 0.87 (s, 9H); 1.04 (s,
H); 1.541.98 (m, 6H); 2.05 (s, 3H); 2.062.10 (m,
9
1
3
H); 2.56 (dd, J = 16.1, 5.0 Hz, 1H); 2.63 (dd, J = 16.1, 7.5 Hz, 1H); 3.41 (s, 3H); 3.553.70 (m, 2H);
.753.81 (m, 1H); 3.904.01 (m, 1H); 4.394.44 (m, 1H); 4.68 (s, 1H); 5.305.37 (m, 1H); 7.287.44
(
m, 11H); 7.657.72 (m, 4H).
Absolute configuration determination:
δ H
A
δ H
B
δ H
C
R=R-MPA
R=S-MPA
ΔRS
2.05
1.81
0.24
2.59
2.48
0.11
0.78
0.94
0.16
(
2S,4S)-1-[(2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]-2-methyl-6-oxoheptan-4-yl (S)-2-methoxy-2-phenylacetate (S6c).
S-Methoxyphenylacetic acid (50 mg, 0.3 mmol) and
alcohol 10b (32 mg, 0.05 mmol) led to ester S6c (22 mg,
1
5
8%). H NMR (400 MHz, CDCl
3
) δ 0.05 (s, 3H); 0.00
(
s, 3H); 0.79 (s, 9H); 0.94 (d, J = 5.9 Hz, 3H); 1.05 (s,
H); 1.401.65 (m, 6H); 1.81 (s, 3H); 2.122.19 (m,
9
1
3
1
7
H); 2.47 (dd, J = 16.2, 4.8 Hz, 1H); 2.55 (dd, J = 16.2, 7.7 Hz, 1H); 3.38 (s, 3H); 3.723.78 (m, 2H);
.813.88 (m, 2H); 4.30 (dt, J = 6.1, 3.8 Hz, 1H); 4.69 (s, 1H); 5.305.37 (m, 1H); 7.307.42 (m,
1H); 7.667.72 (m, 4H). HRMS (+ESI): m/z calcd. for C44
64 7 2
H O NaSi (M+Na) 783.4083, found
83.4070.
SI 17

(
2S,4S)-1-[(2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]-2-methyl-6-oxoheptan-4-yl (R)-2-methoxy-2-phenylacetate (S6d).
R-Methoxyphenylacetic acid (50 mg, 0.3 mmol) and
alcohol 10b (32 mg, 0.05 mmol) led to ester S6d (30 mg,
1
7
8%). H NMR (400 MHz, CDCl
3
) δ 0.06 (s, 3H); 0.00
(
s, 3H); 0.79 (s, 9H); 0.80 (d, J = 5.9 Hz, 3H); 1.05 (s,
H); 1.251.53 (m, 6H); 2.05 (s, 3H); 2.052.12 (m,
9
1
3
1
7
H); 2.59 (dd, J = 16.2, 5.1 Hz, 1H); 2.65 (dd, J = 16.2, 7.5 Hz, 1H); 3.40 (s, 3H); 3.673.75 (m, 3H);
.803.86 (m, 1H); 4.27 (dt, J = 6.2, 3.8 Hz, 1H); 4.68 (s, 1H); 5.285.36 (m, 1H); 7.287.42 (m,
1H); 7.667.72 (m, 4H). HRMS (+ESI): m/z calcd. for C44
H
64
O
7 2
NaSi (M+Na) 783.4083, found
83.4075.
Absolute configuration determination:
δ H
A
δ H
B
δ H
C
R = R-MPA
R = S-MPA
ΔRS
2.11
1.86
0.25
2.68
2.57
0.11
0.86
0.99
0.13
General procedure for TIPS protection:
Triisopropylsilyl trifluoromethanesulfonate (1.2 eq.) was added to a solution of 10 (1 eq.),
imidazole (2 eq.) and DMAP (0.1 eq.) in DMF, and the reaction mixture was stirred at 95 ºC for 6 h.
The solvent was removed under reduced pressure and the residue was dissolved in water and extracted
2 4
with Et O. The organic extracts were dried over MgSO , filtered and concentrated under reduced
2
pressure. Purification by silica gel column chromatography with hexane-Et O (95:5) yielded the
corresponding protected aldol 11 as a colorless oil.
(
4S,6S)-7-[(2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]-6-methyl-4-(triisopropylsilyloxy)heptan-2-one (11a).
Alcohol 10a (1.5 g, 2.45 mmol) led to protected 11a (1.79 g,
9
3%). [α]
930, 2864, 1719, 1476, 1427, 1251, 1112 cm . H NMR
) δ 0.03 (s, 3H); 0.05 (s, 3H); 0.87 (s, 9H);
.93 (d, J = 6.3 Hz, 3H); 1.051.06 (3bs, 30H); 1.251.65 (m, 6H); 2.11 (s, 3H); 2.23 (dt, J = 12.6, 6.5
Hz, 1H); 2.54 (d, J = 5.7 Hz, 2H); 3.65 (dd, J = 11.0, 3.9 Hz, 1H); 3.70 (dd, J = 11.0, 3.9 Hz, 1H); 3.83
dt, J = 4.4, 3.9 Hz, 1H); 4.114.19 (m, 1H); 4.364.43 (m, 1H); 4.47 (td, J = 6.2, 4.4 Hz, 1H);
D
=27.6 (c 1.0, CHCl
3
). IR (KBr film)  2956,
-
1
1
2
(
400 MHz, CDCl
3
0
(
7
1
.347.44 (m, 6H); 7.667.72 (m, 4H). 13C NMR (100.6 MHz, CDCl
7.9 (s); 18.2 (q); 19.2 (s); 21.0 (q); 25.8 (q); 26.8 (q); 27.5 (d); 31.7 (q); 41.6 (t); 44.7 (t); 45.4 (t); 50.9
3
) δ 4.8 (q); 4.6 (q); 12.7 (d);
(
t); 64.1 (t); 67.7 (d); 73.1 (d); 76.7 (d); 85.6 (d); 127.6 (d); 129.6 (d); 133.4 (s); 133.5 (s); 135.6 (d);
07.9 (s). HRMS (+ESI): m/z calcd. for C44 NSi (M+NH ) 786.5339, found 786.5365.
2
H
80
O
5
3
4
SI 18

(
4S,6S)-7-[(2R,4S,5S)-4-(tert-butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)tetra-
hydrofuran-2-yl]-6-methyl-4-(triisopropylsilyloxy)heptan-2-one (11b).
Alcohol 10b (0.97 g, 1.58 mmol) led to protected 11b (0.96
g, 77%). [α] = 25.6 (c 1.0, CHCl ). IR (KBr film)  2931,
864, 1719, 1463, 1428, 1254, 1113 cm . H NMR (400
D
3
-
1
1
2
MHz, CDCl ) δ 0.05 (s, 3H); 0.00 (s, 3H); 0.80 (s, 9H); 0.91
3
(
d, J = 6.3 Hz, 3H); 1.04 and 1.05 (2bs, 30H); 1.301.66 (m, 7H); 2.12 (s, 3H); 2.23 (dt, J = 13.2, 6.7
Hz, 1H); 2.55 (d, J = 5.7 Hz, 1H); 3.723.80 (m, 2H); 3.813.88 (m, 1H); 3.903.97 (m, 1H); 4.32 (dt,
J = 6.0, 3.7 Hz, 1H); 4.354.44 (m, 1H); 7.347.44 (m, 6H); 7.667.72 (m, 4H). 13C NMR (100.6
MHz, CDCl
3
) δ 5.2 (q); 4.6 (q); 12.6 (d); 17.8 (s); 18.2 (q); 19.2 (s); 20.1 (q); 25.7 (q); 26.9 (q);
7.4 (d); 31.7 (q); 41.9 (t); 44.9 (t); 45.2 (t); 50.8 (t); 63.7 (t); 67.8 (d); 72.6 (d); 75.6 (d); 83.3 (d);
27.5 (d); 129.5 (d); 133.7 (s); 134.0 (s); 135.6 (d); 135.7 (d); 208.0 (s). HRMS (+ESI): m/z calcd. for
NSi (M+NH4) 786.5339, found 786.5316.
2
1
C
44
H
80
O
5
3
General procedre for ketone reduction:
A solution of NaBH (1.2 eq.) and ketone 11 (1 eq.) in THF-EtOH 2:1 was stirred at r.t. for 16
h. After this time, aqueous sat. NH Cl was added and the residue was extracted with CH Cl2. The
organic extracts were dried over MgSO , filtered and concentrated under reduced pressure. Purification
4
4
2
4
by silica gel column chromatography with hexane-EtOAc (95:5) yielded a 6:4 mixture of the
corresponding alcohol S7 as a colorless oil.
(
2RS,4S,6S)-7-[(2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)-
tetrahydrofuran-2-yl]-6-methyl-4-(triisopropylsilyloxy)heptan-2-ol (S7a).
Ketone 11a led to a 6:4 mixture of alcohol S7a (4.79 g, 89%).
IR (KBr film)  3506, 2955, 2931, 2865, 1463, 1428, 1252,
-
1 1
1
113 cm . H NMR (400 MHz, CDCl
s, 3H); 0.87 (s, 9H); 0.91 (d, J = 6.1 Hz, 3H); 1.061.09
3bs, 30H); 1.11 and 1.15 (2d, J = 6.2 Hz, 3H); 1.301.75 (m, 8H); 2.24 (dt, J = 12.8, 6.6 Hz, 1H);
3
) δ 0.03 (s, 3H); 0.05
(
(
3
7
1
2
.623.96 (m, 2H); 3.843.88 (m, 1H); 3.984.06 (m, 1H); 4.124.26 (m, 2H); 4.424.50 (m, 1H);
.347.44 (m, 6H); 7.667.72 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 4.8 (q); 4.6 (q); 12.4 (d);
3
3.1(d); 17.7 (s); 17.9 (s); 18.1 (q); 18.2 (q); 19.2 (s); 19.6 (q); 19.7 (q); 23.8 (q); 23.9 (q); 25.8 (q);
6.8 (q); 27.4 (d); 27.7 (d); 41.2 (t); 41.4 (t); 41.6 (t); 42.6 (t); 44.6 (t); 44.7 (t); 45.1 (t); 45.2 (t); 64.1
(
t); 64.2 (d); 66.9 (d); 70.7 (d); 72.1 (d); 73.1 (d); 73.3 (d); 76.9 (d); 85.9 (d); 127.6 (d); 129.6 (d);
1
7
78 5 3
33.4 (s); 133.5 (s); 135.6 (d). HRMS (+ESI): m/z calcd. for C44H O NaSi (M+Na) 793.5049, found
93.5068.
SI 19

(
2RS,4S,6S)-7-[(2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)-
tetrahydrofuran-2-yl]-6-methyl-4-(triisopropylsilyloxy)heptan-2-ol (S7b).
Ketone 11b (1.81 g, 2.36 mmol) led to a 6:4 mixture of
alcohol S7b (1.69 g, 92%). IR (KBr film)  3456 (br), 2955,
-
1
1
2
931, 2863, 1463, 1428, 1255, 1113 cm . H NMR (400
MHz, CDCl ) δ 0.04 (2s, 3H); 0.01 (s, 3H); 0.81 (2s, 9H);
3
0
1
4
.89 (d, J = 6.3 Hz, 3H); 1.05and 1.09 (2s, 9H); 1.08 (bs, 21H); 1.09 and 1.15 (2d, J = 6.2 Hz, 3H);
.301.75 (m, 8H); 2.152.25 (m, 1H); 3.723.80 (m, 2H); 3.833.88 (m, 1H); 3.914.00 (m, 1H);
.014.07 and 4.114.25 (2m, 2H); 4.304.35 (m, 1H); 7.347.45 (m, 6H); 7.667.72 (m, 4H). 13C
NMR (100.6 MHz, CDCl
3
) δ 5.2 (q); 4.6 (q); 12.3 (d); 13.1 (d); 17.7 (s); 18.0 (s); 18.1 (q); 18.2 (q);
9.2 (s); 19.7 (q); 19.8 (q); 23.8 (q); 25.7 (q); 26.9 (q); 27.4 (d); 27.5 (d); 40.9 (t); 41.7 (t); 41.9 (t);
2.0 (t); 44.3 (t); 45.2 (t); 45.3 (t); 63.5 (t); 63.6 (t); 64.3 (d); 67.0 (d); 70.9 (d); 72.4 (d); 72.5 (d); 72.6
1
4
(
(
d); 75.4 (d); 75.5 (d); 83.3 (d); 127.5 (d); 129.4 (d); 129.5 (d); 133.8 (s); 133.9 (s); 135.6 (d); 135.7
d). HRMS (+ESI): m/z calcd. for C44 Si (M+H) 771.5230, found 771.5217.
H
79
O
5
3
General procedure for thioester formation by Mitsunobu reaction:
Diisopropyl azodicarboxylate (1.5 eq.) was added to a solution of alcohol S7a (1 eq.), 1-R-1H-
3
tetrazole-5-thiol (1.5 eq.) and PPh (1.5 eq.) in THF. The reaction mixture was stirred at r.t. for 5 h. The
solvent was removed under reduced pressure and the residue was purified by silica gel column
chromatography with hexane-EtOAc (98:2 to 95:5) to yield the corresponding thioester S8 as a
colorless oil.
5
-[(2RS,4S,6S)-7-((2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)-
tetrahydrofuran-2-yl)-6-methyl-4-(triisopropylsilyloxy)heptan-2-yl-thio]-1-phenyl-1H-tetrazole
S8a).
(
Alcohol S7a (4.9 g, 6.35 mmol) and 1-phenyl-1H-tetrazole-
-thiol (1.69 g, 9.5 mmol) led to thioester S8a (4.19 g, 71%).
IR (KBr film)  2930, 2864, 1598, 1500, 1462, 1428, 1388,
5
-
1
1
1
3
251, 1113 cm . H NMR (400 MHz, CDCl
3
) δ 0.03 (2s,
H); 0.04 and 0.05 (2s, 3H); 0.86 and 0.87 (2s, 9H); 0.92 (d,
J = 6.3 Hz, 3H); 1.01 (s, 13H); 1.04, 1.05 and 1.06 (3s, 17H); 1.351.50 (m, 2H); 1.56 and 1.58 (2d, J
6.7 Hz, 3H); 1.541.68 (m, 5H); 1.852.02 (m, 1H); 2.202.27 (m, 1H); 3.613.71 (m, 2H);
.803.85 (m, 1H); 4.044.22 (m, 3H); 4.434.50 (m, 1H); 7.347.44 (m, 6H); 7.527.56 (m, 5H);
=
3
7
1
3
.657.71 (m, 4H). C NMR (100.6 MHz, CDCl ) δ 4.8 (q); 4.6 (q); 12.9 (d); 17.8 (s); 17.9 (s); 18.2
3
(
q); 18.3 (q); 19.2 (s); 19.8 (q); 21.8 (q); 23.1 (q); 25.8 (q); 26.8 (q); 27.4 (d); 41.3 (t); 41.6 (t); 42.0 (d);
4
1
3.2 (t); 44.7 (t); 44.9 (t); 45.1 (t); 64.1 (t); 68.6 (d); 68.7 (d); 73.1 (d); 76.9 (d); 85.6 (d); 85.7 (d);
24.0 (d); 127.6 (d); 129.6 (d); 129.9 (d); 130.0 (d); 133.4 (s); 133.5 (s); 133.8 (s); 135.6 (d); 153.8 (s).
82 4 4 3
HRMS (+ESI): m/z calcd. for C51H O N NaSSi (M+Na) 953.5257, found 953.5268.
SI 20

5
-[(2RS,4S,6S)-7-((2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)-
tetrahydrofuran-2-yl)-6-methyl-4-(triisopropylsilyloxy)heptan-2-yl-thio]-1-tert-butyl-1H-tetrazole
(
S8b).
Alcohol S7b (490 mg, 0.63 mmol), and 1-(tert-butyl)-1H-
tetrazole-5-thiol[5] (140 mg, 0.89 mmol) led to S8b (529 mg,
9
2%). IR (KBr film)  2931, 2864, 1463, 1390, 1253, 1112
-
1
1
cm . H NMR (400 MHz, CDCl
3
) δ 0.05 and 0.04 (2s,
3
H); 0.00 and 0.00 (2s, 3H); 0.79 and 0.80 (2s, 9H); 0.91
(
(
2d, J = 6.2 Hz, 3H); 1.03 (s, 10H); 1.05, 1.06 and 1.07 (3s 20H); 1.361.48 (m, 3H); 1.53 and 1.54
2d, J = 6.6 Hz, 3H); 1.571.67 (m, 4H); 1.68 and 1.70 (2s, 9H); 1.842.02 (m, 1H); 2.192.26 (m,
1
1
H); 3.723.80 (m, 2H); 3.823.86 (m, 1H); 3.873.96 (m, 1H); 4.074.26 (m, 2H); 4.304.36 (m,
H); 7.327.42 (m, 6H); 7.677.72 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 5.2 (q); 4.7(q); 4.6
3
(
(
q); 12.9 (d); 17.9 (s); 18.2 (q); 18.3 (q); 19.2 (s); 19.9 (q); 21.8 (q); 23.2 (q); 25.7 (q); 26.9 (q); 27.4
d); 28.7 (q); 41.7 (t); 41.8 (t); 41.9 (d); 42.3 (d); 43.1 (t); 43.2 (t); 44.9 (t); 45.0 (t); 45.1 (t); 60.8 (s);
6
3.7 (t); 68.8 (d); 72.6 (d); 75.6 (d); 75.9 (d); 83.2 (d); 83.3 (d); 127.5 (d); 129.4 (d); 132.2 (s); 133.7
(
s); 135.6 (d); 135.7 (d); 152.1 (s). HRMS (+ESI): m/z calcd. for C49 SSi (M+H) 911.5750,
H
87
N
4
O
4
3
found 911.5740.
General procedure for oxidation to the sulfone:
A solution of 70% m-CPBA (2.2 eq) and thioester S8 (1 eq.) in CH
The reaction mixture was diluted with sat. Na and sat. NaHCO and the residue was extracted
with CH Cl . The organic extracts were dried over MgSO , filtered and concentrated under reduced
2 2
Cl was stirred for 16 h.
2
S
2
O
3
3
2
2
4
pressure. Purification by silica gel column chromatography with hexane-EtOAc (95:5) yielded the
corresponding sulfone 2 as a colorless oil.
5
-[(2RS,4S,6S)-7-((2R,4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)-
tetrahydrofuran-2-yl)-6-methyl-4-(triisopropylsilyloxy)heptan-2-yl-sulfonyl]-1-phenyl-1H-
tetrazole (2a).
Thioester S8a (4.19 g, 4.5 mmol) led to sulfone 2a (3.85 g,
8
1
9%). IR (KBr film)  2930, 2865, 1498, 1463, 1338, 1252,
-
1 1
3
113 cm . H NMR (400 MHz, CDCl ) δ 0.03, 0.04, 0.05
and 0.06 (4s, 6H); 0.88 and 0.89 (2s, 9H); 0.89 and 0.92 (2d,
J = 6.0 Hz, 3H); 1.06, 1.07 and 1.08 (3s, 30H); 1.381.70
and 1.831.91 (2m, 7H); 1.49 and 1.56 (2d, J = 6.8 Hz, 3H); 2.122.28 and 2.422.50 (2m, 2H);
3
7
.623.71 (m, 2H); 3.773.85 (m, 1H); 4.074.21 and 4.244.31 (2m, 3H); 4.404.51 (m, 1H);
.347.43 (m, 6H); 7.557.62 (m, 3H); 7.647.71 (m, 6H). 13C NMR (100.6 MHz, CDCl
) δ 4.8 (q);
4.7 (q); 12.9 (d); 13.5 (q); 15.9 (q); 17.7 (s); 17.9 (s); 18.2 (q); 18.3 (q); 19.0 (s); 19.2 (q); 19.7 (q);
5.8 (q); 26.8 (q); 27.3 (d); 27.4 (d); 34.1 (t); 35.7 (t); 41.4 (t); 41.6 (t); 44.6 (t); 45.0 (t); 45.1 (t); 58.6
3

2
(
d); 58.8 (d); 64.1 (t); 64.3 (t); 67.5 (d); 69.3 (d); 73.1 (d); 73.3 (d); 76.5 (d); 76.9 (d); 85.8 (d); 85.9
SI 21

(
(
d); 125.3 (d); 125.4 (d); 127.6 (d); 129.5 (d); 129.6 (d); 131.3 (d); 133.2 (s); 133.4 (s); 133.5 (s); 135.6
d); 152.6 (s); 152.7 (s). HRMS (+ESI): m/z calcd. for C51 SSi (M+H) 963.5336, found
H
83
O
6
N
4
3
9
63.5351.
5
-[(2RS,4S,6S)-7-((2R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxymethyl)-
tetrahydrofuran-2-yl)-6-methyl-4-(triisopropylsilyloxy)heptan-2-yl-sulfonyl]-1-tert-butyl-1H-
tetrazole (2b).
Thiotetrazole S8b (2.56 g, 2.80 mmol) led to sulfone 2b
(
2.10 g, 80%). IR (KBr film)  2941, 2865, 1463, 1332,
-
1
1
1
3
158, 1113 cm . H NMR (400 MHz, CDCl
3
) δ 0.04 (s,
H); 0.00 and 0.01 (2s, 3H); 0.80 (2s, 9H); 0.91 (d, J = 6.2
Hz, 3H); 1.05 (2s, 9H); 1.06 and 1.07 (2s, 21H); 1.371.70
m, 7H); 1.50 and 1.56 (2d, J = 6.9 Hz, 3H); 1.84 (s, 9H);
.122.26 and 2.422.49 (2m, 2H); 3.713.78 (m, 2H); 3.823.96 (m, 2H); 4.074.16 and 4.244.43
2m, 3H); 7.327.42 (m, 6H); 7.677.71 (m, 4H). 13C NMR (100.6 MHz, CDCl
) δ 5.2 (q); 4.6 (q);
(
2
(
3
1
2
2.9 (d); 13.9 (q); 16.3 (q); 18.0 (s); 18.2 (q); 18.3 (q); 19.1 (q); 19.2 (s); 19.6 (q); 25.7 (q); 26.9 (q);
7.4 (d); 27.5 (d); 29.6 (q); 29.7 (q); 34.2 (t); 35.9 (t); 41.7 (t); 41.9 (t); 45.0 (t); 45.2 (t); 45.3 (t); 58.8
(
(
d); 59.3 (d); 63.5 (t); 65.3 (s); 65.4 (s); 67.6 (d); 69.5 (d); 72.5 (d); 75.6 (d); 75.9 (d); 83.2 (d); 83.3
d); 127.5 (d); 129.5 (d); 133.7 (s); 133.8 (s); 134.0 (s); 135.6 (d); 135.7 (d); 153.2 (s); 153.3 (s).
90 5 6 3 4
HRMS (+ESI): m/z calcd. for C49H N O SSi (M+NH ) 960.5914, found 960.5907.
(
2S,3S,5R)-5-[(2S,4S,6RS)-6-(1-(tert-Butyl)-1H-tetrazol-5-yl-sulfonyl)-2-methyl-4-(triisopropyl-
silyloxy)heptyl]-2-(hydroxymethyl)tetrahydrofuran-3-ol (S9).
PPTS (666 mg, 2.6 mmol) was added to a solution of sulfone 2b
250 mg, 0.26 mmol) in MeOH (10 mL) and the reaction was
(
stirred at 65 ºC for 5 h. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography with hexane-EtOAc (80:20 to 50:50) to yield S9
-
1
(
114 mg, 95%) as a colorless oil. IR (KBr film)  3419 (br), 2943, 2867, 1464, 1377, 1332, 1159 cm .
1H NMR (400 MHz, CDCl
) δ 0.92 and 0.94 (2d, J = 6.3 Hz, 3H); 1.08 (bs, 21H); 1.411.78 and
.942.03 (m, 6H); 1.55 and 1.61 (2d, J = 6.8 Hz, 3H); 1.86 (2s, 9H); 2.202.27 and 2.362.50 (2m,
H); 3.733.80 (m, 1H); 3.864.01 (m, 3H); 4.164.30 (m, 1H); 4.334.41 (m, 1H); 4.434.51 (m,
H). 13C NMR (100.6 MHz, CDCl
) δ 12.7 (d); 12.9 (d); 14.4 (q); 16.0 (q); 18.2 (q); 19.8 (q); 20.1 (q);
6.9 (d); 27.4 (d); 29.7 (q); 33.7 (t); 36.4 (t); 42.7 (t); 42.9 (t); 43.1 (t); 44.0 (t); 44.5 (t); 45.0 (t); 59.2
3
1
3
1
2
3
(
d); 59.3 (d); 61.7 (t); 61.8 (t); 65.5 (s); 65.6 (s); 68.1 (d); 69.6 (d); 73.9 (d); 74.1 (d); 75.2 (d); 75.3 (d);
0.6 (d); 80.7 (d); 153.1 (s); 153.2 (s). HRMS (+ESI): m/z calcd. for C27 SSi (M+H) 591.3606,
found 591.3608.
8
55 4 6
H N O
SI 22

1
-(tert-Butyl)-5-[(2RS,4S,6S)-7-((2R,4S,5S)-5-(tert-butyldiphenylsilyloxymethyl)-4-(trimethylsilyl-
oxy)tetrahydrofuran-2-yl)-6-methyl-4-(triisopropylsilyloxy)heptan-2-yl-sulfonyl]-1H-tetrazole
2c).
(
TBDPSCl (71 µL, 0.27 mmol) was added to a solution of
diol S9 (150 mg, 0.25 mmol) and imidazole (68 mg, 1 mmol)
2 2
in CH Cl (10 mL) and the reaction was stirred for 1 h. After
this time, TMSCl (48 µL, 0.37 mmol) was added and the
reaction was stirred for further 15 min. Finally, the resulting
4
mixture was washed with water, dried over MgSO , filtered
and the solvent was removed under reduced pressure. Purification by silica gel column chromatography
with hexane-EtOAc (97:3) yielded 2c (165 mg, 73%) as a colorless oil. IR (KBr film)  2943, 2866,
-
1
1
1
1
1
4
3
463, 1333, 1113 cm . H NMR (400 MHz, CDCl ) δ 0.05 and 0.06 (2s, 9H); 0.91 (d, J = 5.9 Hz, 3H);
.04 (s, 9H); 1.07 (2bs, 21H); 1.381.68 (m, 7H); 1.50 and 1.56 (2d, J = 6.8 Hz, 3H); 1.84 (s, 9H);
.891.94, 2.132.30 and 2.412.49 (3m, 2H); 3.703.77 (m, 2H); 3.833.93 (m, 2H); 4.074.16 and
.234.31 (2m, 1H); 4.324.44 (m, 2H); 7.327.43 (m, 6H); 7.667.74 (m, 4H). 13C NMR (100.6
MHz, CDCl
3
) δ  (q); 12.9 (d); 14.0 (q); 16.2 (q); 18.2 (q); 18.3 (q); 19.2 (s); 19.2 (q); 19.7 (q); 26.9
(
q); 27.4 (d); 27.5 (d); 29.6 (q); 29.7 (q); 34.2 (t); 35.9 (t); 41.8 (t); 41.9 (t); 44.7 (t); 45.0 (t); 45.1 (t);
5
8
8.9 (d); 59.2 (d); 62.8 (t); 65.3 (s); 65.4 (s); 67.7 (d); 69.4 (d); 72.1 (d); 75.5 (d); 75.9 (d); 82.8 (d);
3.0 (d); 127.5 (d); 129.5 (d); 133.7 (s); 133.8 (s); 134.0 (s); 135.6 (d); 135.7 (d); 153.2 (s); 153.3 (s).
84 5 6 3 4
HRMS (+ESI): m/z calcd. For C46H N O Ssi (M+NH ) 918.5445, found 918.5443.
Kinetic resolution of 12: [6]
Lipase PS-30 (4.32 g) was added to a solution of (±)-12 (2.15 g, 12.5 mmol) in vinyl acetate
(
10 mL) and pentane (25 mL), and the suspension was stirred for 48 h at 37 ºC. The residue was
filtered through Celite® 545, and the solvent was removed under reduced pressure. Purification by
silica gel column chromatography with hexane-EtOAc (90:10) yielded R-12 (1.05 g, 49%) and S-Ac-
1
1
2 (1.28 g, 48%) as colorless oils. R-12: H NMR (400 MHz, CDCl
3
) δ 1.46 (s, 9H); 2.43 (dd, J = 16.2,
8
.3 Hz, 1H); 2.51 (dd, J = 16.2, 4.0 Hz, 1H); 3.11 (bs, OH); 4.454.52 (m, 1H); 5.14 (dt, J = 10.5, 1.4
1
Hz, 1H); 5.30 (dt, J = 17.2, 1.4 Hz, 1H); 5.87 (ddd, J = 17.2, 10.5, 5.5 Hz, 1H). S-Ac-12: H NMR (400
MHz, CDCl
3
) δ 1.44 (s, 9H); 2.05 (s, 3H); 2.52 (dd, J = 15.3, 5.8 Hz, 1H); 2.60 (dd, J = 15.3, 8.0 Hz,
H); 5.20 (dd, J = 10.5, 1.0 Hz, 1H); 5.30 (dd, J = 17.2, 1.0 Hz, 1H); 5.575.63 (m, 1H); 5.83 (ddd, J =
7.2, 10.5, 6.2 Hz, 1H).
1
1
tert-Butyl (R)-3-(triisopropylsilyloxy)pent-4-enoate (S10).
Triisopropylsilyl trifluoromethanesulfonate (1.98 mL, 7.34 mmol) was added to a
solution of aldol (R)-12 (1.05 g, 6.1 mmol), imidazole (830 mg, 12.2 mmol) and
SI 23

DMAP (20 mg) in THF (60 mL), and the reaction mixture was stirred for 16 h at reflux temperature.
The solvent was removed under reduced pressure and the residue was dissolved in water and extracted
with CH
2 2 4
Cl . The organic extracts were dried over MgSO , filtered and concentrated under reduced
pressure. Purification by silica gel column chromatography with hexane-EtOAc (97:3) yielded S10
(
1.78 g, 89%) as a colorless oil. [α]
D
= 3.8 (c 1.0, CHCl
3
). IR (KBr film)  2944, 2867, 1732, 1464,
-
1 1
1
1
1
367, 1256, 1161 cm . H NMR (400 MHz, CDCl ) δ 1.041.07 (m, 21H); 1.43 (s, 9H); 2.37 (dd, J =
3
4.4, 7.5 Hz, 1H); 2.56 (dd, J = 14.4, 5.8 Hz, 1H); 4.594.65 (m, 1H); 5.06 (ddd, J = 10.4, 1.7, 1.1 Hz,
H); 5.20 (ddd, J = 17.2, 1.7, 1.1 Hz, 1H); 5.87 (ddd, J = 17.2, 10.4, 6.7 Hz, 1H). 13C NMR (100.6
MHz, CDCl
3
) δ 12.3 (d); 18.0 (q); 18.1 (q); 28.1 (q); 45.2 (t); 71.3 (d); 80.4 (s); 114.5 (t); 140.6 (d);
Si (M+H) 329.2507, found 329.2506.
1
70.1 (s). HRMS (+ESI): m/z calcd. for C18H O
37 3
tert-Butyl (R)-4-oxo-3-(triisopropylsilyloxy)butanoate (3).
Ozone gas was bubbled into a solution of olefin S10 (1.45 g, 4.41 mmol) in a 4:1
mixture of CH Cl -MeOH (100 mL) at 78ºC until the blue color persisted.
Argon was passed through the solution for 10 min at 78ºC to remove any excess ozone. Then, PPh
1.5 g, 5.73 mmol) was added and the solution was stirred at r.t. for 16 h. The reation mixture was
concentrated under reduced pressure and filtered through silica to yield 3 (1.35 g, 93%) as a colorless
2
2
3
(
-
1 1
oil. [α]
NMR (400 MHz, CDCl
.78 (dd, J = 15.7, 4.0 Hz, 1H); 4.32 (ddd, J = 5.8, 4.0, 0.8 Hz, 1H); 9.80 (t, J = 0.8, 1H). 13C NMR
100.6 MHz, CDCl ) δ 12.1 (d); 17.8 (q); 28.0 (q); 41.22 (t); 74.2 (d); 81.4 (s); 169.0 (s); 204.2 (d).
HRMS (+ESI): m/z calcd. for C17
D
= + (c 1.0, CHCl
3
). IR (KBr film)  2944, 2868, 1736, 1464, 1367, 1256, 1157 cm . H
3
) δ 1.041.07 (m, 21H); 1.44 (s, 9H); 2.66 (ddd, J = 15.7, 5.8, 0.8 Hz, 1H);
2
(
3
H
35
O
4
Si (M+H) 331.2299, found 331.2297.
SI 24

6
. NMR data table of macrocycles 1a-c. Spectra recorded in CDCl
3
1a
1b
1c
H, mult, J (Hz)
C, mult
H, mult, J (Hz)
C, mult
H, mult, J (Hz)
C, mult
1
2
3
4
5
6
7
8
9
-
170.9, s
46.6, t
67.8, d
131.6, d
134.8, s
40.0, t
71.0, d
47.2, t
27.2, d
42.0, t
78.5, d
34.3, t
77.7, d
84.4, d
64.9 t
-
170.6, s
44.3, t
66.8, d
131.3, d
133.4, s
40.2, t
70.1, d
45.9, t
28.8, d
43.3, t
77.5, d
40.8, t
74.3, d
81.4, d
62.8 t
-
170.8, s
46.1, t
67.0, d
131.5, d
135.0, s
40.3, t
71.1, d
47.1, t
27.0, d
43.6, t
77.0, d
35.1 t
2
2
.42, dd, 15.1, 8.4
.30, dd, 15.1, 4.0
2.62, dd, 15.1, 5.3
2.47 dd, 15.1, 6.2
2.65, d, 5.3
4.97, m
4.86, td, 8.4, 4.0
4.75 dt, 7.8, 5.8
5.41, d, 7.7
5.21, d, 8.4
-
5.33, m
-
-
2
2
.48, dd, 14.0, 6.9
.29 dd, 14.0, 4.4
2.36, dd, 13.6, 6.7
2.03, dd, 13.6, 6.0
2.42, dd, 14.3, 5.8
2.31 dd, 14.3, 5.0
4.11, m
4.04, m
1.34, m
1.63, m
3.95, m
1
.69, dt, 13.5, 6.6
1.60, m
1.33, m
1
.42, m
1.56, m
1.34 m
2
1
.05, m
.42, m
1.57, m
1.44, m
1.66, m
1.38, m
1
0
1
2
3
4
5
2
3
1
1
1
1
1
3
3
4.46, m
.22, ddd, 13.8, 7.8, 5.8
3.78, m
4.22, m
2
2.48, dt, 13.7, 7.0
1.36, m
2.17, m
1.99, dd, 14.2, 2.1
2
.01, d, 13.8
5.27, d, 5.6
4.10, m
5.18, m
3.84, m
5.33, m
4.04, td, 6.6, 3.4
3.82, m
74.6, d
82.2, d
62.3 t
3
3
.66, dd, 10.9, 4.0
.80, dd, 10.9, 3.3
3.86, m
1.78, s
24.6, q
20.6, q
1.72, d, 1.2
1.00, d, 6.6
25.5, q
20.5, q
1.74, d, 1.4
0.88 d, 5.2
25.3, q
20.5, q
0.94, d, 6.3
SI 25

7
. NMR Spectra of compounds
SI 27

SI 28

SI 29