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Enantioselective Chemical Syntheses of the Furanosteroids (–)-Viridin and (–)-Viridiol

Matthew Del Bel,# Alexander R. Abela,‡ Jeffrey D. Ng, ‡ and Carlos A. Guerrero*,†

Department of Chemistry and Biochemistry

University of California, San Diego
9500 Gilman Drive
La Jolla, CA 92093-0358
United States

email: Carlos.Guerrero@bms.com

Present Addresses

#
Pfizer Worldwide Research and Development
10770 Science Center Drive
San Diego, CA 92121

†
Bristol-Myers Squibb
One Squibb Drive
New Brunswick, NJ 08903

‡
These authors contributed equally.

SI-1



Table of Contents

Additional References to Medicinal Chemistry Work SI-3

Additional References to Total Synthesis-Relevant Work SI-5

Retrosynthesis and Discussion SI-7

Step Counting: General Considerations and Conclusions SI-8

Entire Current Synthetic Route with All Steps Listed and Demarcated SI-10

Entire Sorensen Synthetic Route with All Steps Listed and Demarcated SI-12

General Procedures and Instrumentation SI-14

Individual Experimental Procedures and Tabulated Compound Data SI-15

Tabulated 1H NMR Data for Synthetic Versus Natural (–)-Viridin (3) SI-55

Discussion of Optical Rotation for Viridin SI-56

Determinantion of Enantiomeric Excess for Compound (+)-14 SI-57

Discussion of Optimization of the Intramolecular Enantioselective Heck Reaction SI-59

References for Supporting Information SI-60

1
H and 13C NMR Spectra SI-61

Comparison Between Synthetic Materials: Current Work Versus Alexanian Thesis

(–)-Viridin 1H NMR SI-101

(–)-Viridin 13C NMR SI-102

(–)-Viridiol 1H NMR SI-103

(–)-Viridiol 13C NMR SI-104

SI-2



Additional References to Medicinal Chemistry Work

(please note: some references may also appear in the manuscript)

Lewis Cantley/John H. Hartwig/Lee Josephson/Ralph Weissleder group(s)

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Med. Chem. Lett. 2009, 19, 4223.
(9) Stangenberg, L.; Ellson, C.; Cortez-Retamozo, V.; Ortiz-Lopez, A.; Yuan, H.; Blois, J.;
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C. J.; Sato, M. Bioorg. Med. Chem. Lett. 1995, 5, 1713.
(8) Schultz, R. M.; Merriman, R. L.; Andis, S. L.; Bonjouklian, R.; Grindey, G. B.; Rutherford,
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(9) Creemer, L. C.; Kirst, H. A. Stereochemical Wortmannin derivatives. U. S. Patent
5,480,906, 02 January 1996.

SI-3



(10) Norman, B. H.; Shih, C.; Toth, J. E.; Ray, J. E.; Dodge, J. A.; Johnson, D. W.; Rutherford,
P. G.; Schultz, R. M.; Worzalla, J. F.; Vlahos, C. J. J. Med. Chem. 1996, 39, 1106.
(11) Creemer, L. C.; Kirst, H. A.; Vlahos, C. J.; Schultz, R. M. J. Med. Chem. 1996, 39, 5021.
(12) Norman, B. H.; Srinivasan, U.; Dodge, J. A.; Sato, M. Wortmannin analogs for inhibiting
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(13) Thomas, J. E.; Venugopalan, M.; Galvin, R.; Wang, Y.; Bokoch, G. M.; Vlahos, C. J. J.
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(14) Giner, J. L.; Kehbein, K. A.; Cook, J. A.; Smith, M. C.; Vlahos, C. J.; Badwey, J. A.
Bioorg. Med. Chem. Lett. 2006, 16, 2518.

Dennis L. Wright group

(1) Viswanathan, K.; Ononye, S. N.; Cooper, H. D.; Hadden, M. K.; Anderson, A. C.; Wright, D.
L. Bioorg. Med. Chem. Lett. 2012, 22, 6919.

SI-4



Additional References to Total Synthesis-Relevant Work

(please note: some references may also appear in the manuscript)

Martin G. Banwell
(1) Findlay, A. D.; Gebert, A.; Cade, I. A.; Banwell, M. G. Aust. J. Chem. 2009, 62, 1173.

Brian C. Goess
(1) Ungureanu, S.; Meadows, M.; Smith, J.; Duff, D. B.; Burgess, J. M.; Goess, B. C.
Tetrahedron Lett. 2011, 52, 1509.

Peter A. Jacobi
(1) Mascall, K. C.; Jacobi, P. A. Heterocycles 2014, 88, 1527.
(2) Jacobi, P. A.; Könekamp, T.; Mascall, K. C.; O’Connor, R. T.; Onyango, E. O.; Sessions, E.
H. Adv. Heterocycl. Chem. 2013, 110, 119.
(3) Onyango, E. O.; Jacobi, P. A. Synth. Commun. 2013, 43, 2748.
(4) Mascall, K. C.; Jacobi, P. A. Tetrahedron Lett. 2012, 53, 1620.
(5) Onyango, E. O.; Jacobi, P. A. J. Org. Chem. 2012, 77, 7411.
(6) Sessions, E. H.; O’Connor, Jr., R. T.; Jacobi, P. A. Org. Lett. 2007, 9, 3221.
(7) Sessions, E. H.; Jacobi, P. A. Org. Lett. 2006, 8, 4125.

Ken Kanematsu
(1) Yamaguchi, Y.; Hayakawa, K.; Kanematsu, K. J. Chem. Soc., Chem. Commun. 1987, 515.

Brian A Keay
(1) Muller, K. M.; Keay, B. A. Synlett 2011, 1618.
(2) Rankic, D. A.; Lucciola, D.; Keay, B. A. Tetrahedron Lett. 2010, 51, 5724.
(3) Muller, K. M.; Keay, B. A. Synlett 2008, 1236.
(4) Hopkins, J. M.; Gorobets, E.; Wheatley, B. M. M.; Pervez, M.; Keay, B. A. Synlett 2006,
3120.
(5) Gorobets, E.; Wheatley, B. M. M.; Hopkins, J. M.; McDonald, R.; Keay, B. A. Tetrahedron
Lett. 2005, 46, 3843.
(6) Balcells, D.; Maseras, F.; Keay, B. A.; Ziegler, T. Organometallics 2004, 23, 2784.
(7) Lau, S. Y. W.; Keay, B. A. Synlett 1999, 605.
(8) Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.; Keay, B. A. J. Am. Chem. Soc. 1996,
118, 10766.
(9) Nieman, J. A.; Keay, B. A. Tetrahedron Lett. 1994, 35, 5335.
(10) Cristofoli, W. A.; Keay, B. A. Tetrahedron Lett. 1991, 32, 5881.

Tuoping Luo
(1) Lu, Y.; Yaun, H.; Zhou, S.; Luo, T. Org. Lett. 2017, 19, 620.

Russell Rodrigo
(1) Lang, Y.; Souza, F. E. S.; Xu, X.; Taylor, N. J.; Assoud, A.; Rodrigo, R. J. Org. Chem.
2009, 74, 5429.
(2) Souza, F. E. S.; Sutherland, H. S.; Carlini, R.; Rodrigo, R. J. Org. Chem. 2002, 67, 6568.

SI-5



(3) Souza, F. E. S.; Rodrigo, R. Chem. Commun. 1999, 1947.

(4) Carlini, R.; Higgs, K.; Older, C.; Randhawa, S.; Rodrigo, R. J. Org. Chem. 1997, 62, 2330.

Masakatsu Shibasaki
(1) Shigehisa, H.; Mizutani, T.; Tosaki, S.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61,
5057.
(2) Honzawa, S.; Mizutani, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 311.
(3) Miyazaki, F.; Uotsu, K.; Shibasaki, M. Tetrahedron 1998, 54, 13073.
(4) Honzawa, S.; Nakada, M.; Kurosu, H.; Hazeki, O.; Katada, T.; Shibasaki, M. Chem. Pharm.
Bull. 1995, 43, 2276.
(5) Kurosu, H.; Hazeki, O.; Kukimoto, I.; Honzawa, S.; Shibasaki, M.; Nakada, M.; Ui, M.;
Katada, T. Biochem. Biophys. Res. Commun. 1995, 216, 655.

SI-6



Retrosynthesis and Discussion

We include here a retrosynthesis of our successful synthesis, in contradistinction to a

retrosynthetic analysis. It is our opinion that the two are erroneously used interchangeably, but
that a retrosynthetic analysis – emphasis on analysis – should include: multiple different
pathways to a target; multiple different pathways to key intermediates; consideration of absolute
and relative stereochemical configurations; functional group incompatibilities; consideration of
available starting materials, catalysts, and reagents; topology-based strategies; mechanism-based
transforms, and numerous other sub-discussions. Because such a discussion is likely to be very
detail-focused and lengthy, we have opted not to include a retrosynthetic analysis. For a full
delination of the elements of a complete, formal retrosynthetic analysis, please see Part One in:
Corey, E. J.; Cheng, X. M. The Logic of Chemical Synthesis, Wiley, 1989.
O O O
17 selective diastereoselective epoxidation
HO CH HO CH HO CH
3 C D oxidation 3 demethoxylation H 3CO 3 (in CH 3OH)
H 3CO 1 H 3CO H 3CO
2 A B
O 3 O HO O HO O
E
O O O
3 (viridin) 4 (viridiol) (–)-19

O O O
regio- and double
HO CH diastereo- O CH oxidation; HO CH diastereo-
3 selective 3 selective 3 selective
H 3CO reduction H 3CO methylation HO dihydroxylation

O O O
O O O
(–)-18 TBS (+)-16 TBS (+)-15

O
O
Liebeskind
enantioselective stannane- O
CH3 intramolecular thioester
Heck reaction TfO coupling CH3
+
O TfO
TBS O
O TBS Sn(CH3)3
O
O CH3 PhS O
TBS 8 12
(+)-14

13
ring-closing
alkene activation,
metathesis, displacement
CH3 stannylation CH3 with allyl anion HO CH3

TBS O Sn(CH3)3 TBS O TBS O

12 10 9

O O deprotection, Heck
intramolecular reaction,
FGI Friedel-Crafts reduction
O
O O OTf
TfO HO OH
H 3C O O H 3C O O
CH3 CH3
PhS O HO O
6 SI-2
8 7

SI-7



Step Counting

General Considerations. We provide here a clear, comprehensive discussion of our step

counting assumptions, methodology, and exceptions, as this is an issue of much current debate
and as we count steps for our own synthesis as well as that of Sorensen and coworkersS1,S2 to
make an objective comparison.

We define a step as a any set of chemical transformations that may be accomplished in a single
reaction vessel regardless of how many additions of reagents, catalysts, solvents, and other
additives are performed and regardless of hold points and temperature changes, but that the
removal of any component from the reaction mixture demarcates one step from one that may
follow. As an obvious example, aqueous workup demarcates the end of one step because this
experimental procedure is used to remove water-soluble impurities. By this logic, solvent
evaporations also demarcate a step, whether they are performed using a rotary evaporator, an
atmospheric distillation, distillation under vacuum, constant volume distillation, etc. However,
these and other operations, when already part of a workup or purification are ignored, because
they would unnecessarily inflate the step count.

Under this regime, “telescopes,” “sequences,” and “cascades” are broken into individual steps
when a work-up or evaporation takes place, regardless if silica gel chromatography or
precipitation/trituration has been avoided. Stated differently but explicitly, we do not demarcate
a step solely based on chromatography, crystallization, precipitation, or trituration, but rather
adopt a more comprehensive view of purification.

In cases where several reagents are added sequentially and/or where there are various hold
points, but no removal of any reaction component, we count such opearations as a single step.
For example, the alkylation of an enolate generated with LDA at low temperature, followed by a
hold then alkyl halide addition, and terminated by quenching and workup is one step. Similarly,
we consider much more intricate bond constructions, such as Smith’s multi-stage indole
synthesis in his synthesis of (–)-penitrem DS3 (see Scheme 4 and the Supplementary Information
in this work) to be one to two steps despite that the numbering scheme used in this work would
suggest each addition of each reagent is a step (five total). In both our own viridin synthesis as
well as in the work by Sorensen and coworkers, there is at least one such multi-stage step (see
(+)-17 to (–)-18 for our synthesis and SI-18 to SI-19 in the Sorensen work).

Conclusions. We have illustrated both our own and Sorensen and coworkers’ syntheses of
viridn, traced back to commercially-available materials (see below; commercially-available from
a single, arbitrarily-chosen vendor, Sigma-Aldrich) and have specifically indicated operations
that demarcate a step. We do not consider the synthesis of reagents and/or catalysts, but we do
consider all fragments that eventually find their way into the target structure. On this basis, our
work requires 16 steps to generate (–)-viridiol and 17 steps to generate (–)-viridin according to
the longest linear sequence (LLS) back to commercially-available materials (seven steps each are
required to generate each coupling partner, 8 and 12, from commercially-available materials for
the Liebeskind coupling). The total step count for our work is 23 and 24 steps to (–)-viridiol and
(–)-viridin, respectively. The LLS to these targets from compounds previously reported in the
literature is 14 and 15 steps, respectively, going back to compound SI-2.

SI-8



In comparison, the Sorensen work requires 26 and 27 steps to generate (±)-viridin and (±)-
viridiol, respectively, from commercially available materials; these numbers rise to 28 and 29,
respectively, when the synthesis of SI-8 is considered. The LLS to (±)-viridin and (±)-viridiol
from the most-advanced material reported in the literature, compound SI-9, is 24 and 25 steps,
respectively.

We apologize to the readership if this discussion is overly technical, but we wish for consistency
and fairness in step counting, regardless of how reagents might be listed in figure and scheme
captions, which are often at the discretion of the manuscript’s authors. On another note,
comparisons based on step counting alone may be insufficient for comparing one synthesis to
another, as other metrics (e.g. theoretical overall yield) may be more important. Finally, it is apt
to remember that the goal of organic synthesis in different eras reflects different priorities, and
that new methods, reagents, and catalysts are constantly introduced for synthesis. Thus,
comparisons based on step counts may hold little value if significant time has elapsed between
published works toward the same target.

(Note: in the schemes that follow, FCC = flash column chromatography)

SI-9



Entire Current Synthetic Route with All Steps Listed and Demarcated

Synthesis of fragment 8.
acetone, SOCl 2 benzyl acrylate, cat. Pd(OAc) 2
cat. DMAP C5H 5N, cat. PPh 3, K 2CO 3, (CH 3)4NBr
DME, 20 °C Tf2O, 0 °C DMF, 100 °C
O OH O OTf
HO OH
(66%) (84%) (75%)
H 3C O O H 3C O O
O OH elution through CH3 aqueous CH3 solvent evaporation
pad of SiO 2 then extractive then FCC
2,6-hydroxybenzoic acid crystallization SI-1 workup then SI-2
CAS #: 303-07-1 crystallization
commercially available from reference:
Sigma-Aldrich Synth. Commun. reference:
(catalog #: D109606) 1994, 24, 1025 Tetrahedron
1996, 52, 15071

3.4 atm H 2, cat. Pd/C ClSO 3H (PhS) 2, Bu 3P

O 1:1 EtOAc:CH 3OH O 0 °C to r.t. CH2Cl2
O O HO
OBn (>99%, crude) OH (98%) (81%)
H 3C O O H 3C O O HO O
CH3 filtration through CH3 aqueous solvent evaporation
5 Celite and 6 quench 7 then FCC
evaporation, then
then used as-is trituration

O C5H 5N, Tf2O O

CH2Cl2
0 °C to r.t.

HO (84%) TfO

aqueous
PhS O PhS O
extractive
SI-3 workup then 8
FCC

Synthesis of fragment 12.

BuLi, DME, –78 °C;
BuLi, HMPA warm to r.t.; B(OMe) 3;
TBSCl, imid. THF, –78 °C cat. Pd(PPh 3)4
HO TBSO HO
DMF, r.t. warm to r.t. 2-bromopropene, 70 °C HO CH3

(95%) (87%) TBS (59%)

O O O TBS O
aqueous aqueous aqueous
furan-3-methanol extractive SI-4 extractive SI-5 extractive 9
CAS #: 4412-91-3 workup then workup then workup then
commercially available from distillation distillation FCC
Sigma-Aldrich
(catalog number: D109606) reference: reference: reference:
Synlett Synlett Synlett
2011, 1618 2011, 1618 2011, 1618

cat. BuLi, THF

MsCl, Et 3N allylMgCl Grubbs II –78 to 0 °C;
CH2Cl2 THF CH2Cl2 (CH 3)3SnCl
0 °C to r.t. reflux reflux CH3 0 °C to r.t. CH3
Cl CH3
CH3
(85%) (98%) (99%) (91%, crude)
TBS TBS TBS Sn(CH3)3
O O O
aqueous aqueous TBS solvent aqueous
O
extractive extractive evaporation extractive
workup then SI-6 workup then 10 then FCC 11 workup then 12
FCC FCC used as-is

(cont’d)

SI-10



Entire Current Synthetic Route with All Steps Listed and Demarcated (cont’d)

Synthesis of advanced intermediates (–)-19 and (+)-20.

O
O
cat. PdCl 2•(CH 3CN)2
O cat. TFP cat. Pd(OAc) 2
CuOP(O)Ph2 cat. (S)-t-Bu PHOX CH3
CH3 DMF TfO PMP, tol, µw, 175 °C
+
O
TfO (83%) O (75%, >99% ee)
TBS Sn(CH3)3 TBS O
O
aqueous solvent evaporation
PhS O exractive CH3 then FCC O
8 12 workup then TBS
FCC (+)-14

13

O O
1. DMSO, TFAA O
HO CH CH2Cl2, –60 °C; O CH TFA
cat. OsO4 3 i-Pr2EtN, –60 °C; 3 CH 3NO 2 O CH
3
NMO, acetone HO AcOH, warm to r.t. H 3CO (1:1)
H 3CO
(90%) 2. KN(TMS) 2, THF; (91%)
O (CH 3)2SO 4 O
aqueous 0 °C to r.t. solvent O
extractive O O evaporation O
workup then TBS (64%, two steps) TBS then FCC
FCC (+)-15 (+)-16 (+)-17
aqueous extractive
workup for each
step; FCC only after
second step
(i) TBSOTf, 2,6-lut.
CH2Cl2, –30 °C; O O O
(ii) BH 3•THF, –30 °C;
(iii) Et 3N•3HF, –30 °C HO CH HO CH HO CH
then warm to r.t. 3 AcOOH, CH 3OH H 3CO 3 H 3CO 3
H 3CO H 3CO + H 3CO
(72%) (53%;
dr = 1:2 (–)-21:(+)-22,
aqueous O inconsequential, HO O HO O
extractive O see below & text) O O
workup then
FCC (–)-18 aqueous extractive (–)-19 (+)-20
workup then FCC

Completion of the synthesis of (–)-3 (viridin).

O O O

HO CH TMSOTf, BH 3•S(CH 3)2 HO CH TEMPO, PhI(OAc) 2 HO CH

3
H 3CO 3 CH2Cl2, –30 °C; 3 CH2Cl2
H 3CO H 3CO
H 3CO
C5H 5N, AcOH; Et 3N•3HF (46%)
HO O HO O O O
(49%) solvent evaporation
O O then FCC O
aqueous extractive
(–)-19 workup then FCC (–)-4 (viridiol) (–)-3 (viridin)

O O O

HO CH TMSOTf, Et 3SiH HO CH TEMPO, PhI(OAc) 2 HO CH

H 3CO 3 CH2Cl2, –30 °C 3 CH2Cl2 3

H 3CO H 3CO H 3CO

(43%) (48%)
HO O aqueous extractive HO O solvent evaporation O O
O workup then FCC O then FCC O
(+)-20 (–)-21 (epi-viridiol) (–)-3 (viridin)

SI-11



Entire Sorensen Synthetic Route with All Steps Listed and Demarcated

Fragment synthesis and linear synthesis of (±)-viridin.

K 2CO 3, cat. Pd(PPh 3)4
2,4,6-trivinylboroxine
Br LDA, THF Br H 2O, DME
–78 °C; TMSCl reflux

(92%) TMS (90%) TMS

O O O
aqueous aqueous
3-bromofuran extractive SI-7 extractive SI-8
CAS #: 22037-28-1 workup then workup then
commercially available from used as-is elution through
Sigma-Aldrich pad of alumina
(catalog #: 176524)

TMSCCH
BuLi, THF
Swern –78 °C then OH imid., DMAP OTBS
OH oxidation O warm to r.t. TBSCl, CH2Cl2

(95%) (96%) quantitative

TMS TMS
XX aqueous SI-9 aqueous aqueous
extractive extractive SI-10 extractive SI-11
4-pentyn-1-ol workup then workup then workup then
CAS #: 5390-04-5 used as-is FCC FCC
commercially available from
Sigma-Aldrich reference:
(catalog #: 302481) J. Med. Chem.
1991, 34, 1585

2-bromo-3-butyne
Zn0, cat. HgCl 2 OTBS
BuLi, THF OTBS
–40 °C, DMF THF, 65 °C CH3 MeOH, K 2CO 3

(89%) (96%) TMS (100%)

TMS CHO
aqueous aqueous OH aqueous
extractive extractive extractive
SI-12 SI-13 workup then
workup then workup then
elution through FCC used as-is
pad of SiO 2

OTBS OTBS TMS

OTBS O
cat. RhCl(PPh 3)3 Swern BuLi, THF
CH3 EtOH, reflux oxidation –78 °C

(88%) (85%) (94%)

H 3C H 3C
OH solvent evaporation aqueous aqueous
then FCC OH extractive O extractive
workup then workup then
SI-14 SI-15 SI-16
FCC used as-is

OTBS OTBS OTBS

CsF, allyl
imid., DMAP i. i-Pr2EtN bromide
TESCl xylenes DMF, 0 °C
DMF, 0 °C reflux H 3C warm to r.t.
H 3C H 3C
(88%) ii. DDQ (67%)
HO TESO OTES
O aqueous O aqueous aqueous
extractive extractive O extractive
workup then workup then TMS workup then
TMS TMS
FCC FCC FCC
SI-17 SI-18 SI-19

(cont’d)

SI-12



Entire Sorensen Synthetic Route with All Steps Listed and Demarcated (cont’d)
OTBS OTBS
OTBS
i-Pr2EtN SeO 2
mesitylene CH3 dioxane
H 3C reflux cat. Grubbs II CH3 100 °C

(91%) (95%) (60%)

O O
solvent evaporation solvent evaporation O aqueous
O then FCC O then FCC extractive
O
workup then
SI-22 FCC
SI-20 SI-21

OTBS Dess-Martin OTBS OTBS

periodinane
HO CH2Cl2, 0 °C O NaBH 4 HO TMEDA, OsO4
CH3 warm to r.t. CH3 EtOH, 0 °C CH3 CH2Cl2, –78 °C

(97%) (98%) (76%)

O aqueous O aqueous O aqueous
extractive extractive extractive
O O O
workup then workup then workup then
SI-23 used as-is SI-24 used as-is SI-25 used as-is

OTBS OTBS OTBS

ethyl vinyl
HO C5H 5N, triphosgene HO ether, cat. EEO
CH3 CH2Cl2, –78 °C CH3 PPTS, CH2Cl2 CH3
HO O O
(95%) O (91%) O
HO O O O O O
aqueous aqueous
O extractive O extractive O
workup then workup then
SI-26 FCC SI-27 FCC SI-28

OTBS OTBS
NaHMDS
THF EEO TBSOTf, 2,6-lut. EEO THF, –78 °C
aq. LiOH CH3 CH2Cl2, –78 °C CH3 MeOTf
HO HO
(97%) (95%) (76%)

aqueous HO O aqueous TBSO O aqueous

extractive O extractive O extractive
workup then workup then workup then
used as-is SI-29 FCC SI-30 FCC

OTBS OH Dess-Martin O
periodinane
EEO EEO CH2Cl2, 0 °C EEO
CH3 Bu 4NF, THF CH3 warm to r.t. CH3
H 3CO H 3CO H 3CO
(99%) (98%)
TBSO O aqueous HO O aqueous O O
O extractive O extractive O
workup then workup then
SI-31 used as-is SI-32 used as-is SI-33

O O
NaBH 4
PPTS HO EtOH, CH2Cl2 HO
MeOH, CH2Cl2 CH3 0 °C CH3
H 3CO H 3CO
(84%) (93%)

aqueous O O aqueous HO O
extractive O extractive O
workup then workup then
FCC viridin used as-is viridiol

SI-13



General procedures. All reactions were carried out under an inert argon atmosphere with
anhydrous solvents using anhydrous techniques unless otherwise stated. Anhydrous
tetrahydrofuran (THF), dichloromethane (CH2Cl2), toluene (tol), and N,N-dimethylformamide
(DMF) were obtained by passing these previously-degassed solvents through activated alumina
columns unless otherwise stated. Anhydrous acetone, methanol (CH3OH), and pyridine (C5H5N,
py) were obtained from either Sigma Aldrich Corporation or Acros Organics in Sure SealTM or
AcroSealTM vessels, respectively. Anhydrous diisopropylethylamine (i-Pr2EtN) and
triethylamine (Et3N) were obtained by distilling the reagent-grade material over CaH2 and
storing the purified material over spherical molecular sieves in amber glass bottles on the
benchtop. Commercially-available reagents were used when available and were purchased at
ACS Reagent Grade or higher purity. Organic solvents not mentioned above or used for
extractive workups included ethyl acetate (EtOAc), Et2O, CH2Cl2, or hexanes purchased at ACS
Reagent Grade specification or similar levels of purity. Yields refer to isolated material that was
found to be chromatographically and spectroscopically homogenous unless otherwise stated.
Reaction were monitored by thin layer chromatography (TLC) using glass plates pre-coated with
a 0.25 mm layer of silica gel (60 Å pore size) impregnated with a fluorescent indicator (254 nm);
these were visualized by exposure to ultraviolet light and subsequent staining with acidic,
ethanolic anisaldehyde; basic aqueous ammonium molybdate (CAM); or acidic ninhydrin in 1-
butanol followed by heating on a laboratory hot plate (~200 °C) for 5–60 seconds. Purifications
of intermediates were performed according to the procedures of Still and coworkers using silica
gel obtained from Sigma Aldrich Corporation (catalog # 717185, technical grade, pore size 60 Å,
230–400 mesh particle size, 40-63 µm particle size) using ACS Reagent Grade solvents. “High
vacuum” refers to pressures ≪ 1 Torr typically achieved with the use of a belt-driven oil pump.

Instrumentation. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a 500
MHz JEOL ECA 500 spectrometer or a 500 MHz Varian VX 500 spectrometer with XSense 2
channel Cold Probe and were calibrated using perdeuterated solvents containing residual
undeuterated solvent. Multiplicities are abbreviated using the following abbreviations or
combinations thereof: s = singlet, d = doublet, t = triplet, q = quartet, a = apparent, br = broad, m
= multiplet. Each discrete signal is reported in the following format: chemical shift in parts per
million (multiplicity, coupling constant in Hertz, integration). Carbon nuclear magnetic
resonance spectra (13C NMR) data were recorded on the aforementioned instruments at 125 MHz
and were calibrated using perdeuterated solvents containing residual undeuterated solvent.

SI-14



benzyl acrylate, cat. Pd(OAc) 2

cat. PPh 3, K 2CO 3, (CH 3)4NBr
DMF, 100 °C O
O OTf O
(75%) OBn
H 3C O O H 3C O O
CH3 solvent evaporation CH3
then FCC
SI-2 5

To a flame-dried 500 mL flask was added SI-2S4 (29.00 g, 88.9 mmol, 1.00 equiv.), benzyl
acrylate (20.02 mL, 133 mmol, 1.50 equiv.), palladium acetate (Pd(OAc)2, 0.998 g, 4.44 mmol,
0.05 equiv.), triphenylphosphine (PPh3, 2.332 g, 8.89 mmol, 0.1 equiv.), potassium carbonate
(K2CO3, 30.70 g, 222 mmol, 2.50 equiv.) and tetramethylammonium bromide ((CH3)4NBr, 13.69
g, 88.9 mmol, 1.00 equiv.). A Vigreux condenser was attached to the top of flask and then the
whole reaction vessel was evacuated using high vacuum and then refilled with argon. This
process was repeated twice more before the flask was removed from the manifold and rapidly
sealed using a rubber septum equipped with a balloon filled with argon. Then DMF (148 mL,
0.60 M) was added via syringe, the reaction vessel was immersed in an oil bath preheated to 100
°C, and was stirred. Upon complete consumption of starting material as judged by TLC (12
hours), the reaction was terminated by being allowed to attain room temperature and directly
concentrated under vacuum on a rotary evaporator. The resulting residue was directly purified
by flash column chromatography (100% hexanes → 100% toluene → 100% CH2Cl2 → 3% Et2O
in CH2Cl2) furnishing 22.58 g (75%) of 5.

SI-15



O
O

H 3C OBn
O O
CH3
5

1
H NMR (500 MHz, CDCl3):
8.71 (d, J = 15.9 Hz, 1H) 7.28 (dt, J = 7.9, 1.0 Hz, 1H)
7.53 (td, J = 8.0, 0.5 Hz, 1H) 7.02 (dd, J = 8.2, 1.0 Hz, 1H)
7.46 – 7.42 (m, 2H) 6.39 (d, J = 16.0 Hz, 1H)
7.40 – 7.37 (m, 2H) 5.28 (s, 2H)
7.36 – 7.33 (m, 1H) 1.74 (s, 6H)
13
C NMR (126 MHz, CDCl3):
166.16 135.66 118.80
159.97 128.68 111.83
157.03 128.34 105.80
143.41 128.31 66.55
138.77 122.33 25.7
136.03 122.03

HRMS (ESI–TOF):
calculated: [M + H+] = 339.1227 for [C20H18O5 + H+]
observed: [M + H+] = 339.1229
error: 0.6 ppm

physical appearance: white solid

TLC: Rf = 0.33 (100% CH2Cl2)

SI-16



3.4 atm H 2, cat. Pd/C

O 1:1 EtOAc:CH 3OH O
O O
OBn (>99%, crude) OH
H 3C O O H 3C O O
CH3 filtration through CH3
5 Celite and 6
evaporation,
then used as-is

To a 500 mL pressure vial (heavy wall flask) was added 5 (12.50 g, 36.9 mmol, 1.00 equiv.) and
palladium on carbon (0.983 g of Pd/C powder (10% Pd on C by weight), 0.92 mmol, 0.025
equiv. of Pd). Argon gas was flushed through the vial for 5 minutes before it was sealed with a
rubber septum and fitted with an argon balloon. Then EtOAc (123 mL, 0.30 M) and CH3OH
(123 mL, 0.30 M) were added via syringe and the pressure vial was loaded into a Parr
hydrogenation apparatus, pressurized to 50 psi using hydrogen gas, and subjected to mechanical
shaking. Upon complete consumption of starting material as judged by TLC (12 hours), the
reaction was terminated by vacuum removal of the hydrogen and replacement with argon. The
suspension was filtered through Celite® and concentrated under vacuum on a rotary evaporator,
furnishing 9.24 g (>99%) of 6, which was used without further purification.

SI-17



O
O

H 3C OH
O O
CH3
6

1
H NMR (500 MHz, (CD3)2SO):
7.54 (t, J = 7.9 Hz, 1H) 3.23 (t, J = 7.6 Hz, 2H)
7.06 (dd, J = 7.7, 1.2 Hz, 1H) 2.49 (t, J = 7.7 Hz, 2H)
6.96 (dd, J = 8.2, 1.2 Hz, 1H) 1.65 (s, 6H)
13
C NMR (126 MHz, (CD3)2SO):
174.13 136.36 105.60
159.97 125.70 35.10
156.96 116.13 29.49
145.89 112.17 25.52

HRMS (ESI–TOF):
calculated: [M – H+] = 249.0768 for [C13H14O5 – H+]
observed: [M – H+] = 249.0770
error: 0.8 ppm

physical appearance: white solid

TLC: Rf = 0.58 (100% EtOAc)

SI-18



ClSO 3H
O 0 °C to r.t.
O HO
OH (98%)
H 3C O O HO O
CH3 aqueous
6 quench 7
then
trituration

A 100 mL amber glass bottle of chlorosulfonic acid was chilled to 0 °C and 6 (8.56 g, 34.2
mmol, 1.00 equiv.) was added directly to the bottle (0.35 M). The resulting suspension was
allowed to warm to room temperature and stirred for 12 hours. The reaction was terminated by
slowly pouring the solution onto ice. The resulting heterogeneous mixture was filtered and the
solids were rinsed with water followed by CH3OH, furnishing 6.43 g (98%) of 7, which was used
without further purification.

SI-19



HO

HO O

1
H NMR (500 MHz, (CD3)2SO):
7.71 (d, J = 8.5 Hz, 1H)
6.99 (d, J = 8.4 Hz, 1H)
3.32 – 3.23 (m, 2H)
2.63 – 2.53 (m, 2H)
13
C NMR (126 MHz, (CD3)2SO):
204.40 130.02 36.11
172.58 129.70 27.98
167.67 118.13
160.07 111.71

HRMS (ESI–TOF):
calculated: [M – H+] = 191.0350 for [C10H7O4 – H+]
observed: [M – H+] = 191.0349
error: –0.5 ppm

physical appearance: off-white solid

TLC: Rf = 0.24 (5% AcOH in EtOAc)

SI-20



O O
(PhS) 2, Bu 3P
CH2Cl2

HO (81%) HO

solvent evaporation
HO O then FCC PhS O

7 SI-3

To a flame-dried 100 mL flask was added 7 (3.28 g, 17.1 mmol, 1.00 equiv.) and diphenyl
disulfide ((PhS)2, 4.47 g, 20.5 mmol, 1.20 equiv.). The flask was evacuated using high vacuum
and then refilled with argon. This process was repeated twice more before the flask was
removed from the manifold and rapidly sealed using a rubber septum equipped with a balloon
filled with argon. Then CH2Cl2 (34 mL, 0.50 M) was added via syringe followed by
tributylphosphine (Bu3P, 6.0 mL, 24.6 mmol, 1.45 equiv.) and the mixture was stirred. Upon
complete consumption of starting material as judged by TLC (1.5 hours), the reaction was
terminated by directly concentrating under vacuum on a rotary evaporator. The resulting residue
was purified by flash column chromatography (100% hexanes → 100% toluene → 100%
CH2Cl2) furnishing 3.92 g (81%) of SI-3.

SI-21



HO

PhS O

SI-3

1
H NMR (500 MHz, CDCl3):
12.35 (s, 1H) 7.03 (d, J = 8.5 Hz, 1H)
7.88 (d, J = 8.5 Hz, 1H) 3.68 – 3.61 (m, 2H)
7.55 – 7.50 (m, 5H) 2.83 – 2.76 (m, 2H)
13
C NMR (126 MHz, CDCl3):
166.08 135.95 118.72
159.89 135.58 111.75
156.95 128.60 105.72
143.32 128.26 66.47
143.32 122.25 25.63
138.69 121.95

HRMS (ESI–TOF):
calculated: [M + H+] = 285.0580 for [C16H13O3 + H+]
observed: [M + H+] = 285.0578
error: –0.7 ppm

physical appearance: white solid

TLC: Rf = 0.44 (40% EtOAc in hexanes)

SI-22



O C5H 5N, Tf2O O

CH2Cl2
0 °C to r.t.

HO (84%) TfO

aqueous
PhS O extractive PhS O
SI-3 workup then 8
FCC

To a 100 mL flask was added SI-3 (3.91 g, 13.8 mmol, 1.00 equiv.). The flask was evacuated
using high vacuum and then refilled with argon. This process was repeated twice more before
the flask was removed from the manifold and rapidly sealed using a rubber septum equipped
with a balloon filled with argon. Then CH2Cl2 (46 mL, 0.30 M) was added via syringe and the
flask cooled to 0 °C and was stirred. Pyridine (3.34 mL, 41.3 mmol, 3.00 equiv.) was added via
syringe followed by trifluoromethanesulfonic anhydride (Tf2O, 3.48 mL, 20.6 mmol, 1.50
equiv.) via syringe. Upon complete consumption of starting material as judged by TLC (2
hours), the reaction was terminated by transferring the solution to a separatory funnel containing
saturated aqueous NaHCO3 (50 mL) and EtOAc (100 mL). After shaking and phase separation,
the organic portion was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and
concentrated under vacuum on a rotary evaporator. The resulting residue was purified by flash
column chromatography (50% CH2Cl2 in hexanes → 75% CH2Cl2 in hexanes → 100% CH2Cl2)
furnishing 4.79 g (84%) of 8.

SI-23



TfO

PhS O
8

1
H NMR (500 MHz, CDCl3):
7.94 (d, J = 8.4 Hz, 1H) 7.44 (d, J = 8.4 Hz, 1H)
7.56 – 7.53 (m, 2H) 3.37 – 3.31 (m, 2H)
7.52 – 7.49 (m, 3H) 2.82 – 2.75 (m, 2H)
13
C NMR (126 MHz, CDCl3):
203.76 134.62 125.63
187.71 131.15 121.87
154.72 130.41 118.48 (J = 322 Hz)
149.16 129.70 36.20
137.27 127.58 25.13

HRMS (ESI–TOF):
calculated [M + Na+] = 438.9894 for [C17H11F3O5S2 + Na+]
observed: [M + Na+] = 438.9894
error: <0.1 ppm

physical appearance: tan solid

TLC: Rf = 0.57 (100% CH2Cl2)

SI-24



MsCl, Et 3N
CH2Cl2
HO CH3 0 °C to r.t. Cl CH3

(85%)
TBS TBS
O O
aqueous
9 extractive SI-6
workup then
FCC

To a 250 mL flask was added 9S5 (6.15 g, 24.4 mmol, 1.00 equiv.). The flask was evacuated
using high vacuum and then refilled with argon. This process was repeated twice more before
the flask was removed from the manifold and rapidly sealed using a rubber septum equipped
with a balloon filled with argon. Then CH2Cl2 (61 mL, 0.40 M) was added via syringe and the
flask cooled to 0 °C and allowed to stir. Triethylamine (Et3N, 5.09 mL, 36.5 mmol, 1.50 equiv.)
was added via syringe followed by methanesulfonyl chloride (MsCl, 2.28 mL, 29.2 mmol, 1.20
equiv.) via syringe. After addition of reagents the solution was allowed to warm to room
temperature. Upon complete consumption of starting material as judged by TLC (16 hours), the
reaction was terminated by transferring the solution to a separatory funnel containing saturated
aqueous NaHCO3 (50 mL) and Et2O (100 mL). After shaking and separation, the organic
portion was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and
concentrated under vacuum on a rotary evaporator. The resulting residue was purified by flash
column chromatography (100% hexanes) furnishing 5.60 g (85%) of SI-6.

SI-25



Cl CH3

TBS
O

SI-6

1
H NMR (500 MHz, CDCl3):
7.58 (s, 1H) 2.06 (dd, J = 1.5, 0.8 Hz, 3H)
5.37 (dd, J = 1.5, 0.8 Hz, 1H) 0.93 (s, 9H)
5.12 (dd, J = 1.5, 0.8 Hz, 1H) 0.35 (s, 6H)
4.63 (s, 2H)
13
C NMR (126 MHz, CDCl3):
159.34 126.56 23.97
144.92 113.86 17.49
134.75 37.82 –5.66
130.79 26.55

HRMS (ESI–TOF):
calculated: [M + H+] = 271.1279 for [C14H23ClOSi + H+]
observed: [M + H+] = 271.1279
error: <0.1 ppm

physical appearance: colorless oil

TLC: Rf = 0.43 (100% hexanes)

SI-26



allylMgCl
THF
reflux
Cl CH3 CH3
(98%)
TBS aqueous TBS
O O
extractive
SI-6 workup then 10
FCC

To a 250 mL flask was added SI-6 (5.60 g, 20.7 mmol, 1.00 equiv.). A water condenser was
attached to the top of flask and the whole assembly was evacuated using high vacuum and then
refilled with argon. This process was repeated twice more before the assembly was removed
from the manifold and rapidly sealed using a rubber septum equipped with a balloon filled with
argon. Then THF (69 mL, 0.30 M) was added via syringe and allowed to stir. Allylmagnesium
chloride (36.0 mL, 1.15 M in THF, 41.3 mmol, 2.00 equiv.) was added via syringe. The solution
was heated to reflux (66 °C). Upon complete consumption of starting material as judged by TLC
(14 hours), the reaction was terminated by transferring the solution to a separatory funnel
containing saturated aqueous NH4Cl (50 mL) and Et2O (100 mL). After shaking and separation,
the organic portion was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and
concentrated under vacuum on a rotary evaporator. The resulting residue was purified by flash
column chromatography (100% hexanes) furnishing 5.63 g (98%) of 10 (83% starting from 9).

SI-27



CH3

TBS O
10

1
H NMR (500 MHz, CDCl3):
7.55 (s, 1H) 2.71 – 2.60 (m, 2H)
5.86 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H) 2.31 – 2.21 (m, 2H)
5.11 (dd, J = 1.8, 0.9 Hz, 1H) 2.04 (t, J = 1.1 Hz, 3H)
5.05 (dq, J = 17.2, 1.7 Hz, 1H) 0.92 (s, 9H)
5.00 – 4.96 (m, 2H) 0.28 (s, 6H)
13
C NMR (126 MHz, CDCl3):
154.83 126.76 24.94
144.67 114.70 24.01
138.26 112.10 17.71
136.28 35.01 –5.22
134.25 26.64

HRMS (ESI–TOF):
calculated: [M + H+] = 277.1982 for [C17H28OSi + H+]
observed: [M + H+] = 277.1983
error: 0.4 ppm

physical appearance: colorless oil

TLC: Rf = 0.60 (100% hexanes)

SI-28



cat.
Grubbs II
CH2Cl2
reflux
CH3 CH3

(99%)
TBS O solvent TBS O
evaporation
10 then FCC 11

To a 250 mL flask was added 10 (5.63 g, 20.4 mmol, 1.00 equiv.). A water condenser was
attached to the top of flask and evacuated using high vacuum and then refilled with argon. This
process was repeated twice more before the flask was removed from the manifold and rapidly
sealed using a rubber septum equipped with a balloon filled with argon. Then CH2Cl2 (102 mL,
0.20 M) was added via syringe and allowed to stir. Grubbs’s second generation alkylidene
metathesis catalyst (0.432 g, 0.509 mmol, 0.025 equiv.) was rapidly added in one portion by
removing the water condenser and replacing it immediately after addition. The solution was
heated at reflux (40 °C). Upon complete consumption of starting material as judged by TLC (6
hours), the reaction was terminated by directly concentrating under vacuum on a rotary
evaporator. The resulting residue was purified by flash column chromatography (100% hexanes)
furnishing 5.00 g (>99%) of 11.

SI-29



CH3

TBS O
11

1
H NMR (500 MHz, CDCl3):
7.46 (s, 1H) 1.94 (aq, J = 1.8 Hz, 3H)
5.53 – 5.49 (m, 1H) 0.91 (s, 9H)
2.65 (t, J = 7.5 Hz, 2H) 0.26 (s, 6H)
2.30 – 2.24 (m, 2H)
13
C NMR (126 MHz, CDCl3):
151.70 124.60 19.65
139.58 122.16 19.38
131.94 26.50 17.83
126.93 24.53 –5.9

HRMS (ESI–TOF):
calculated: [M + H+] = 249.1669 for [C15H24OSi + H+]
observed: [M + H+] = 249.1668
error: –0.4 ppm

physical appearance: colorless oil

TLC: Rf = 0.57 (100% hexanes)

SI-30



BuLi, THF
–78 to 0 °C;
(CH 3)3SnCl
CH3 0 °C to r.t. CH3

aqueous
TBS O
extractive TBS O Sn(CH3)3
workup then
11 used as-is 12

To a 250 mL flask was added 11 (7.80 g, 31.4 mmol, 1.00 equiv.). The flask was evacuated
using high vacuum and then refilled with argon. This process was repeated twice more before
the flask was removed from the manifold and rapidly sealed using a rubber septum equipped
with a balloon filled with argon. Then THF (105 mL, 0.20 M) was added via syringe and the
flask cooled to –78 °C and allowed to stir. n-Butyllithium (BuLi, 13.2 mL, 2.50 M, 33.0 mmol,
1.05 equiv.) was added via syringe and the flask was warmed to 0 °C. After 1 hour at 0 °C,
chlorotrimethylstannane (33.0 mL, 1.0 M in THF, 33.0 mmol, 1.05 equiv.) was added and
allowed to stir for an additional 30 minutes. The reaction was terminated by transferring the
solution to a separatory funnel containing saturated aqueous NaHCO3 (50 mL) and Et2O (75
mL). After shaking and separation, the organic portion was washed with saturated aqueous
NaCl, dried over anhydrous MgSO4, and concentrated under vacuum on a rotary evaporator to
furnish 11.73 g of crude 12 (purity not determined; see note below). The resulting oil was used
immediately in the subsequent reaction without purification due to its tendency to undergo
protodestannylation upon storage.

Note: a reviewer requested that we omit a one step yield for this material, because it was not
purified and used in crude form. We have retained the relatively high quality characterization
and graphical spectral data to give an indication of the relatively high purity we observed using
the above procedure, and so that future researchers might benefit from these data. After
familiarization, we routinely omitted a purity determination because intermediate 12 was usually
generated in excellent conversion as determined by 1H NMR analysis of the crude reaction
mixture and because the next step in our synthesis, the Liebeskind stannane–thioester coupling,
uses an excess of stannane.

SI-31



CH3

TBS O Sn(CH3)3

12

1
H NMR (500 MHz, CDCl3):
5.53 – 5.49 (m, 1H) 0.92 (s, 9H)
2.64 (t, J = 7.5 Hz, 2H) 0.35 (s, 9H)
2.27 – 2.21 (m, 2H) 0.24 (s, 6H)
1.98 (aq, J = 1.7 Hz, 3H)
13
C NMR (126 MHz, CDCl3):
158.65 122.37 17.85
155.78 26.56 –5.83
134.74 24.53 –7.78
132.12 21.09
128.37 19.89

HRMS (ESI–TOF):
not stable to analysis

physical appearance: pale yellow oil

TLC: Rf = 0.60 (100% hexanes)

SI-32



O
cat. PdCl 2•(CH 3CN)2
O cat. TFP
CuOP(O)Ph2
CH3 DMF TfO
+
O
TfO (83%) O
TBS Sn(CH3)3 TBS
O
aqueous
PhS O extractive CH3
8 12 workup then
FCC
13

To a 250 mL flask was added 8 (7.20 g, 17.3 mmol, 1.00 equiv.), crude 12 (11.73 g, 28.5 mmol,
1.65 equiv.), bis(acetonitrile)dichloropalladium(II) (PdCl2•(CH3CN)2), 0.224 g, 0.865 mmol,
0.05 equiv.), ((diphenylphosphoryl)oxy)copper(I)S6 (7.28 g, 25.9 mmol, 1.50 equiv.), and tri(2-
furyl)phosphine (TFP, 0.602 g, 2.59 mmol, 0.15 equiv.). The flask was evacuated using high
vacuum and then refilled with argon. This process was repeated twice more before the flask was
removed from the manifold and rapidly sealed using a rubber septum equipped with a balloon
filled with argon. Then DMF (86 mL, 0.20 M) was added via syringe and the reaction was
stirred. Upon complete consumption of starting material as judged by TLC (3 hours), the
reaction was terminated by transferring the solution to a separatory funnel containing aqueous 1
M HCl (50 mL) and Et2O (150 mL). After shaking and separation, the organic portion was
subsequently washed successively with aqueous 2 M NaOH, saturated aqueous NaCl, dried over
anhydrous MgSO4, and concentrated under vacuum on a rotary evaporator. The resulting residue
was purified by flash column chromatography (100% hexanes → 5% EtOAc in hexanes → 10%
EtOAc in hexanes) furnishing 8.00 g (83%; yield based on component 8) of 13.

SI-33



TfO
O
TBS O

CH3

13

1
H NMR (500 MHz, CDCl3):
7.92 (d, J = 8.4 Hz, 1H) 2.62 (t, J = 7.4 Hz, 2H)
7.40 (d, J = 8.4 Hz, 1H) 2.32 – 2.26 (m, 2H)
6.02 – 5.99 (m, 1H) 2.30 (s, 3H)
3.17 – 3.10 (m, 2H) 0.78 (s, 9H)
2.74 (t, J = 7.4 Hz, 2H) 0.13 (s, 6H)
13
C NMR (126 MHz, CDCl3):
204.55 132.37 25.98
179.08 132.02 24.72
157.91 130.92 24.18
155.71 128.80 21.38
149.69 126.38 19.25
148.08 121.22 17.28
136.69 118.36 (J = 321 Hz) –6.36
135.63 36.24

HRMS (ESI–TOF):
calculated: [M + H+] = 555.1479 for [C26H29F3O6SSi + H+]
observed: [M + H+] = 555.1478
error: –0.2 ppm

physical appearance: light yellow solid

TLC: Rf = 0.47 (100% CH2Cl2)

SI-34



O
O
cat. Pd(OAc) 2
cat. (S)-t-Bu PHOX CH3
TfO PMP, tol, µw, 175 °C

O
O (75%, >99% ee)
TBS O
solvent evaporation
CH3 then FCC O
TBS
(+)-14
13

To a 20 mL microwave vial was added 13 (1.06 g, 1.91 mmol, 1.00 equiv.), (S)-t-BuPHOXS7
(0.222 g, 0.573 mmol, 0.30 equiv.), and palladium acetate (Pd(OAc)2, 0.043 g, 0.191 mmol, 0.10
equiv.). The vial was sealed with a rubber septum and evacuated using high vacuum (the septum
was pierced with a needle connected to a Schlenk manifold) and then refilled with argon. This
process was repeated twice more before the vial was removed and equipped with a balloon filled
with argon. Toluene (tol, 13 mL, 0.15 M) and 1,2,2,6,6-pentamethylpiperidine (PMP, 0.69 mL,
3.8 mmol, 2.00 equiv.) were added via syringe and the septum was rapidly exchanged for a
microwave cap with septum. The vial was placed in a Biotage microwave reactor and heated to
175 °C for 80 minutes. The reaction was terminated by directly concentrating under vacuum on
a rotary evaporator. The resulting residue was purified by flash column chromatography (5%
EtOAc in hexanes → 10% EtOAc in hexanes → 15% EtOAc in hexanes) furnishing 0.578 g
(75%) of (+)-14.

SI-35



CH3

O
O
TBS
(+)-14

1
H NMR (500 MHz, CDCl3):
7.97 (d, J = 8.0 Hz, 1H) 3.33 (ddd, J = 20.1, 3.1, 2.3 Hz, 1H)
7.78 (d, J = 8.0 Hz, 1H) 2.81 – 2.68 (m, 2H)
6.62 (ddd, J = 9.8, 3.1, 1.2 Hz, 1H) 1.53 (s, 3H)
6.12 (ddd, J = 9.7, 5.2, 2.3 Hz, 1H) 0.97 (s, 9H)
3.86 (ddd, J = 19.4, 7.0, 4.6 Hz, 1H) 0.37 (s, 3H)
3.72 (ddd, J = 19.4, 7.0, 4.6 Hz, 1H) 0.36 (s, 3H)
3.40 (ddd, J = 20.1, 5.2, 1.3 Hz, 1H)
13
C NMR (126 MHz, CDCl3):
206.73 131.29 36.59
173.35 131.21 28.38
161.27 131.18 26.38
158.65 127.03 23.17
155.76 126.68 17.58
147.18 124.92 –6.14
144.39 39.51 –6.20
136.97 36.61

HRMS (ESI–TOF):
calculated: [M + H+] = 405.1880 for [C25H28O3Si + H+]
observed: [M + H+] = 405.1882
error: 0.5 ppm

physical appearance: white foam

TLC: Rf = 0.25 (15% EtOAc in hexanes)

optical rotation: [α]D = +18.8 (αD = +0.160, c = 0.85, CH2Cl2)

SI-36



O O

CH3 HO CH
cat. OsO4 3
NMO, acetone HO

(90%)
O O
aqueous
O extractive O
TBS workup then TBS
FCC
(+)-14 (+)-15

To a 100 mL flask was added (+)-14 (2.35 g, 5.81 mmol, 1.00 equiv.), 4-methylmorpholine N-
oxide (NMO, 1.20 g, 6.97 mmol, 1.20 equiv.) and acetone (39 mL, 0.15 M) and the mixture was
stirred. Osmium tetroxide (OsO4, 0.18 mL, 4% w/w in water, 0.029 mmol, 0.005 equiv.) was
added via syringe. Upon complete consumption of starting material as judged by TLC (30
minutes), the reaction was terminated by transferring the solution to a separatory funnel
containing saturated aqueous NaHCO3 (25 mL), saturated aqueous Na2S2O3 (25 mL) and EtOAc
(100 mL). After shaking and separation, the aqueous layer was back extracted with EtOAc (25
mL). The combined organic portion was washed with saturated aqueous NaCl, dried over
anhydrous MgSO4, and concentrated under vacuum on a rotary evaporator. The resulting residue
was purified by flash column chromatography (60% EtOAc in hexanes → 70% EtOAc in
hexanes) furnishing 2.30 g (90%) of (+)-15.

SI-37



HO CH
3
HO

O
O
TBS
(+)-15

1
H NMR (500 MHz, CDCl3):
7.89 (d, J = 7.9 Hz, 1H) 2.75 – 2.54 (m, 4H)
7.64 (d, J = 8.0 Hz, 1H) 1.49 (s, 3H)
4.70 – 4.65 (m, 2H) 0.95 (s, 9H)
3.80 (ddd, J = 19.5, 7.8, 3.8 Hz, 1H) 0.35 (s, 3H)
3.62 (ddd, J = 19.5, 7.8, 3.8 Hz, 1H) 0.34 (s, 3H)
3.33 (dd, J = 16.6, 7.6 Hz, 1H)
13
C NMR (126 MHz, CDCl3):
207.07 132.01 33.00
173.33 129.93 28.50
162.57 127.01 26.83
159.14 124.45 26.50
154.83 74.71 17.88
149.52 68.05 –6.09
142.08 43.87 –6.20
137.20 36.60

HRMS (ESI–TOF):
calculated: [M + H+] = 439.1935 for [C25H30O5Si + H+]
observed: [M + H+] = 439.1934
error: –0.2 ppm

physical appearance: white foam

TLC: Rf = 0.59 (100% EtOAc)

optical rotation: [α]D = +18.8 (αD = +0.179, c = 0.95, CH2Cl2)

SI-38



O O
1. DMSO, TFAA
HO CH CH2Cl2, –60 °C; O CH
3 i-Pr2EtN, –60 °C; 3
HO AcOH, warm to r.t. H 3CO

2. KN(TMS) 2, THF;
O (CH 3)2SO 4 O
0 °C to r.t.
O O
TBS (64%, two steps) TBS
(+)-15 aqueous extractive (+)-16
workup for each
step; FCC only after
second step

A 250 mL flask was evacuated using high vacuum and then refilled with argon. This process
was repeated twice more before the flask was removed from the manifold and rapidly sealed
using a rubber septum equipped with a balloon filled with argon. Then CH2Cl2 (41 mL, 0.10 M)
and DMSO (3.6 mL, 51.2 mmol, 10.0 equiv.) were added via syringe and the flask was cooled to
–60 °C and the contents were stirred. Trifluoroacetic anhydride (TFAA, 2.17 mL, 15.4 mmol,
3.00 equiv.) was added via syringe and this mixture was stirred for 15 minutes at –60 °C. During
this time, a solution of (+)-15 (2.244 g, 5.12 mmol, 1.00 equiv.) dissolved in 10 mL CH2Cl2, was
prepared and also cooled to –60 °C. After 15 minutes, chilled (+)-15 was added via cannula to
the solution of activated DMSO. 90 minutes after this addition, N,N-diisopropylethylamine (i-
Pr2EtN, 8.91 mL, 51.2 mmol, 10 equiv.) was added via syringe to the reaction mixture, still at –
60 °C. After 90 minutes the reaction was terminated by the addition of acetic acid (AcOH, 4.39
mL, 77.0 mmol, 15 equiv.) and was allowed to warm to room temperature. Once at room
temperature 1 M aqueous HCl (50 mL) was added and the mixture was stirred vigorously for 2
hours. The solution was transferred to a separatory funnel containing Et2O (100 mL). After
shaking and separation, the organic portion was washed with saturated aqueous NaHCO3 (50
mL), saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under vacuum on
a rotary evaporator. The resulting solid was transferred to a 250 mL flask which was evacuated
using high vacuum and then refilled with argon. This process was repeated twice more before
the flask was removed from the manifold and rapidly sealed using a rubber septum equipped
with a balloon filled with argon. Then THF (51 mL, 0.10 M) was added via syringe and the flask
was cooled to 0 °C and was stirred. Potassium bis(trimethylsilyl)amide (KN(TMS)2, 11.3 mL,
0.5 M in toluene, 5.63 mmol, 1.10 equiv.) was added via syringe. After five minutes dimethyl
sulfate (4.89 mL, 51.2 mmol, 10 equiv.) was added via syringe, also at 0 °C, and the reaction was
stirred at this temperature. After 12 hours the reaction was terminated by the addition of acetic
acid (0.59 mL, 10 mmol, 2.0 equiv.) and was allowed to warm to room temperature. The
solution was transferred to a separatory funnel containing saturated aqueous NaHCO3 (50 mL)
and EtOAc (100 mL). The organic portion was washed with saturated aqueous NaCl, dried over
anhydrous MgSO4, and concentrated under vacuum on a rotary evaporator. The resulting residue
was purified by flash column chromatography (10% EtOAc in hexanes → 20% EtOAc in
hexanes) furnishing 1.48 g (64%) of (+)-16.

SI-39



O CH
3
H 3CO

O
O
TBS
(+)-16

1
H NMR (500 MHz, CDCl3):
8.54 (d, J = 8.1 Hz, 1H) 3.75 – 3.66 (m, 1H)
8.03 (d, J = 8.1 Hz, 1H) 2.78 – 2.70 (m, 2H)
6.49 (s, 1H) 1.86 (s, 3H)
3.88 – 3.81 (m, 1H) 0.99 (m, 9H)
3.83 (s, 3H) 0.43 (s, 6H)
13
C NMR (126 MHz, CDCl3):
206.76 138.56 49.55
192.51 137.50 36.53
173.30 131.03 36.08
162.50 129.15 28.68
158.28 127.02 26.49
150.47 126.95 17.68
149.62 103.03 –5.81
148.89 56.26 –5.86

HRMS (ESI–TOF):
calculated: [M + H+] = 449.1779 for [C26H28O5Si + H+]
observed: [M + H+] = 449.1777
error: –0.4 ppm

physical appearance: white solid

TLC: Rf = 0.27 (25% EtOAc in hexanes)

optical rotation: [α]D = +155 (αD = +0.933, c = 0.60, CH2Cl2)

SI-40



O
O
O CH TFA
3 CH 3NO 2 O CH
3
H 3CO (1:1)
H 3CO
(91%)
O
solvent O
O evaporation O
TBS then FCC
(+)-16 (+)-17

To a 50 mL flask containing (+)-16 (1.48 g, 3.30 mmol, 1.00 equiv.) were added nitromethane
(16.5 mL, 0.20 M) and trifluoroacetic acid (16.5 mL, 0.20 M) and the mixture was stirred. Upon
complete consumption of starting material as judged by TLC (36 hours), the reaction was
terminated by directly concentrating under vacuum on a rotary evaporator. The resulting residue
was purified by flash column chromatography (5% Et2O in CH2Cl2) furnishing 1.00 g (91%) of
(+)-17.

SI-41



O CH
3
H 3CO

O
O

(+)-17

1
H NMR (500 MHz, CDCl3):
8.53 (d, J = 8.3 Hz, 1H) 3.85 (s, 3H)
8.04 (d, J = 8.2 Hz, 1H) 3.75 – 3.67 (m, 1H)
7.73 (s, 1H) 2.77 – 2.73 (m, 2H)
6.48 (s, 1H) 1.87 (s, 3H)
3.87 – 3.79 (m, 1H)
13
C NMR (126 MHz, CDCl3):
206.80 142.64 101.03
192.09 138.76 56.39
173.19 137.53 49.40
158.29 130.76 36.47
150.94 129.19 35.91
149.51 127.12 28.71
145.79 117.56

HRMS (ESI–TOF):
calculated: [M + H+] = 335.0914 for [C20H14O5 + H+]
observed: [M + H+] = 335.0916
error: 0.6 ppm

physical appearance: white solid

TLC: Rf = 0.37 (10% Et2O in CH2Cl2)

optical rotation: [α]D = +254.8 (αD = +1.402, c = 0.55, CH2Cl2)

SI-42



(i) TBSOTf, 2,6-lut.

O CH2Cl2, –30 °C; O
(ii) BH 3•THF, –30 °C;
O CH (iii) Et 3N•3HF, –30 °C HO CH
3 then warm to r.t. 3
H 3CO H 3CO
(72%)
O aqueous O
O extractive O
workup then
(+)-17 FCC (–)-18

To a 100 mL flask was added (+)-17 (0.200 g, 0.598 mmol, 1.00 equiv.). This was evacuated
using high vacuum and then refilled with argon. This process was repeated twice more before
the flask was removed from the manifold and rapidly sealed using a rubber septum equipped
with a balloon filled with argon. Then CH2Cl2 (30 mL, 0.02 M) was added via syringe and the
flask was cooled to –30°C and the mixture was stirred. 2,6-Lutidine (2,6-lut., 0.21 mL, 1.8
mmol, 3.0 equiv.) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 0.21
mL, 0.88 mmol, 1.5 equiv.) were added via syringe, and the reaction was stirred at –30 °C. After
20 minutes, BH3•THF complex (6.0 mL, 1.0 M in THF, 6.0 mmol, 10 equiv.) was added via
syringe, and the reaction was stirred, still at –30 °C. After four hours, the reaction was
terminated by the addition of triethylamine trihydrofluoride (1.77 mL, 10.8 mmol, 18.0 equiv.) at
–30 °C. After 45 minutes, the reaction was warmed to room temperature and stirred for an
additional 12 hours. The solution was transferred to a separatory funnel containing saturated
aqueous NaHCO3 (50 mL) and EtOAc (100 mL). The mixture was shaken, the layers were
allowed to separate, and the aqueous layer was extracted with EtOAc (25 ml). The combined
organic portions were washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and
concentrated under vacuum on a rotary evaporator. The resulting residue was purified by flash
column chromatography (5% EtOAc in CH2Cl2 → 7.5% EtOAc in CH2Cl2) furnishing 0.145 g
(72%) of (−)-18.

SI-43



HO CH
3
H 3CO

O
O
(–)-18

1
H NMR (500 MHz, CDCl3):
8.49 (dd, J = 8.2, 0.9 Hz, 1H) 3.85 (s, 3H)
7.93 (d, J = 8.1 Hz, 1H) 3.75 – 3.65 (m, 1H)
7.47 (s, 1H) 3.51 – 3.50 (m, 1H)
5.62 (d, J = 1.8 Hz, 1H) 2.75 – 2.71 (m, 2H)
4.80 (t, J = 1.7 Hz, 1H) 1.52 (s, 3H)
3.87 – 3.79 (m, 1H)
13
C NMR (126 MHz, CDCl3):
206.97 139.76 73.14
173.65 137.24 56.37
157.99 130.91 42.12
157.11 128.08 36.56
156.12 127.00 28.60
145.07 119.61 25.05
140.11 86.24

HRMS (ESI–TOF):
calculated: [M + H+] = 337.1071 for [C20H16O5 + H+]
observed: [M + H+] = 337.1069
error: –0.6 ppm

physical appearance: white solid

TLC: Rf = 0.37 (10% Et2O in CH2Cl2)

optical rotation: [α]D = −17.5 (αD = −0.132, c = 0.75, CH2Cl2)

melting point: 240–248°C (decomposed)

SI-44



O O O

HO CH HO CH HO CH
3 AcOOH, CH 3OH H 3CO 3 H 3CO 3
H 3CO H 3CO + H 3CO
(53%;
dr = 1:2 (– )-21:(+)-22,
O inconsequential, HO O HO O
O see below & text) O O
(–)-18 aqueous extractive (–)-19 (+)-20
workup then FCC

To a 25 mL flask was added (−)-18 (0.040 g, 0.12 mmol, 1.00 equiv.) and the vessel was
evacuated using high vacuum and then refilled with argon. This process was repeated twice
more before the flask was removed from the manifold and rapidly sealed using a rubber septum
equipped with a balloon filled with argon. Then CH2Cl2 (2.0 mL, 0.060 M) and CH3OH (2.0
mL, 0.060 M) were added via syringe followed by peroxyacetic acid (AcOOH, 0.066 mL, 36%
in acetic acid, 0.36 mmol, 3.0 equiv.), also added via syringe. After three hours, a second charge
of peroxyacetic acid (0.066 mL, 36% in acetic acid, 0.36 mmol, 3.0 equiv.) was added via
syringe. A third charge of peroxyacetic acid (0.066 mL, 36% in acetic acid, 0.36 mmol, 3.0
equiv.) was added via syringe a further three hours later. After nine hours the reaction was
terminated by being transferred to a separatory funnel containing saturated aqueous NaHCO3 (20
mL), saturated aqueous Na2S2O3 (10 mL), and EtOAc (25 mL). The aqueous portion was
extracted twice successively with EtOAc (10 mL). The combined organic portions was washed
with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under vacuum on
a rotary evaporator. The resulting residue was purified by flash column chromatography (10%
EtOAc in CH2Cl2 → 20% EtOAc in CH2Cl2 → 30% EtOAc in CH2Cl2) furnishing 8.0 mg (18%)
of (−)-19 and 16.0 mg (35%) of (+)-20.

SI-45



HO CH
H 3CO 3

H 3CO

HO O
O
(–)-19

1
H NMR (500 MHz, CDCl3):
8.17 (dd, J = 8.1, 0.9 Hz, 1H) 3.60 (d, J = 1.0 Hz, 3H)
7.97 (dd, J = 8.1, 0.8 Hz, 1H) 3.45 (d, J = 6.6 Hz, 1H)
7.78 (s, 1H) 3.12 (d, J = 0.9 Hz, 3H)
4.96 (s, 1H) 2.76 – 2.72 (m, 2H)
4.15 (d, J = 6.1 Hz, 1H) 2.66 (brs, 1H)
3.83 (ddd, J = 19.4, 7.1, 4.6 Hz, 1H) 1.75 (s, 3H)
3.70 (ddd, J = 19.2, 6.9, 4.3 Hz, 1H)

13
C NMR (126 MHz, CDCl3):
206.84 137.09 50.89
206.83 130.01 49.46
173.58 127.50 42.66
158.92 127.42 36.62
158.21 122.29 30.89
145.66 101.90 28.59
145.21 76.33
142.95 65.41

HRMS (ESI–TOF):
calculated: [M – H+] = 383.1136 for [C21H20O7 – H+]
observed: [M – H+] = 383.1138
error: 0.6 ppm

physical appearance: colorless oil

TLC: Rf = 0.30 (50% EtOAc in CH2Cl2)

optical rotation: [α]D = −41.9 (αD = −0.113, c = 0.27, CH2Cl2)

SI-46



HO CH
H 3CO 3

H 3CO

HO O
O
(+)-20

1
H NMR (500 MHz, CDCl3):
8.38 (d, J = 8.3 Hz, 1H) 3.72 (d, J = 7.7 Hz, 1H)
7.93 (d, J = 8.3 Hz, 1H) 3.66 (s, 3H)
7.72 (d, J = 1.7 Hz, 1H) 3.49 (d, J = 8.8 Hz, 1H)
5.12 (d, J = 8.3 Hz, 1H) 3.36 (s, 3H)
4.24 (d, J = 7.7 Hz, 1H) 2.72 (t, J = 5.7 Hz, 2H)
3.75 (dd, J = 4.9 Hz, 4.9 Hz, 2H) 1.50 (s, 3H)

13
C NMR (126 MHz, CDCl3):
207.03 137.21 69.33
173.46 130.55 51.70
157.90 129.42 50.34
154.94 126.61 41.64
145.60 124.72 36.53
143.71 98.88 28.68
139.07 78.31 23.05

HRMS (ESI–TOF):
calculated: [M – H+] = 383.1136 for [C21H20O7 – H+]
observed: [M – H+] = 383.1137
error: 0.3 ppm

physical appearance: colorless oil

TLC: Rf = 0.40 (50% EtOAc in CH2Cl2)

optical rotation: [α]D = +6.44 (αD = +0.0676, c = 1.05, CH2Cl2)

SI-47



O O

HO CH TMSOTf, BH 3•S(CH 3)2 HO CH

H 3CO 3 CH2Cl2, –30 °C; 3

H 3CO H 3CO
C5H 5N, AcOH; Et 3N•3HF
HO O (49%) HO O
O O
aqueous extractive
(–)-19 (–)-4 (viridiol)
workup then FCC

To a flame-dried vial was added (−)-19 (14.2 mg, 0.0370 mmol, 1.00 equiv.). The vial was
sealed using a threaded screw cap with hole and a PTFE/silicone septum. The vial was then
evacuated using high vacuum (the septum was pierced with a needle connected to a Schlenk
manifold) and then refilled with argon. This process was repeated twice more. Then CH2Cl2
(1.5 mL, 0.025 M) was added via syringe and the reaction was allowed to stir. The solution was
subsequently cooled to –35 °C. Borane dimethylsulfide complex (BH3•S(CH3)2, 63 µL, 33.3%
v/v in CH2Cl2, 0.222 mmol, 6.0 equiv.) was added via microliter syringe in one portion followed
by trimethylsilyl trifluoromethanesulfonate (TMSOTf, 66 µL, 33.3% v/v in CH2Cl2, 0.122 mmol,
3.3 equiv.). Upon complete consumption of starting material as judged by TLC (20 minutes), the
reaction was terminated by the addition of pyridine (60 µL, 0.74 mmol, 20 equiv.) and acetic
acid (42 µL, 0.74 mmol, 20 equiv.), both via microliter syringe, and was stirred at –35 °C for 10
minutes followed by warming to room temperature over 20 minutes. Once at room temperature
triethylamine trihydrofluoride (Et3N•3HF, 60 µL, 0.37 mmol, 10 equiv.) was added. After 70
minutes the contents of the vial were transferred to a separatory funnel containing saturated
aqueous NaHCO3 (20 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted three times
successively with CH2Cl2 (5 mL). The combined organic portions were washed with saturated
aqueous NaCl, dried over anhydrous MgSO4, and concentrated under vacuum on a rotary
evaporator. The resulting residue was purified by flash column chromatography (12% acetone in
CH2Cl2 → 14% acetone in CH2Cl2 → 20% acetone in CH2Cl2) furnishing 6.4 mg (49%) of (−)-4
(viridiol).

SI-48



HO CH
3
H 3CO

HO O
O
(–)-4 (viridiol)

1
H NMR (500 MHz, CDCl3):
8.26 (d, J = 8.2 Hz, 1H) 3.73 (s, 3H)
7.96 (d, J = 8.1 Hz, 1H) 3.63 (dd, J = 6.2, 4.6 Hz, 1H)
7.79 (s, 1H) 3.42 (brs, 1H)
5.14 (d, J = 4.6 Hz, 1H) 2.90 (brs, 1H)
4.36 – 4.30 (m, 1H) 2.74 – 2.70 (m, 2H)
3.82 (ddd, J = 19.5, 7.0, 4.6 Hz, 1H) 1.73 (s, 3H)
3.74 – 3.65 (m, 1H)
13
C NMR (126 MHz, CDCl3):
206.81 137.09 61.76
173.55 129.98 60.86
158.74 127.47 42.43
158.14 127.40 36.60
145.84 122.20 30.63
145.71 81.79 28.55
142.50 71.87

HRMS (ESI–TOF):
calculated: [M – H+] = 353.1031 for [C20H18O6 – H+]
observed: [M – H+] = 353.1032
error: 0.3 ppm

physical appearance: white solid

TLC: Rf = 0.42 (50% acetone in hexanes)

optical rotation: [α]D = −53.3 (αD = −0.117, c = 0.22, CH2Cl2)

SI-49



O O

HO CH TMSOTf, Et 3SiH HO CH
H 3CO 3 CH2Cl2, –30 °C 3

H 3CO H 3CO
(43%)
HO O aqueous extractive HO O
O workup then FCC O
(+)-20 (–)-21 (epi-viridiol)

To a flame-dried vial was added (+)-20 (19.5 mg, 0.0507 mmol, 1.00 equiv.). The vial was
sealed using a PTFE/silicone septum and a threaded screw cap with hole. The vial was then
evacuated using high vacuum (the septum was pierced with a needle connected to a Schlenk
manifold) and then refilled with argon. This process was repeated twice more. Then CH2Cl2 (2.1
mL, 0.025 M) was added via syringe and the reaction was allowed to stir. The solution was
subsequently cooled to –20°C. Triethylsilane (Et3SiH, 203 µL, 1.27 mmol, 25.0 equiv.) was
added via syringe in one portion followed by trimethylsilyl trifluoromethanesulfonate (344 µL,
33.3% v/v in CH2Cl2, 0.380 mmol, 7.5 equiv.). Upon complete consumption of starting material
as judged by TLC (15 minutes), the reaction was terminated by injecting methanol (400 µL).
After five minutes the reaction was warmed to room temperature and the contents of the vial
were transferred to a separatory funnel containing saturated aqueous NaHCO3 (20 mL) and
CH2Cl2 (10 mL). The aqueous layer was extracted three times with CH2Cl2 (5 mL). The
combined organic portion was washed with saturated aqueous NaCl, dried over anhydrous
MgSO4, and concentrated under vacuum on a rotary evaporator. The resulting residue was
purified by flash column chromatography (20% acetone in CH2Cl2 → 22.5% acetone in CH2Cl2
→ 25% acetone in CH2Cl2) furnishing 7.7 mg (43%) of (−)-21 (epi-viridol).

SI-50



HO CH
3
H 3CO

HO O
O
(–)-21 (epi-viridiol)

1
H NMR (500 MHz, CDCl3):
8.33 (d, J = 8.2 Hz, 1H) 3.84 – 3.64 (m, 6H)
7.93 (d, J = 8.1 Hz, 1H) 3.59 (ddd, J = 6.3, 5.1, 0.7 Hz, 1H)
7.76 (d, J = 1.6 Hz, 1H) 2.72 (dt, J = 6.9, 4.3 Hz, 2H)
5.12 (dd, J = 5.0, 1.6 Hz, 1H) 1.50 (s, 3H)
4.18 (t, J = 6.5 Hz, 1H)
13
C NMR (126 MHz, CDCl3):
207.08 137.09 67.05
173.59 130.11 60.51
158.11 128.26 42.05
157.00 127.16 36.55
145.53 123.82 28.60
143.97 87.11 27.73
141.31 71.10

HRMS – (ESI–TOF):
calculated: [M – H+] = 353.1031 for [C20H18O6 – H+]
observed: [M – H+] = 353.1033
error: 0.6 ppm

physical appearance: off-white solid

TLC: Rf = 0.44 (50% acetone in hexanes)

optical rotation: [α]D = −12 (αD = −0.026, c = 0.21, CH2Cl2)

SI-51



O O

HO CH TEMPO, PhI(OAc) 2 HO CH
3
3 CH2Cl2
H 3CO H 3CO

(46%)
HO O O O
solvent evaporation
O then FCC O

(–)-4 (viridiol) (–)-3 (viridin)

To a 4 mL vial was added (−)-4 (viridiol) (5.9 mg, 0.017 mmol, 1.0 equiv.), iodobenzene
diacetate (10.7 mg, 0.33 mmol, 2.0 equiv.) and CH2Cl2 (0.8 mL, 0.02 M) and allowed to stir.
TEMPO (66 µL, 0.13 M in CH2Cl2, 0.0085 mmol, 0.50 equiv.) was added via syringe. After 2
hours additional TEMPO (66 µL, 0.13 M in CH2Cl2, 0.0085 mmol, 0.50 equiv.) was added.
Upon complete consumption of starting material as judged by TLC (19 hours), the reaction was
terminated by concentrating under vacuum on a rotary evaporator. The resulting residue was
purified by flash column chromatography (10% acetone in hexanes → 25% acetone in hexanes)
furnishing 2.7 mg (46%) of (−)-3 (viridin).

SI-52



O O

HO CH TEMPO, PhI(OAc) 2 HO CH
3 CH2Cl2 3
H 3CO H 3CO
(48%)
HO O solvent evaporation O O
O then FCC O
(–)-21 (epi-viridiol) (–)-3 (viridin)

To a 4 mL vial was added (−)-21 (8.2 mg, 0.023 mmol, 1.0 equiv.), iodobenzene diacetate (14.9
mg, 0.046 mmol, 2.0 equiv.) and CH2Cl2 (1.2 mL, 0.02 M) and allowed to stir. TEMPO (105
µL, 0.11 M in CH2Cl2, 0.011 mmol, 0.50 equiv.) was added via syringe. After four hours
additional TEMPO (53 µL, 0.11 M in CH2Cl2, 0.058 mmol, 0.25 equiv.) was added and again at
six hours. Upon complete consumption of starting material as judged by TLC (10 hours), the
reaction was terminated by concentrating under vacuum on a rotary evaporator. The resulting
residue was purified by flash column chromatography (10% acetone in hexanes → 25% acetone
in hexanes) furnishing 3.9 mg (48%) of (−)-3 (viridin).

SI-53



HO CH
3
H 3CO

O O
O

(–)-3 (viridin)

1
H NMR (500 MHz, CDCl3):
8.66 (dd, J = 8.2, 0.8 Hz, 1H) 3.87 – 3.78 (m, 1H)
8.33 (s, 1H) 3.76 (s, 3H)
7.98 (d, J = 8.2 Hz, 1H) 3.72 – 3.64 (m, 1H)
4.37 (s, 1H) 2.79 – 2.73 (m, 2H)
3.89 (d, J = 5.0 Hz, 1H) 1.69 (s, 3H)
13
C NMR (126 MHz, CDCl3):
206.66 143.13 73.31
187.09 137.30 61.10
173.43 129.65 42.10
158.18 127.95 36.49
156.61 127.77 29.95
149.53 121.77 28.59
147.09 83.58

HRMS (ESI–TOF):
calculated: [M – H+] = 351.0874 for [C20H16O6 – H]
observed: [M – H+] = 351.0877
error: 0.9 ppm

TLC: Rf = 0.45 (40% acetone in hexanes)

physical appearance: white solid

optical rotation: [α]D = −145 (αD = −0.333, c = 0.23, CHCl3)

SI-54



Tabulated 1H NMR Data for Synthetic Versus Natural (–)-Viridin (3)

1
H NMR data for viridin (CDCl3 for both samples):

synthetic (–)-viridin (3) (this work): natural (–)-viridin (3) (ref. S8):

8.66 (dd, J = 8.2, 0.8 Hz) 8.8 (d, J = 8 Hz)

8.33 (s) 8.45 (s)
7.98 (d, J = 8.2 Hz) 8.1 (d, J = 8 Hz)
4.37 (bs) 4.45 (d, J = 5 Hz)
3.89 (d, J 5.0 Hz) 3.95 (d J = 5 Hz)
3.87 – 3.78 (m) 3.8 (multiplicity not given)
3.76 (s) 3.75 (s)
3.72 – 3.64 (m) (grouped with signal at 3.8)
2.79 – 2.73 (m) 2.9 (multiplicity not given)
1.69 (s) 1.63 (multiplicity not given)

Commentary: the 1H NMR spectrum of (–)-viridin (3) as recorded by Grove, McCloskey, and
MoffattS8 in 1966 was taken on a 60 MHz instrument, leading to relatively low resolution,
perhaps explaining why nine, not ten, signals were reported. Importantly, their sample contained
“a trace of CF3CO2H” and so some of the chemical shifts may differ slightly relative to our own
reported values. We also note that their sample used tetramethylsilane (TMS) as an internal
standard for calibration and their data was reported using the tau (τ) scale. We have converted τ
units to δ units using the following expression: δ = 10 – τ. Also, the signal at δ = 4.37 ppm
appears as a broad singlet in our own material. This signal correspondons to the C–H bond of
the secondary alcohol substructure, and the difference in observed multiplicity is caused by
splitting by the adjacent O–H. In turn, the tendency for this happen is sensitive to water and/or
acid content in a sample.

Regarding (–)-viridiol (4), Moffatt and coworkers also publishedS9 its isolation and structure
elucidation, but only gave partial 1H NMR data (not all signals were presented); hence, we have
not included a comparison like the one above for (–)-viridiol (4).

For the sake of completeness, we have also graphically compared the 1H and 13C spectra of our
synthetic materials, (–)-viridin (3) and (–)-viridiol (4), to the spectra in Alexanian’s Ph.D. thesis,
which includes the corresponding spectra of his synthetic (±)-viridin (3) and (±)-viridiol (4) (see
pages SI-101–SI-104). (To the best of our knowledge, graphical NMR spectra of (–)-viridin (3)
and (–)-viridiol (4) do not exist, and so we compare our synthetic material to that of others.)

SI-55



Discussion of Optical Rotation for Viridin

Our measured specific optical rotation for synthetic (–)-viridin, [α]D = −145, falls short of the
value reportedS10 by the isolation chemists, [α]D = −222, although the sign is identical. The
differencein magnitude may be ascribed to the determination of this data using small quantities
of material. We still claim a highly enantioselective synthesis on the basis of chiral HPLC data.
In the section that follows, we measured (Spring 2015) and re-measured (7 March 2017) the
enantiomeric excess of our enantioselective Heck product and found it to be >99%. See pages
SI-57 and SI-58 for this data.

SI-56



Chiral HPLC Data for (+)-14 (Enantioselective Heck Product)

Data Set 1:

In this measurement (Spring 2015), the ee of (+)-14 was determined at 254 nm on an Agilent
1100 series HPLC. Conditions:

Column: Phenomenex Lux® 5 µm Amylose-2, 250 × 4.6 mm

Column temperature: 25 °C
Solvents & elution rates: 40% acetonitrile in water, 1.0 mL/min

ee > 99%

SI-57



Data Set 2:

In this measurement (7th March 2017), the ee of (+)-14 was determined by MS on an Agilent
1260 Infinity series SFC/MS equipped with an A5 CO2 booster. Detection via MS SIM (single-
ion mode) [M + H]. Conditions:

Column: Phenomenex Lux® 5 µm Cellulose-4, 100 × 4.6 mm

Column temperature: 25 °C
Solvents & elution rates: 40% MeOH, 120 bar, 4 mL/min

ee > 99%

Inset of “chiral” run with areas visible:

SI-58



Discussion of Optimization of the Intramolecular Enantioselective Heck Reaction

A reviewer has requested that we provide additional detail regarding the optimization of our
enantioselective, intramolecular Heck reaction. Our studies began with racemic Heck reactions
to generate a product marker as well as to gain familiarization with the reaction. Early on, we
observed what we have tentatively assigned as structure SI-34, undesired alkene migration
product, with racemic diphosphine ligands such as (±)-BINAP as a significant component of the
crude reaction mixture, along with (±)-14. A working 1H NMR spectrum of SI-34 recorded in
CDCl3 at 300 MHz is shown below to support our assignment. Instead of using BINAP-based
conditions as a starting point to exclude the formation of SI-34, we moved directly to using P,N-
chelating ligands, given their success in numerous other settings (for relevant reviews, see refs
S11 and and S12). Purely by chance, our Heck reactions with commercially-availalbe t-Bu
PHOX as a ligand dramatically reduced the formation of SI-34 and led to the desired Heck
product (+)-14 in high enantiomeric excess, even in early runs. Therefore our protocol on page
SI-35 largely reflects our early reaction conditions.

Working 1H NMR spectrum of (±)-SI-34 in CDCl3 at 300 MHz

SI-59



References

(S1) Anderson, E. A; Alexanian, E. J.; Sorensen, E. J. Angew. Chem. Int. Ed. 2002, 43, 1998.
(S2) Alexanian, E. J. Ph.D. Thesis, Princeton University, 2006.
(S3) Smith, A.B.; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am. Chem. Soc. 2000, 122, 11254.
As drawn in the manuscript figure, Scheme 4, it would appear, at least superficially, that five
steps are involved. However, reading the Supporting Information section indicates that the
indole product is formed to some extent prior to stage 5, in addition to an amino ketone
intermediate. Thus, we would count the first four stages as one step. In our opinion, the fifth
stage would count as a second step (and the language in the Supporting Information section of
the manuscript would support this). However, even after this stage, additional recycling is
performed. It is not clear how recycling of material would contribute to step count.
(S4) Fürstner, A.; Konetzki, I. Tetrahedron 1996, 52, 15071.
(S5) Lucciola, D.; Keay, B. Synlett 2011, 1618.
(S6) Saito, T.; Fuwa, H.; Sasaki, M. Tetrahedron 2011, 67, 429.
(S7) Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Syn. 2009, 86, 181. Note: we purchased this
commercially-available ligand from Combi-Blocks Inc. (San Diego).
(S8) Grove, J. F.; McCloskey, P.; Moffatt, J. S. J. Chem. Soc. (C) 1966, 743.
(S9) Moffatt, J. S.; Bu’Lock, J. D.; Yuen, T. H. J. Chem. Soc. D: Chem. Commun. 1969, 839.
(S10) Brian, P. W.; McGowan, J. C. Nature 1945, 156, 144.
(S11) Loiseleur, M.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338.
(S12) Mc Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122.

SI-60


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-61


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-62


1
H NMR (500 MHz, (CD3)2SO with residual (CH3)2SO)

SI-63


13
C NMR (126 MHz, (CD3)2SO with residual (CH3)2SO)

SI-64


1
H NMR (500 MHz, (CD3)2SO with residual (CH3)2SO)

SI-65


13
C NMR (126 MHz, (CD3)2SO with residual (CH3)2SO)

SI-66


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-67


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-68


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-69


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-70


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-71


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-72


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-73


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-74


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-75


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-76


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-77


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-78


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-79


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-80


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-81


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-82


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-83


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-84


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-85


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-86


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-87


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-88


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-89


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-90


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-91


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-92


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-93


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-94


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-95


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-96


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-97


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-98


1
H NMR (500 MHz, CDCl3 with residual CHCl3)

SI-99


13
C NMR (126 MHz, CDCl3 with residual CHCl3)

SI-100



1
H NMR of synthetic (–)-viridin (3) (500 MHz, CDCl3) (this work)

1
H NMR of synthetic (±)-viridin (3) (500 MHz, CDCl3) (Alexanian thesis)

SI-101



13
C NMR of synthetic (–)-viridin (3) (126 MHz, CDCl3) (this work)

13
C NMR of synthetic (±)-viridin (3) (150 MHz, CDCl3) (Alexanian thesis)

SI-102



1
H NMR of synthetic (–)-viridiol (4) (500 MHz, CDCl3) (this work)

1
H NMR of synthetic (±)-viridiol (3) (400 MHz, CDCl3) (Alexanian thesis)

SI-103



13
C NMR of synthetic (–)-viridiol (4) (126 MHz, CDCl3) (this work)

13
C NMR of synthetic (±)-viridiol (4) (100 MHz, CDCl3) (Alexanian thesis)

SI-104