Total synthesis of (+)-papulacandin D

Article abstract of DOI:10.1016/j.tet.2010.03.093

A total synthesis of (+)-papulacandin D has been achieved in 31 steps, in a 9.2% overall yield from commercially available materials. The synthetic strategy divided the molecule into two nearly equal sized subunits, the spirocyclic C-arylglycopyranoside and the polyunsaturated fatty acid side-chain. The C-arylglycopyranoside was prepared in 11 steps in a 30% overall yield from triacetoxyglucal. The fatty acid side-chain was also prepared in 11 steps in a 30% overall yield from geraniol. The key strategic transformations in the synthesis are: (1) a palladium-catalyzed, organosilanolate-based cross-coupling reaction of a dimethylglucal-silanol with an electron-rich and sterically hindered aromatic iodide and (2) a Lewis-base catalyzed, enantioselective allylation reaction of a dienal and allyltrichlorosilane. A critical element in the successful execution of the synthesis was the development of a suitable protecting group strategy that satisfied a number of stringent criteria.

Full text of DOI:10.1016/j.tet.2010.03.093

Tetrahedron 66 (2010) 4745–4759
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (þ)-papulacandin D
*
Scott E. Denmark , Tetsuya Kobayashi, Christopher S. Regens
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of (þ)-papulacandin D has been achieved in 31 steps, in a 9.2% overall yield from
commercially available materials. The synthetic strategy divided the molecule into two nearly equal sized
subunits, the spirocyclic C-arylglycopyranoside and the polyunsaturated fatty acid side-chain. The C-
arylglycopyranoside was prepared in 11 steps in a 30% overall yield from triacetoxyglucal. The fatty acid
side-chain was also prepared in 11 steps in a 30% overall yield from geraniol. The key strategic trans-
formations in the synthesis are: (1) a palladium-catalyzed, organosilanolate-based cross-coupling re-
action of a dimethylglucal-silanol with an electron-rich and sterically hindered aromatic iodide and (2)
a Lewis-base catalyzed, enantioselective allylation reaction of a dienal and allyltrichlorosilane. A critical
element in the successful execution of the synthesis was the development of a suitable protecting group
strategy that satisfied a number of stringent criteria.
Received 31 December 2009
Received in revised form 22 March 2010
Accepted 23 March 2010
Available online 30 March 2010
Keywords:
C-Arylglycosides
Silicon-based cross-coupling
Asymmetric allylation
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction and background
This potential has stimulated the search for new papulacandin
derivatives and other inhibitors of fungal cell wall synthesis. All of
The papulacandins are a family of antifungal agents, isolated
from the deuteromycetous fungus Papularia sphaerosperma1 that
have demonstrated potent in vitro antifungal activity against such
pathogens as: Candida albicans, Geotrichum lactis, Saccharomyes
cerevisiae, Pneumocytis carinii, etc.2 Interestingly, the papulacandins
are inactive against filamentous fungi, bacteria, and protozoa.1a
Compounds effective in treating fungal infections in mammals by
mechanisms that do not interfere with metabolic pathways are rare
and so the discovery and synthesis of such new antifungal agents
are of great importance to human health.2g,3
the papulacandins are amphipathic molecules; each contain
a hydrophilic domain of a different glycoside nature, and a hydro-
phobic domain characterized by the presence of modified fatty
acids. This hydrophobic domain is thought to be essential for
activity.1c Papulacandins A–D are complex molecules, composed of
an aromatic moiety resembling terrestrial fungal polyketides:
6-methylsalicylic acid or orsellinic acid, linked via a spirocyclic
structure to a lactose moiety with two different aliphatic acyl side-
chains, one shorter fatty acid chain at the O-(60) position of the
b
-galactoside and a second longer side-chain at the O-(3) position
All of the members of the papulacandin family target (1,3)-beta-
of the glucose moiety.1b The simplest member of the papulacandin
D
-glucan synthase,4 thereby preventing uptake of glucose in the
family, papulacandin D, lacks the O-(60-acyl-
b-galactoside) at the
biosynthesis of glucan, one of the most abundant polysaccharide
components of the cell wall.2a As with many secondary metabolites
displaying potential medical applications, the papulacandins
have stimulated interest in their isolation, structural elucidation,
investigation into their biological activity, and chemical synthe-
sis.1b,c,4,5 Specifically, the interest in the biological activity of these
compounds has focused on their value as potential therapeutic
agents to combat human fungal infections; which are linked to
the high mortality of immuno compromised hosts such as
AIDS patients.6
O-(4) position of the glucose residue (Fig. 1).
Several new compounds structurally related to the pap-
ulacandins have also been isolated.4 These papulacandin congeners
vary with respect to the degree of oxidation and saturation of the
shorter acyl side-chain; however, some analogs display more
drastic modifications to the overall papulacandin structure. Some of
these analogs exhibit an inhibitory effect of glucan synthase similar
to that of papulacandin B, the most potent papulacandin.4b–h This
behavior indicates that slight modifications to the acyl chains do
not significantly retard the antifungal activity of the papulacandins.
Yet, the more drastically modified analogs display markedly
reduced activity. For example, saricandin, a papulacandin-related
analog possessing a cinnamyl ester in place of the C(60) acyl
chain, displays significantly less potent antifungal activity.4e
Papulacandins devoid of their fatty acid side-chain(s) are found to
be ineffective as inhibitors.1b
* Corresponding author. 245 Roger Adams Laboratory, Box 18, Department of
Chemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL 61801, United
States. Tel.: þ1 217 333 0066; fax: þ1 217 333 3984; e-mail address: sdenmark@
illinois.edu (S.E. Denmark).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.093

4746
S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
1 (Scheme 1). The major challenges in the synthesis resided in these
OR
6'
HO
HO
OH
HO
1
Me
14''
independent units, namely: (1) the construction of the arylglycoside
bond and (2) control of the C(700) and C(1400) stereogenic centers.
Moreover, potential solutions to both of these problems could be
identified in ongoing methodological studies in these laboratories.
First, the C-spirocyclic arylglycopyranoside could be reduced to
arylhexenopyranose3, wherethe C(2) hydroxylgroupand C(1) spiro
ketalcouldbe installedthroughan oxidativespiroketalizationevent.
Disconnection of 3 at C(1) reduced the problem to a palladium-
catalyzed cross-coupling reaction of glucal silanol 5 and aryl
iodide 6. Although this approach makes rational disconnects it
provides for challenging reaction sequences. Namely, in the cross-
coupling reaction the aromatic iodide is both electron-rich and
2,6-disubstituted. Both of these features lead to problematic cross-
coupling reactions. In addition, the cross-coupling reaction condi-
tions need to be tolerant of the array of protecting groups on 5 and 6.
6
3
O
1'
Me
Me
O
O
O
OH
3'
HO
H
7''
O
HO
OH
O
O
papulacandin A
papulacandin B
papulacandin C
R =
R =
R =
Me
Me
7'''
O
OH
7'''
1'''
O
3'''
7'''
Me
OH
1'''
3'''
OH
OH
Me
Me
HO
1
6
O
Me
14''
HO
Me
HO
O
Me
7''
HO4
HO
3
14''
Me
O
O
OH
HO
7''
O
OH
O
3
HO
O
OH
O
(+)-papulacandin D
(+)-papulacandin D
Figure 1. Representative papulacandins from the fermentation of P. sphaerosperma.
Me
PO
O 1
Me
14''
Me
R2Si
R2Si
O
The antibiotic and antifungal properties, together with the
structural complexity of these unique spiro C-arylated glycopyr-
anoside derivatives have stimulated the development of creative
solutions for the construction of the tricyclic spiro ketal ring system.
Representative examples include a synthesis of a racemic spiro ketal
unit via a hetero-Diels–Alder5a reaction and dihydroxylation of
5-aryl-2-vinylfurans followed by Achmatowicz rearrangement.5b–d
The majority of work has focused on the addition of functionalized
OP
O
HO
CO2H
7''
PO
O
OTES
2
1
Me
Me
Me
PO
O 1
O
O
PO
14''
organolithium reagents with cyclic or acyclic derivatives of D-glu-
CHO
3
colactone.5e–j,u These methods provide rapid access tothe spiroketal
core, but suffer from moderate to low yields. Alternatively, nucleo-
philic 1,2-addition of a lithiated hexenopyranose to a functionalized
OP
4
OP
quinone has been utilized to access the aryl-b-D-C-glycopyr-
Me
anoside.5k Furthermore, a (tributyl)stannylhexenopyranose has
been employed in a palladium(0)-catalyzed cross-coupling reaction
with sterically hindered aryl bromides. Unfortunately, excess
amounts of the tin reagent are required because of dimerization of
the organotin donor.5l–q Although these methods provide access to
the arylglycopyranoside core of the papulacandins, there has been
only one total synthesis of one the members of the papulacandin
family, that of papulacandin D by Barrett and co-workers in 1996.5r
They accomplished the first total synthesis and assigned the
absolute configuration of the C(700) and C(1400) stereogenic centers of
papulacandin D. Barrett’s approach employed combination of an
R2Si
O
Me
O
14''
Me
Si
OH
O
PO
Me
PO
I
7
5
O
OP
PO
Me
6
OH
Me
Me
geraniol
aryllithium reagent and a protected
D-gluconolactone to assemble
the spiro ketal moiety. The C(1400) center in the carboxylic acid
Scheme 1.
side-chain was derived from L-isoleucine, and kinetic resolution was
employed to separate the C(700) epimers. The two fragments were
then coupled via acylation using a mixed anhydride of the
side-chain.
Second, disconnection of side-chain 2 at the C(600)–C(700) bond
essentially divides the molecule in half. A routine carbonyl addition
reaction (aldol or allylation) to the unsaturated aldehyde 4 would
set the configuration of the C(700) hydroxyl group, concurrently
providing a locus for further elaboration to 2. The dienyl aldehyde 4
could arise from a vinylogous Horner–Wadsworth–Emmons olefi-
nation reaction of substituted hexenal 7. Finally, the C(1400) ster-
eogenic center could be set through an asymmetric hydrogenation
of geraniol.
Therefore, the crucial components to this strategy would be the
fluoride-free, silicon-based, cross-coupling reaction of a glucal
silanol with a sterically hindered, electron-rich aromatic iodide, as
well as the diastereoselective installation of the C(700) hydroxyl
As part of our program on the development of new silicon-
based, cross-coupling reactions, we have recently demonstrated
the synthetic power of fluoride-free activation for a variety of
silanol containing reagents.7 Our plan was to amalgamate this new
technology with the previous success in the cross-coupling reaction
of 2-pyranylsilanols with aryl iodides.8 We felt that the total
synthesis of papulacandin D was well suited to highlight the
synthetic potential of silanols in complex molecule synthesis.
The synthetic plan for papulacandin D makes the obvious dis-
connection at the O–C(3) ester linkage to acid 2 and glycopyranoside

S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
4747
group in key intermediate 4. We report herein a full account for the
efficient, enantioselective total synthesis of (þ)-papulacandin D that
highlights our recently developed methods as key strategic steps.5s,t
a major problem (Scheme 3, Eq. 2). The results suggested that
a complete survey of reaction variables (solvent, temperature, ac-
tivator, etc.) was needed to develop a general and robust cross-
coupling reaction.
To carry out a systematic evaluation of different reaction pa-
rameters, a model study was conducted using aromatic iodide 9
and acetonide-protected glucal silanol 25. Aromatic iodide 9 could
be prepared in bulk following a straightforward synthetic sequence
from 3,5-dihydroxybenzoic acid.9
2. Results
2.1. Construction of the C-spirocyclic arylglycoside
2.1.1. Silicon-Based, cross-coupling of glucal silanols. Orienting
experiments. Previous studies from these laboratories have de-
scribed the synthesis of C-aryl-2-H-pyrans from 2-pyranylsilanol 8,
under fluoride activation.8 These conditions were successfully ap-
plied to the cross-coupling reaction of 8 with electron-rich and
sterically hindered aromatic iodides such as 9 (vide infra) that are
similar to those that would be required for the total synthesis of
papulacandin D (Scheme 2, Eq. 1). However, extension of these
conditions to the cross-coupling reaction of glucal silanol 11 and 9
led to protiodesilylation of the silanol and concomitant depro-
tection of the C(3)-triisopropylsilyl (TIPS) ether (Scheme 2, Eq. 2).
These results demonstrated that tetrabutylammonium fluoride
(TBAF) activation would not be a suitable activator for the desired
cross-coupling reaction. Thus, one of the first requirements in the
total synthesis was the development of fluoride-free conditions
that could be adapted for the desired glucal silanol.
The preparation of glucal silanol 25 began with peracetylation of
a-
D
-glucose with Ac2O and NaOAc to provide pentaacetylglucose 16
selectively as its -isomer in 62% yield after recrystallization
(Scheme 4). The -anomer 16 was treated with thiophenol in the
presence of BF3$OEt2 to afford an 82% yield of -phenylthioglyco-
b
b
b
side 17.10 The acetyl groups of 17 were removed using LiOH in
MeOH to provide the corresponding tetrol, which was immediately
protected as the bis-acetonide 18 in 82% yield over the two steps.11
The bis-acetonide 18 was subjected to reductive cleavage using
lithium naphthalenide in THF10 providing glucal 12 quantitatively.
Finally, the C(3) hydroxy group of glucal acetonide 12 was protected
as its methyl ether using NaH and MeI to give an 81% yield of
protected glucal 19. Attempts to selectively introduce a silyl moiety
at the C(1) position of glucal 19 proved to be difficult as lithiation/
silylation occurred preferentially at the C(3) position to afford 20.12a
Scheme 2.
Preliminary results for the cross-coupling reaction of 11 with
4-iodoanisole (13) under activation by tetrabutylammonium
hydroxide (TBAOH) were encouraging (Scheme 3, Eq.1). Once again
for more complex substrates, such as 9, protiodesilylation was
Scheme 4. Conditions: (a) Ac2O, NaOAc, reflux, 1 h, 62%; (b) PhSH, BF3$Et2O, CHCl3, rt,
5 h, 82%; (c) LiOH, MeOH, rt, 1 h, NH4Cl, rt, 20 min; (d) 2-methoxypropene, CSA, DMF,
rt, 3 h, 82% (two steps); (e) lithium naphthalenide, THF, ꢀ78 ꢁC, 30 min, >99%; (f) NaH,
MeI, THF, rt, 2 h, 81%; (g) t-BuLi, THF, ꢀ78 ꢁC to 0 ꢁC, 30 min then Me2SiHCl, ꢀ78 ꢁC to
rt, 1 h, 44%.
To circumvent this problem, an alternative route for the prepa-
ration of the C(1) silane was considered (Scheme 5). First, protection
of the C(3) hydroxyl group of glucal 12 as its TIPS ether 15 was
followed by selective metalation at the C(1) position and haloge-
nationwith diiodoethane to provide iodo-glucal 21 in 93% yield. The
TIPS ether was cleaved with TBAF to afford a 96% yield of 22. The
C(3)-hydroxyl group was then reprotected as a methyl ether with
NaH and MeI, followed byiodine–lithium exchange and trapping the
pyranyllithium reagent with chlorodimethylsilane to provide the
desired C(1) silane 24 in 65% yield over the two steps. Silane 24 was
subjected to oxidative hydrolysis catalyzed by bis[chloro(p-cyme-
ne)ruthenium(II)] in the presence of 2.0 equiv of water to afford the
desired silanol 25 in 81% yield.13
Scheme 3.

4748
S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
2.1.2. Protecting group strategy. With successful cross-coupling
reaction conditions in hand, the focus shifted to designing the
global protection/deprotection strategy for the C-spirocyclic aryl-
glycopyranoside hydroxyl groups. The protecting group strategy
needs to meet the following criteria (Fig. 2): (1) the conditions for
the final global deprotection must be mild because of the acid-,
base-, and photo-sensitivity of the pendant unsaturated side-chain
in i, as well as its obvious incompatibility toward hydrogenolysis
and oxidation, (2) the protecting group for the C(3) hydroxyl group
of v (P7) has to be complimentary with P2, P3, P4, P5, and P6 to allow
for selective acylation at the C(3) position of the arylglycopyrano-
side, (3) the C(3) protecting group (P7) needs to be bulky to direct
the metalation to the C(1) position of glucal viii (as was the case for
OTIPS ether in 15) but not so sterically demanding as to prevent
introduction of P2 and, (4) the protecting group for the benzylic
alcohol of the aromatic iodide vii has to be cleaved in the presence
of P4, P5, P6, P7 prior to oxidative spiroketalization. Taken together,
it was decided that fluoride deprotection conditions should be
sufficiently mild and selective to allow a late stage global depro-
tection. This decision mandated that the protecting groups for the
C-spirocyclic arylglycopyranoside must be fluoride cleavable (i.e.,
silyl-derived groups) and be carried through the synthesis.
Scheme 5. Conditions: (a) TIPSCl, imidazole, DMF, 90 ꢁC, 10 h, 89%; (b) t-BuLi, THF,
ꢀ78 ꢁC to 0 ꢁC; then ICH2CH2I, ꢀ78 ꢁC to rt, >93%; (c) TBAF, THF, rt, 30 min, 96%; (d)
MeI, NaH, THF, 92%; (e) n-BuLi, THF, ꢀ78 ꢁC; then Me2SiHCl, ꢀ78 ꢁC to rt, 71%; (f)
[RuCl2(p-cymene)]2 (2 mol %) CH3CN/H2O, rt, 1 h, 81%.
(+)-papulacandin D
The critical palladium-catalyzed cross-coupling of 9 with 25
could now be tested in the presence of Brønsted base activators
(Table 1). Unfortunately, the combination of 9 and 25 under
standard Brønsted base activation conditions7d failed to give the
desired product (Table 1, entries 1–3). In these cases, protiode-
silylation was the major pathway. Tetrahydropyran (THP) pro-
tected aromatic iodide 26 was then synthesized14 and subjected
to the cross-coupling reaction under NaOt-Bu activation. Grati-
fyingly, cross-coupling of 25 and 26, promoted by 2.0 equiv of
NaOt-Bu in toluene at ambient temperature for 12 h afforded
a 69% yield of the desired product 27b along with trace amounts
of 19 (Table 1, entry 4).
Me
P4O
P5O
P6O
Me
Me
OP3
O
O
P2O
O
i
OP1
O
Me
P4O
O
Me
P5O
P6O
HO
Me
+
OP3
O
OH
P2O
OP1
ii
iii
O
P4O
O
P4O
P5O
P5O
P6O
P7O
O
O
P6O
OP3
OP3
OP3
Table 1
P7O
HO
P2O
v
Cross-coupling of 25 with 9 and 26
O
iv
MeO
OMe
conditions
rt
I
+
25
P4O
O
P4O
O
OP3
OR
9 (R = H)
P5O
P6O
P5O
P6O
vii
26 (R = THP)
OH
OP8
OP7
OP7
MeO
O
OMe
vi
O
O
O
Me
+
Me
+
19
Me Me
Si
O
P4O
OP3
O
OR
O
Me
P5O
P6O
viii
Me
OH
OMe
2
OMe
+
I
27a: R = H
27b: R = THP
28
OP7
OP8
ix
Entry
R
Conditionsa
Yield,b
%
Figure 2. Outline for the protecting group strategy.
27
28
19
Aryl–I
1
2
3
H
H
H
[allylPdCl]2, TBAOH, MeOH, 5 h
APC, KOSiMe3, THF, 5 h
Pd2(dba)3$CHCl3, NaOt-Bu,
toluene, 4 h
Pd2(dba)3$CHCl3, NaOt-Bu,
toluene, 12 h
d
d
d
d
d
40
38
12
d
62
44
17
2.1.3. Optimization of protecting groups for the glucal silanol. The
protecting group optimization strategy focused initially on the C(3)
hydroxyl group. The C(3)-O-methyl group was replaced with
a bulky silyl protecting group such as TIPS or triethylsilyl (TES). The
silanols for the following study were prepared from glucal 12 as
shown in Scheme 6. Unlike the methyl ether derivative 19, direct
metalation of the protected glucal occurred selectively at the C(1)
4
THP
69
20
Trace
27
a
Pd catalyst (5 mol %) and activator (2 equiv) were used in all cases.
Yield of isolated material.
b

S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
4749
position thus allowing installation of the silane in excellent yield
for either TIPS or TES ether derivative (Scheme 6). Oxidative hy-
drolysis proceeded smoothly to afford the corresponding silanol 11
or 32 in good yield.
36 in good yield (91%, two steps). Glucal 36 was metalated at the C(1)
position with t-BuLi and the 1-lithiopyran was trapped with chlor-
odimethylsilane to provide silane 37 in 89% yield.17
Scheme 7. Conditions: (a) K2CO3 (0.01 equiv), MeOH, rt, 1 h; (b) t-Bu2Si(OTf)2,
2,6-lutidine, DMF, 0 ꢁC to rt, 2 h, 89%; (c) TES-Cl, pyridine, CH2Cl2, rt, 4 h, 92%; (d) t-
BuLi, Me2SiHCl, THF, ꢀ78 ꢁC to rt, 1 h, 89%.
Scheme 6. Conditions: (a) TES-Cl, pyridine, CH2Cl2, rt, 10 h, 84% or TIPSCl, imidazole,
DMF, 90 ꢁC, 10 h, 89%; (b) t-BuLi, THF, ꢀ78 ꢁC to 0 ꢁC, 30 min then Me2SiHCl, ꢀ78 ꢁC to
rt, 1 h, 84–95% for 30 and 99% for 31; (c) [RuCl2(p-cymene)]2, CH3CN/H2O, 1 h, 70% for
32, and 2 h, 61% for 11.
Silane 37 was subjected to oxidative hydrolysis catalyzed by bis[-
chloro(p-cymene)-ruthenium(II)]13 in the presence of 2.0 equiv of
water to afford silanol 38 in 73% yield on small scale (Table 3, entry 1).
However, silane 37 was insoluble in CH3CN and therefore not ame-
nable to larger scale hydrolyses (Table 3, entries 2 and 3). Hence,
finding scalable oxidative hydrolysis conditions of 37 was important
for the efficient synthesis of the spirocyclic C-arylglycopyranoside.
The steric bulk of the C(3) protecting groups in 11 and 32 had
a significant impact on the yields of the cross-coupling reactions at
ambient temperature (Table 2, entries 2 and 3). However, if the
reactions were carried out at slightly elevated temperatures, 50 ꢁC
for 4 h, the effect of the protecting groups was negligible (Table 2,
Table 3
Table 2
Survey of oxidative hydrolysis conditions for hydrosilane 37
Optimization of C(3) protecting group
Me Me
Me Me
O Si
MeO
SiMe2OH
OMe
O
[RuCl2(p-
O
Si
O
O
Si
t-Bu
O
Si
t-Bu
H
OH
cymene)]2
Me
+
t-Bu
t-Bu
O
I
O
O
H2O ( 2 equiv)
Me
OR
OTES
O
OTES
OTHP
25 (R = Me)
32 (R = TES)
11 (R = TIPS)
37
38
26
Me Me
Me2
Si
O
Si
O
MeO
OMe
O
Si
H
O
Si
Pd2dba3·CHCl3
(5 mol %)
NaOt-Bu (2 equiv)
+
t-Bu
36
t-Bu
+
O
O
O
O
t-Bu
t-Bu
Me
OH
OTES
2
O
OTHP
39
40
PhMe
Me
OR
Entrya
Catalyst,
mol %
Solvent
Time, h
Yield,g
%
27b (R = Me)
33 (R = TES)
34 (R = TIPS)
37
38
39
40
36
1b
2c
3d
4e,f
5
6
7
8
4
4
8
3
8
3
3
4
3
3
CH3CN
CH3CN
CH3CN
CH3CN
n-BuCN
n-BuCN
THF
PhCN
C6H6/CH3CN (1:1)
C6H6/CH3CN (1:1)
4
1
2
3
2
4
4
4
1
1
d
d
d
19
d
d
d
d
d
d
73
70
47
52
87
84
54
90
86
84
d
d
d
3
2
4
5
4
7
8
d
d
d
23
d
d
d
d
d
d
d
d
d
d
d
d
27
d
d
d
Entrya
R
Temp, ꢁC
Time, h
Yield,b
%
1
2
3
4
5
6
Me
rt
rt
rt
50
50
50
12
12
12
4
4
4
27b (69)
33 (50)
34 (20)
27b (71)
33 (67)
34 (70)c
TES
TIPS
Me
TES
TIPS
9
a
10h
Silanol (1.0 equiv) and aromatic iodide (1.0 equiv) were used in all cases.
Correspond to isolated yields.
Product was impure.
b
c
a
All the reactions were carried out on 100 mg scale, unless otherwise stated.
110 mg scale.
564 mg scale.
950 mg scale.
[Ir(cod)Cl]2, H2O (2.0 equiv) were used.
TES ether cleavage was observed.
Yield of isolated product.
b
c
d
e
f
entries 4 and 5). Therefore, it was decided that the C(3) hydroxyl
group would be protected as the TES ether, which should provide
for a more selective deprotection prior to acylation. In addition, the
C(4) and C(6) hydroxyl groups were converted to the di-tert-
butylsilylene acetal15 because the acidic deprotection conditions
needed for the acetonide group would not be compatible with the
side-chain in a late stage global deprotection (Scheme 7).
The preparation of silane 37 began by saponification of triacetate
35,16 to form the free hexenopyranose, which was immediately pro-
tected as its di(tert-butyl)silylene acetal. Protection of the C(3)
hydroxyl group with TES-Cl provided fully protected hexenopyranose
g
h
The reaction was run on 1.6 mmol scale and the yield of 38 is of analytically pure
material.
To this end, several conditions and catalysts were surveyed
(Table 3). Hydrolysis of 37 with 3.0 mol % of [IrCl(C8H12)]218 gave 38
in moderate yield but cleavage of the TES ether was a major side
process (Table 3, entry 4).19 In a less polar solvent, n-BuCN, the
reaction proceeded cleanly to the desired silanol in 87% and 84%

4750
S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
yield (Table 3, entries 5 and 6). However, in THF, a significant
amount of protiodesilylated product was observed (Table 3, entry
7).19 Switching the solvent to benzonitrile gave an excellent yield of
38. Unfortunately, the higher boiling point of PhCN made purifi-
cation tedious. Finally, after extensive optimization of mixed sol-
vent systems it was found that a 1:1 mixture of CH3CN/benzene
afforded 38 in 86% yield (Table 3, entry 9). To our delight, these
conditions were amenable to larger scale preparations (>2 g) of 38
in excellent yield (Table 3, entry 10).
the THP ether would lead to spiroketalization and TES ether
cleavage (Scheme 9, Eq. 2).20 Clearly, the pivaloyl protecting group
is the most suitable for the synthesis.
2.1.4. Optimization of protecting groups for the aromatic iodide. In
the next stage of the synthesis, suitable protecting groups for the
resorcinol moiety were surveyed. The cross-coupling reaction of
glucal silanol 38 and iodide 26 proceeded very smoothly to afford
the arylglucal 42 in 77% yield (Scheme 8). Employing benzyl pro-
tecting groups gave the desired product 43 in a 72% yield; however,
the benzyl ethers would obviously need to be replaced prior to
global silyl deprotection. When the phenolic protecting groups
were changed from methyl ethers to tert-butyldimethylsilyl (TBS)
or triisopropylsilyl (TIPS) ethers, the cross-coupling reaction did not
provide any of the desired product.
Scheme 9.
2.1.5. Implementation of the key cross-coupling sequence. The next
objective in the synthesis was to secure large quantities of the
1-arylhexenopyranose 52, which required the cross-coupling re-
action to be scaleable (i.e., >1.0 mmol scale). Gratifyingly, the key
cross-coupling reaction using stoichiometric amounts of aryl iodide
47 and silanol 38 in the presence of 5 mol % of Pd2(dba)3$CHCl3 and
2.0 equiv of NaOt-Bu at 50 ꢁC for 5 h proceeded smoothly and re-
producibly to afford 51 in 82% yield (Scheme 10).21 In addition, the
pivaloyl ester was selectively cleaved by DIBAL-H reduction to give
desired benzylic alcohol 52 in 98% yield (Scheme 10).
Scheme 8.
BnO
O
OBn
Me Me
Si
Finally, various options for the benzylic alcohol protecting group
were surveyed (Table 4).14 Interestingly, protection of the benzylic
alcohol had a significant impact on the yield of the cross-coupling
reaction. The aromatic iodides bearing a 1-ethoxyethyl (EE),
O
47
O
Si
t-Bu
OH
O
Si
t-Bu
.
t-Bu
a. Pd2(dba)3 CHCl3 t-Bu
O
O
RO
NaOt-Bu
OTES
OTES
51: R = Piv
52: R = H
38
b. DIBAL-H
Table 4
Survey of protecting groups for the benzylic alcohol of the aromatic iodide
Scheme 10. Conditions: (a) Pd2(dba)3$CHCl3, NaOt-Bu (2.0 equiv), toluene, 50 ꢁC, 5 h,
82%; (b) DIBAL-H, CH2Cl2, ꢀ78 ꢁC to rt, 1 h, 98%.
BnO
O
OBn
BnO
OBn
Pd2dba3·CHCl3
NaOt-Bu
38
+
O
Si
t-Bu
I
2.1.6. Oxidative spiroketalization and C(2)-hydroxyl group pro-
tection. To assemble the carbon framework of the C-spirocyclic
arylglycopyranoside of papulacandin D, the next challenge was to
effect both stereocontrolled installation of the C(2)-hydroxyl moi-
ety and oxidative spiroketalization. The conditions for oxidative
spiroketalization must be basic to prevent the undesired Brønsted
acid catalyzed spiroketalization (Scheme 10, Eq. 2). Selective for-
t-Bu
PhMe
O
OR
50 °C, 4 h
OR
OTES
R = THP (41)
R = EE (44)
R = MME (45)
R = TMS (46)
R = Piv (47)
R = THP (43)
R = EE (48)
R = MME (49)
R = TMS (50)
R = Piv (51)
mation of
a-glycosyl anhydrides from 1,2-anhydrosugars using
dimethyldioxirane (DMDO) is well known.22 For the current study,
m-chloroperoxybenzoic acid (m-CPBA) under nonequilibrating
conditions was found to be optimal.5p Hence, treatment of 52 with
m-CPBA at 0 ꢁC in the presence of NaHCO3 in CH2Cl2, smoothly
entry
R
Product (yield, %)a
1
2
3
THP
EE
MME
TMS
TMS
Piv
43 (72)
48 (28)
49 (26)
50 (36)
50 (52)
51 (75)
4b
5c
6
provided the chromatographically separable spiro ketals 54-
54- in a 5:1 ratio (Scheme 11).
a and
b
The configuration of the C(2)-hydroxyl group was confirmed by
inspection of the 1H NMR spectra of each anomer as well as more
a
Yield corresponds to isolated product.
The reaction mixture was heated to 80 ꢁC for 2 h.
The reaction mixture was heated to 110 ꢁC for 1 h.
extensive NMR analyses. The 1H NMR spectrum of 54-
a
in dry,
4.32 ppm and
3.84 ppm corresponding to the HC(2) and HC(3) proton resonances,
respectively. The structure of -anomer was confirmed by analysis
of the coupling constants of the vicinal protons in the glucose ring
in the spiro ketal 54-
b
c
neutralized CDCl3 displayed diagnostic signals at
d
1-methoxy-1-methylethyl (MME) or trimethylsilyl (TMS) ether all
afforded the desired product, albeit in low yields (Table 4, entries
2–5). Use of the pivaloyl protected iodide 47 in the cross-coupling
reaction provided the arylglucal 51 in good yield (Table 4, entry
6). The pivaloyl ester could be cleaved quantitatively with DIBAL-H
(Scheme 9, Eq. 1), whereas the acidic conditions for hydrolysis of
a
a
. The key constants (J2,3¼10.0 Hz, J3,4¼10.0 Hz,
J4,5¼10.2 Hz) were consistent with a chair conformation, where
the large coupling constants suggest that mutual trans-diaxial re-
lationships exits between HC(2)/HC(3) and HC(3)/HC(4). The

S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
4751
distorted chair conformation of the
b
-anomer was also confirmed
additives such as tetrabutylammonium iodide (TBAI) and AgOTf24
were tested but with only moderate success, see Supplementary
data for the conditions surveyed. Resubjecting 57 to SEMCl in
DMF, and in the presence of TBAI, again did not afford any of the
tris-SEM ether 58. Ultimately, 58 could be obtained in good yield
using a combination of 3 equiv of TBAI and 9 equiv of AgOTf in DMF.
The final step in the synthesis of the spirocyclic arylglycopyrano-
side, the selective deprotection of the C(3)-TES ether, was accom-
plished using PPTS in ethanol albeit in low yield (53%) (Scheme 13).
by vicinal coupling constants (J2,3¼8.2 Hz, J3,4¼8.2 Hz, J4,5¼9.4 Hz),
which are consistent with the observations of Dubois and Beau for
a similar system.5r
BnO
O
OBn
O
Si
t-Bu
a. m-CPBA
t-Bu
O
OH
OTES
SEMCl
t-Bu
52
(9 equiv)
t-Bu
SEMO
O
t-Bu
Si
i-Pr2NEt
SEMO
O
OSEM
Si
O
HO
t-Bu
Si
O
Si
(15 equiv)
t-Bu
BnO
O
t-Bu
O
OSEM
PPTS, EtOH
O
t-Bu
O
55
OBn
O
t-Bu
O
TESO
O
CH2Cl2
rt
O
SEMO
O
RO
rt, 2 h,
53%
O
TESO
O
+
TESO
59
HO
57 (R = H)
HO
58 (R = SEM)
O
BnO
Scheme 13.
54-α
54-β
OBn
b. 0.1% HCl
2.2. Synthesis of fatty acid side-chain 2 and acylation
Scheme 11. Conditions: (a) m-CPBA, NaHCO3, CH2Cl2, 0 ꢁC, 2 h (dr 5:1, 77%
a, 15% b);
(b) 0.1% HCl in CHCl3, 20 ꢁC, 12 h, 96% recovery.
To set the C(700) stereogenic center of acid 2, one of the most
convergent routes would employ an asymmetric aldol addition re-
action of a doubly vinylogous enolate 60 to aldehyde 4 (Scheme 14).
Numerous attempts were made to set the C(700) stereogenic
center through Lewis-base catalyzed aldol reactions; unfortunately,
a suitable method that provided both high yield and enantiomeric
ratio was not found. For further discussion and examples of the
Lewis-base catalyzed aldol reactions attempted, see Supplementary
data. Given these undesirable results alternative asymmetric car-
bonyl addition reactions were explored.
Finally, the b-anomer could be isomerized to the a-anomer with
a 96% recovery with a solution of chloroform containing with 0.1%
dry HCl. The isomerization experiment also aided in the assignment
and determination of the absolute configuration determination of
the 54-b C(2) hydroxyl group (Scheme 11).
To complete the synthesis of the C-spirocyclic arylglycopyr-
anoside, the following protecting group manipulations were
required: (1) the aromatic benzyl ethers must be switched to
silicon-based protecting groups for the late stage global depro-
tection, (2) the C(2)-hydroxyl group must be replaced with a pro-
tecting group complimentary to the C(3) TES ether, thus allowing
for selective deprotection and acylation of the C(3) hydroxyl group.
Me
Me
Me
Me
Me
Me
Hydrogenolytic debenzylation of 54-a at 1 atm of H2 with Pd/C
+
H
in the presence of NaHCO3 proceeded smoothly to afford triol 55
quantitatively (Scheme 12). Initially, bulky silicon protecting groups
such as tert-butyldiphenylsilyl (TBDPS) or TIPS ethers for the phe-
nolic hydroxyl groups were planned. However, treatment of triol 55
with either TBDPS chloride or TIPS chloride in the presence of
lutidine did not afford any of the desired silyl ethers. Therefore,
silylation with a more reactive silylating agent, TIPSOTf, was
attempted. In this case, only the mono-protected alcohol 56 was
isolated and characterized by 1H NMR analyses.
CO2H
4
OTES
O
2
OSiR3
OR'
60
Scheme 14.
2.2.1. Model study of an asymmetric allylation reaction. An alter-
native strategy for the construction of the C(700) stereogenic center
would employ an asymmetric allylation reaction.25,26 The allyl
group was of interest because it provides a handle for further
elaboration of the side-chain of papulacandin D through a sequen-
tial cross-metathesis and two-carbon homologation. To vouchsafe
this plan, the cross-metathesis reaction of model homoallylic al-
cohol 62 was tested, before starting the investigation into asym-
metric allylation reaction.
t-Bu
t-Bu
BnO
O
HO
Si
Si
OBn
a. Pd/C
OH
t-Bu
O
t-Bu
O
O
O
O
TESO
TESO
HO
HO
O
O
H2
55
54-α
The cross-metathesis of racemic homoallylic alcohol 62 (pre-
pared by the addition of allylmagnesium bromide into aldehyde 61)
was tested with both methyl acrylate and acrolein using 5 mol % of
Grubbs’ second-generation catalyst (Scheme 15).27 The reactions
afforded the desired a,b-unsaturated ester 63 and aldehyde 64 in
87% and 81% yield, respectively (Scheme 15, Eqs. 2 and 3).
t-Bu
HO
TBDPS-Cl
b. TIPS-OTf
Si
OTIPS
t-Bu
O
or
O
O
TIPS-Cl
TESO
HO
O
NR
56
Next, avariety of asymmetric allylation reactions were evaluated.
The use of allyltributyltin in the presence of 0.2 equiv BINOL/Ti(Oi-
Pr)4 and 4 Å molecular sieves as described by Keck et al.28 provided
excellent enantioselectivity (99.4:0.6), albeit in only 30% yield (Table
5, entry 1). The chiral borane reagent, allyl(Ipc)2B, developed by
Brown et al.,29a afforded an improved yield (Table 5, entry 2), and the
enantiomeric ratio reflected the purity of the reagent. The enantio-
meric purity of the borane reagent can be enriched by synthesizing
methoxy(Ipc)2B rather than using chloro(Ipc)2B.29 Therefore,
Scheme 12. Conditions: (a) Pd/C, H2, NaHCO3, THF, rt, 5 h, >99%; (b) TIPSOTf, 2,6-
lutidine, CH2Cl2, 1 h, 69%.
A less sterically demanding protecting group such as 2-(trime-
thylsilyl)-ethoxymethyl (SEM) ether was considered for the pro-
tection of the all three hydroxyl groups of triol 55 (Scheme 13).23
Unfortunately only two SEM groups were introduced to afford 57
as the major product, presumably due to a slow alkylation of the
C(2)-hydroxyl group. To access the C(2) protected hydroxyl group,

4752
S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
Me
CHO
and enantiomeric purity (99%, 97:3 er) (Scheme 16). Tosylation of
Me
a. allylMgBr
C8H17
C8H17
rac-62
the alcohol followed by deoxygenation with LiHBEt3 afforded hy-
drocarbon 67 in 88% yield for the two steps. Alkene 67 was then
subjected to ozonolysis and vinylogous Horner–Wadsworth–
OH
61
(eq. 1)
Me
b. G2 (5 mol %)
CO Me
Emmons olefination to afford unsaturated ester 68 as an in-
C8H17
00 00
rac-62
separable mixture of isomers (D8 ,9 E/Z, 91:9). Subsequently,
CO2Me
(eq. 2)
OH
Me
rac-63
DIBAL-H reduction of the ester followed by chromatographic sep-
aration of the geometrical isomers of the allylic alcohol and oxi-
dation afforded aldehyde 4 in 84% yield (four steps). Now, the
enantioselective allylation of the substrate could be tested. Grati-
fyingly, allylation of 4 using chiral bisphosphoramide (R,R)-65
smoothly provided 70 in good yield and excellent diastereomeric
selectivity (88%, dr 96:4). The expected C(700) S-configuration30 was
confirmed by analysis of the corresponding Mosher esters.33 Olefin
metathesis with acrolein using Grubbs’ second-generation catalyst,
and protection of the C(700) hydroxyl group with TES-Cl gave 72 in
91% yield for the two steps. The synthesis of 2 was completed by
Wittig olefination and saponification with potassium trimethylsi-
lanoate24 in excellent 90% yield (two steps).
c. G2 (5 mol %)
CHO
C8H17
rac-62
CHO
OH
rac-64
(eq.3)
Scheme 15. Conditions: (a) allylMgBr, Et2O, 0 ꢁC, 90%; (b) Grubbs’ second-generation
catalyst (5.0 mol %), methyl acrylate (13 equiv), rt, 1 h, 87%; (c) Grubbs’ second-gen-
eration catalyst (5.0 mol %), acrolein (13 equiv), rt, 1 h, 81%.
Table 5
Survey of asymmetric allylation reactions
Me
Me
conditions
C8H17
C8H17
M
CHO
OH
61
(S)-62
N
O
H
H
P
N
Me
(CH2)5
N
2
(R,R)-65
Yield,a
30
%
erb
M
Entry
1
Conditions
SnBu3
(S)-BINOL (24 mol %), Ti(Oi-Pr)4
(20 mol %), ꢀ78 to ꢀ20 ꢁ
99:1
C
(1.3 equiv)
MgBr
(1.0 equiv)
MgBr
2
3
4
(þ)-Ipc2B-Cl (1 equiv), ꢀ78 ꢁ
C
70
73
71
90:10
96:4
96:4
(þ)-Ipc2B-OMe (1 equiv), ꢀ78 ꢁ
C
(1.5 equiv)
MgBr
(þ)-Ipc2B-OMe (1 equiv), ꢀ100 ꢁ
C
(1.5 equiv)
SiCl3
(R,R)-65 (10 mol %),
i-Pr2NEt/CH2Cl2, ꢀ78 ꢁ
5
76
95:5
C
(2.0 equiv)
a
Yield corresponds to isolated product.
The enantiomeric ratio was determined by CSP-SFC.
b
(ꢀ)-methoxy(Ipc)2B was prepared from (þ)-
a-pinene. The allylation
using (ꢀ)-methoxy(Ipc)2B at ꢀ78 ꢁC afforded homoallylic alcohol
(S)-62 in 73% yield with a 96:4 enantiomeric ratio (Table 5, entry 3).
Lower temperature (ꢀ100 ꢁC) did not improve the enantiose-
lectivity (Table 5, entry 4). Although successful, the Brown-type
allylation was not ideal because it required the synthesis and stoi-
chiometric amounts of a chiral reagent.
Fortunately, an enantioselective allylation method developed in
these laboratories, namely the chiral bisphosphoramide-catalyzed
allylation reaction of allyltrichlorosilanes and aldehydes, was
successful.30 Thus, the addition of allyltrichlorosilane (2.0 equiv) to
61 using 0.05 equiv of chiral bisphosphoramide (R,R)-65 at ꢀ78 ꢁC
for 8 h afforded the desired homoallylic alcohol (S)-62 in 76% yield
with an enantiomeric ratio of 95:5 (Table 5, entry 5). Because the
Lewis-base catalyzed reaction provided excellent enantioselectivity
and yield in the model system it was applied in the synthesis of the
side-chain of papulacandin D.
Scheme 16. Conditions: (a) Ru(OAc)2[(S)-BINAP] (0.7 mol %), H2 (1500 psi), 95% MeOH,
rt, 20 h, 99% (97:3 er); (b) Ts-Cl, pyridine, rt, 10 h, 89%; (c) LiHBEt3, THF, NaOH/H2O2, rt,
1 h, 86%; (d) O3, NaHCO3, CH2Cl2/MeOH, ꢀ78 ꢁ
C to rt, DMS, 2.5 h; (e) (EtO)2
-
POCH2C]C(CH3)CO2Et, LiOH, MS 4 Å, THF, reflux, 2 h, 78% (two steps) (E,E/E,Z 91:9); (f)
DIBAL-H, THF, 0 ꢁC, 0.5 h, 85% (pure E,E); (g) MnO2, CHCl3, reflux, 4 h, 89%; (h) (R,R)-65
(10 mol %), allyltrichlorosilane, CH2Cl2, i-Pr2EtN, ꢀ78 ꢁC, 8 h, 88% (96:4 dr); (i) Grubbs’
second-generation catalyst (5.0 mol %), acrolein (13 equiv), CH2Cl2, 90%; (j) TES-Cl, 2,6-
lutidine, CH2Cl2, rt, 4 h, 92%, Ph3P]CCO2Me, ClCH2CH2Cl, reflux, 18 h, 90% (E/Z 90:10);
(k) TMSOK, THF, rt, 4 h, 94%.
2.3. Model acylation with tris-SEM spirocyclic arylglycoside
and sorbic acid
2.2.2. Preparation of side-chain acid 2. Synthesis of the unsaturated
acid 2 began by asymmetric hydrogenation of geraniol31 with
Ru(OAc)2[(S)-BINAP]32 to provide (S)-citronellol in excellent yield
The next challenge in the synthesis was the union of fragments
59 and 2, through an acylation reaction. Because of the sensitivity of

S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
4753
the side-chain acid 2, the Yamaguchi mixed anhydride protocol was
2.4. Global deprotection and completion of the synthesis
of papulacandin
first tested.34 Barrett et al.5s reported the use of such a mixed
anhydride of 2 in combination with O-4,O-6-di-tert-butylsilylene
acetal and TIPS protecting groups on the spirocyclic arylglycopyr-
anoside to improve the site selectivity of the acylation. In the
present study the C(2) hydroxyl group is protected and therefore,
the acylation should be selective for the C(3) hydroxyl group.
However, the secondary hydroxyl group is in significantly more
hindered environment compared to Barrett’s substrate. Hence, the
acylation was tested with sorbic acid before committing precious
acid 2.
2.4.1. Model study of SEM-deprotection. The last step in the syn-
thesis is the global deprotection of all the silicon-protecting groups
in 74. Standard fluoride sources such as TASF, TBAF, HF$Et3N, etc.
were expected to cleave the protecting groups in one step, thus
revealing the natural product. To find optimal conditions for the
cleavage of the SEM protecting groups, it was decided to work with
a simple model compound, 5-(methoxymethyl)resorcinol, pre-
pared from methyl 3,5-dihydroxybenzoate.
Sorbic acid was activated via a mixed anhydride using 2,4,6-
trichlorobenzoyl chloride in the presence of DMAP and DMF and
then a solution of 59 and DMAP in DMF was added to the mixed
anhydride at ambient temperature. The acylated product 73 was
isolated in 31% yield, where the remaining mass corresponded to
unreacted 59 (Scheme 17). Although the yield of the reaction was
poor, it demonstrated that acylation can proceed at the C(3) posi-
tion. Applying the above conditions to the crucial coupling of
fragments 2 and 59; however, in THF, for 4 h afforded the desired
ester 74 in good yield (88%) (Scheme 18).
A variety of conditions were surveyed that are known for sili-
con- and SEM ether-deprotection,35 see Supplementary data (Table
S4) for a full survey of deprotection conditions. Only a combination
of MgBr2 and n-BuSH provided the fully deprotected resorcinol
derivative. These SEM-deprotection conditions were then applied
to a more appropriate model compound, acyl spirocyclic arylgly-
copyranoside 73. Because of the stability of SEM ethers to fluoride
treatment (vide infra), a two-step deprotection sequence was
employed. First, to cleave the silyl-ether protecting groups, 73 was
treated with 10 equiv of a 1 M solution of TBAF in THF at room
temperature for 1.5 h (Scheme 19). Unfortunately, the product
(isolated in low yield) was a mixture of C(3) and C(4) acylated
isomers 75 and 76, respectively.
Scheme 17.
Scheme 19. Conditions: (a) TBAF (10 equiv), THF, rt, 1.5 h, <40%; (b) MgBr2 (25 equiv),
n-BuSH (23 equiv), Et2O, rt, 1 h, trace product; (c) MgBr2 (60 equiv), n-BuSH (60 equiv),
MeNO2, Et2O, 0 ꢁC to rt, 3 h, >99%.
Nevertheless, sufficient material was secured to investigate the
SEM ether cleavage. Therefore, the mixture of 75 and 76 was sub-
jected to the action of 25 equiv of MgBr2 and 23 equiv n-BuSH in
Et2O at room temperature for 1 h. The reaction became biphasic
and only traces of the desired SEM-deprotected products 77 were
isolated. Next, the inverse of the above sequence was employed, 73
was first treated with 60 equiv MgBr2 and 60 equiv n-BuSH in the
presence of MeNO2 as a co-solvent to provide the desired product
78 quantitatively. Treatment of 78 with an HF$Et3N solution should
cleave the silyl-ether protecting groups to afford the fully depro-
tected product.
Scheme 18.

4754
S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
These results encouraged attempts at the global deprotection of
that could be easily cleaved with HF$NEt3 or HF$pyridine, because
of the observed stability of the side-chain to these conditions. The
survey began with trialkylsiloxymethyl ethers (TBSCH2OR and
74 (Scheme 20). The SEM-protected papulacandin D precursor 74
was treated with 60 equiv MgBr2 and 60 equiv n-BuSH in Et2O/
MeNO2 (100:1 mixture) from 0 ꢁC to room temperature. After 3 h
consumption of 74 was observed by TLC analysis; however, upon
isolation, a mixture of butanethiol-incorporated products were
observed tentatively assigned as 79.
TIPSCH2OR) using methyl 3,5-dihydroxybenzoate as
a model
compound.36 However, it was observed that the protection afforded
a mixture of trialkylsilyl and trialksilyloxymethyl ethers. Because
the introduction of a trialkylsiloxymethyl protecting group was
unsuccessful, 2-(trimethylethylsilylethoxycarbonyl) (TEOC) was
investigated.37 It was anticipated that the TEOC protecting group
could be easily cleaved under HF$Et3N conditions, and was small
enough to protect the sterically encumbered C(2) hydroxyl group.
The 5-(methoxymethyl)resorcinol was then protected as the bis
TEOC carbonate quantitatively using 3 equiv TEOC–Cl, in the pres-
ence of 6 equiv i-Pr2NEt. To our delight, the TEOC groups in-
troduced could be quantitatively removed using a mixture of
HF$NEt3 (40:60) in CH3CN at 40 ꢁC for 9 h.38
The TEOC protection of all three hydroxyl groups in triol 55 was
attempted first. However, only the aromatic hydroxyl groups could
be protected (Scheme 22, Eq. 1). Surprisingly, when the aromatic
hydroxyl groups were protected as TEOC or the benzyl ethers
normal TEOC protection failed at the C(2)-hydroxyl group (Scheme
22, Eq. 2). The acylation of 85 or 86 was slow because of the steric
congestion at the C(2) hydroxyl group.
Scheme 20.
The failure of the deprotection strategy at the last step in the
synthesis was very disappointing. Clearly, the removal of the SEM
protecting group required more forcing conditions than anticipated.
Thus, the search for a new protecting group that could be removed
without damage to the sensitive C(700) hydroxyl group was needed.
Therefore, a number of different protecting groups were examined to
increase the stability of the C(700) hydroxyl group under the SEM-
deprotection conditions (Scheme 21). Regardless of the C(700) hy-
droxyl protecting group, elimination was always the major pathway.
Thus the identification of milder deprotection conditions became
paramount. The stability of the C(700) TES ether 80 was tested using
a solution of 5 equiv TASF in THF. Surprising, TASF induced the elim-
ination of the silyl ether, even though Barrett and co-workers used
similar conditions for their global silyl deprotection.5s In previous
studies, the TES ether was stable in the presence of a buffered
hydrofluoricacidsolutioninCH3CN(HF$NEt3 (46:54)). Unfortunately,
it was observed that neither HF$NEt3 (70:30) or HF$pyridine (60:40)
were strong enough to induce SEM ether cleavage.
Scheme 22.
The C(2) hydroxyl group of 54-a could be acylated, with acetic
anhydride and pyridine albeit very slowly. Even, after 12 h the re-
action did not go to completion and the acetate was isolated along
with some of the starting material. The failure to attach a TEOC
group at C(2) most likely arises from insufficient reactivity of TEOC–
Cl. To circumvent this problem, the TEOC protection group was
affixed in a stepwise manner to allow use of a more reactive acyl-
ating agent, namely triphosgene. The resulting chloroformate could
then be combined with 2-(trimethylsilyl)ethanol to complete the
TEOC protection.
This idea was put into practice by generating
a chloro-
carbonylpyridinium cation with triphosgene and DMAP in a mix-
ture of i-Pr2NEt and CH2Cl2. To this solution was added alcohol 54-
a. However, the reaction did not afford any of the desired product
(Table 6, entries 1 and 2). The experiment was repeated in CDCl3
and was monitored by 1H NMR spectroscopy. In CDCl3, the reaction
mixture became biphasic when i-Pr2NEt was added to the solution
of DMAP and triphosgene (Table 6, entry 3). Therefore, i-Pr2NEt was
added later along with 54-
cation was observed, this solution was transferred to a solution of
54- in CDCl3/i-Pr2NEt. To observe the formation of chloroformate
87 the reaction mixture was diluted with CDCl3 (concn 0.0014 M).
Once complete conversion of 54- to 87 was confirmed, the solu-
tion was treated with 2-(trimethylsilyl)ethanol. At this the low
concentration, the rate of reaction was very slow and required ca.
70 h for complete conversion (Table 6, entry 4). However, at
a. When the chlorocarbonylpyridinium
Scheme 21. Conditions: (a) HF$NEt3 (46:54), CH3CN, rt, 1 h, >99%; (b) TIPSOTf, luti-
dine, CH2Cl2, ꢀ78 to 0 ꢁC, 2 h, >99%; (c) MgBr2, n-BuSH, MeNO2, Et2O, 0 ꢁC to rt, 1–3 h.
a
2.4.2. New protecting group strategy. The failure to cleave the SEM
groups shifted the focus to revising the initial protecting group
strategy that would accommodate the sensitivity of the pendant
side-chain. The study focused on silicon-based protecting groups
a

S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
4755
Table 6
TEOC protection of 54-
2.4.3. Studies on the removal of the TEOC groups. To evaluate if the
sterically congested C(2)-TEOC protecting group could be removed
using HF$NEt3 solution, TEOC protected menthol was used as a test
substrate. A variety of reaction variables were systematically sur-
veyed (time, concentration of fluoride, HF$NEt3 ratio, temperature,
and solvent) and some representative examples are presented in
Table S5 in Supplementary data. These studies concluded that the
rate of TEOC cleavage in DMSO was significantly faster than the
other solvents (Table S5, entries 7 and 8, Supplementary data).
Applying these conditions to the TEOC cleavage of a sorbyl ester of
90 demonstrated that at 40 ꢁC in DMSO the cleavage was not
complete, but at 60 ꢁC after 12 h complete deprotection to 91 was
observed. Finally, to establish that acyl migration did not occur (a
problem observed during the initial SEM-deprotection studies of
73), structure 91 was confirmed (and structures A and B were
eliminated) through a series of NMR experiments (Fig. 3).
a
O
A
O
N
+
Cl
N
Cl3C
CCl3
O
O
NMe2
(3 equiv)
NMe2
(9 equiv)
δ
5.9 ppm
t-Bu
Si
BnO
OBn
C
H
B
t-Bu
O
O
O
85
54-
α
TESO
O
O
O
Cl
87
Entry
Solvent
Result
1a
2b
3c
4d
CH2Cl2
CH2Cl2
CDCl3
CDCl3
54-
54-
a
a
(>99%)
(>99%)
δ 4.47 (t, 10 Hz)
Biphasic mixture
24 h; 87/85¼52:48
48 h; 87/85¼16:84
72 h; 87/85¼0:100
85 (92%)
BnO
OBn
10 Hz
HO
HO
H
O
5e
CDCl3
O
a
A: i-Pr2NEt (1055 equiv), ꢀ78 ꢁC, 20 min; B: ꢀ78 ꢁC, 1 h, (0.002 M); C: TMS/
ethanol (18 equiv), ꢀ78 ꢁC to rt, 4 h (0.0012 M).
HO
H
O
10 Hz
O
b
A: i-Pr2NEt (1055 equiv), ꢀ78 ꢁC, 20 min; B: ꢀ78 ꢁC to rt, 1 h, (0.002 M); C: TMS/
91
ethanol (72 equiv), ꢀ78 ꢁC to rt, 9 h (0.0012 M).
δ 1.94 (d, 10 Hz)
δ 5.23 (t, 10 Hz)
c
A: i-Pr2NEt (28 equiv), ꢀ78 ꢁC to rt, 30 min (DMAP 0.6 M); B: ꢀ78 ꢁC to rt, 1 h,
(0.002 M); C: TMS/ethanol (72 equiv), ꢀ78 ꢁC to rt, 9 h (0.0012 M).
D2O experiment
d
A: ꢀ78 ꢁC to rt, 1 h (DMAP, 1.2 M); B: i-Pr2NEt (28 equiv), ꢀ78 ꢁC to rt, 1 h
δ 4.47 (t, 10 Hz) became (d, 10 Hz)
(0.043 M); C: TMS/ethanol (26 equiv), rt (0.0041 M).
e
A: ꢀ78 ꢁC to rt, 30 min (DMAP 1.2 M); B: i-Pr2NEt (28 equiv), ꢀ78 ꢁC to rt, 1 h,
Decoupling
(0.043 M); C: TMS/ethanol (26 equiv), rt, 12 h (0.043 M).
When δ 4.47 (t, 10 Hz) was irradiated,
δ 5.23 (t, 10 Hz) became (d, 10 Hz) and
δ 1.94 (d, 10 Hz) became (s, 10 Hz).
0.043 M, complete conversion was observed within 12 h to afford
85 in 92% yield (Table 6, entry 5). It is of note that all the attempts
listed in Table 6 were accomplished using a total of 2.4 mg of 54-
BnO
O
OBn
A: R1 = H, R2 =
B: R2 = H, R1 =
HO
R2O
HO
O
O
a
demonstrating the power of 1H NMR for reaction monitoring.
Gratifyingly, only with minor modification to the reagent stoi-
R1O
O
chiometry, treatment of 54-a with a preformed acylpyridinium
Figure 3. Assignment of esterification site in 91.
species followed by the addition of 2-(trimethylsilyl)ethanol gave
the 2-TEOC-protected spiro ketal in 92% yield, on preparative scale
(Scheme 23). Next, debenzylation of 85 with hydrogen and Pd/C
proceeded quantitatively. Subsequent protection of the resorcinol
portion of 88 was achieved under standard TEOC protection con-
ditions to produce the fully silylated spiro ketal 89 in 96% yield
overall. Finally, selective removal of the O-C(3) TES ether with PPTS/
ETOH afforded 90 in 93% yield.
Finally, the side-chain must not degrade under the deprotection
reaction conditions. Before subjecting the very precious, fully pro-
tected papulacandin D to the HF$NEt3 deprotection conditions, the
stability of the side-chain was once again tested. In a Teflon flask
a biphasic solution of DMSO and HF$NEt3 (40:60) was added to
methyl ester 80 (Scheme 21) and the mixture was heated to 60 ꢁC.
Deprotection of the C(700)-silyl ether was rapid under these condi-
tions. However, heating for 15 h was required to remove all the TEOC
groups of the 1-arylglycopyranoside. Therefore, the stability of the
unprotectedside-chain, upon extended heating, needed tobe tested.
Fortunately, it was determined that the side-chain was stable under
prolonged heating and alcohol 81 was isolated in 93% yield.
2.5. Completion of the synthesis of (D)-papulacandin D
With routes for the side-chain 2 and the protected spirocyclic
arylglycopyranoside 81 secured, the penultimate challenge was the
coupling of the two fragments via the mixed anhydride of 2 from
2,4,6-trichlorobenzoyl chloride. The two fragments were united
(1.3 equiv 2, toluene, room temperature, 3 h) in 87% yield, with only
slight modification from the original acylationprotocol (Scheme 24).
Finally, the most daunting step in the synthesis could be
attempted, namely deprotection of all the silicon protecting groups
in protected papulacandin D, 92. Gratifyingly, the extensive opti-
mization of protecting groups and deprotection conditions proved
Scheme 23. Conditions: (a) triphosgene, DMAP, CHCl3, ꢀ56 ꢁC to rt, i-Pr2EtN, 54-
a,
CHCl3, ꢀ56 ꢁC to rt, 2-(trimethylsilyl)ethanol, rt, 12 h, 92%; (b) Pd/C, NaHCO3, H2, THF,
rt, 5 h, >99%; (c) TEOC-Cl, i-Pr2EtN, CH2Cl2, rt, 9 h, 96%; (d) PPTS, EtOH, rt, 4 h, 93%.

4756
S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
heteroarylsilanols.7c,8 It is believed that the co-existence of enol or
heteroarylsilanol and silanolate causes protiodesilylation. There-
fore, a strong, soluble Brønsted base, such as NaOt-Bu, was needed
to bring about rapid formation of the sodium silanolate in situ and
thus suppress protiodesilylation. This idea in combination with
protection of 9 as the corresponding THP acetal, finally provided for
successful cross-coupling.
Protection of the benzylic alcohol may have two benefits: (1)
removal a proton source for potential protiodesilylation and (2) to
suppress coordination of the free benzylic alcohol to the Pd(II) in-
termediate after oxidative addition. It is believed that the rate of
displacement of this alkoxide palladium intermediate by silanolate
may be slow, and thus significantly decrease the rate of cross-
coupling relative to undesirable side processes. Subsequently, it
was found that the protecting group for the benzylic alcohol had
a dramatic impact on the rate and yield of the cross-coupling re-
action (Table 4). This behavior could be rationalized in terms of the
coordinating ability of the protecting group (41, 44, 45, and 47,
Table 4) to a Pd(II) intermediate. The pivaloyl protecting group was
ultimately chosen for the following reasons: (1) the reduced ability
of the carbonyl group to coordinate to the Pd(II) intermediate,
compared to the free alkoxide, MME, and EE protecting groups and
(2) the near quantitative deprotection with DIBAL-H that also did
not induce nonoxidative spirocyclization of the corresponding
arylglucal.
Scheme 24. Conditions: (a) 2,4,6-Cl3C6H2COCl, Et3N, rt, 1 h, 90, toluene, rt, 3 h, 87%;
(b) HF$Et3N (40:60 ratio), DMSO, 60 ꢁC, 15 h, 89%.
3.2. Oxidative spiroketalization of 52
worthwhile. Global deprotection of 92 proceeded smoothly on
>80 mg scale using a buffered HF$Et3N (40:60 ratio) in DMSO at
60 ꢁC for 15 h to afford an 89% yield of synthetic (þ)-papulacandin D.
The physical and spectroscopic data for the synthetic sample
The oxidative spiroketalization of 1-arylglucal 52, most likely
proceeded via: (1)
a-selective epoxidation of the enolic double
bond, generating a glycosyl anhydride 85 or Brigl’s intermediate,39
(2) opening of the internal epoxide to generate an oxocarbenium
ion 86, and (3) trapping of the oxocarbenium ion with the pendant
hydroxyl group of the C(1) aromatic moiety to provide the desired
C-spirocyclic arylglycopyranoside (Scheme 25). Crucial to the suc-
cess of this transformation is the selective epoxidation of the glucal,
were nearly identical in all respects [mp 126–128 ꢁC (lit. 127–
24
130 ꢁC), 1H NMR, 13C NMR, IR, UV–vis, [
a]
þ8.78 (c 0.21, MeOH)];
D
lit. 7ꢂ1 (MeOH) to those reported for natural (þ)-papulacandin D
and that of Barrett’s synthetic material.
3. Discussion
by m-CPBA from the
configuration of the C(2)-hydroxyl group of the spirocyclic aryl-
glycopyranoside 54- . The epoxidation of 52 relies upon substrate-
a-face of the enol ether. This process sets the
The synthesis of (þ)-papulacandin D was undertaken to extend
the applicability of fluoride-free, silicon-based, cross-coupling for
a challenging synthetic target. This key step proceeded after minor
optimization, in gratifyingly high yield. Once it was established that
a glucal dimethylsilanol could be activated using a simple Brønsted
base (NaOt-Bu), the optimized conditions for this key step could be
directly applied to the cross-coupling reaction of a variety of pro-
tected glucal and aromatic iodides with excellent results. Therefore,
discussion of the key strategic maneuver shall receive only minor
comment; instead the influence of the protecting groups on the
cross-coupling reaction will be discussed more thoroughly.
a
controlled diastereoselectivity in the initial oxidation event. The
use of sterically demanding protecting groups on the C(3)-, C(4)-,
and C(6)-hydroxyl groups, shielded the
tion to proceed exclusively from the -face. The diastereoselectivity
of the oxidation was supported by determination of the absolute
b-face, allowing epoxida-
a
configuration of the C(2)-hydroxyl group in both a- and b-anomers.
3.1. Synthesis of fragment 52
To overcome the obvious limitations associated with fluoride
activation of a glucal 2-dimethylsilanol, we sought to develop
a cross-coupling reaction of a glucal 2-dimethylsilanol with a ste-
rically hindered and electron-rich and sterically hindered aromatic
iodide. The major questions that needed to be addressed were: (1)
how is a silicon donor, such as a silanol, activated for productive
cross-coupling reaction and (2) would these conditions be com-
patible with the protecting groups on the silanol and aromatic
iodide.
Scheme 25.
The 5:1 mixture of
a
- and
b
-anomers represented the kinetic
In the initial studies on the cross-coupling of 25 with 9, both
TBAOH and KOSiMe3 were unsuitable activators as they afforded
the protiodesilylated glycal 19 exclusively. This outcome is not
surprising, because these types of activators have been problematic
in the cross-coupling reaction of substituted enol silanols and
ratio, as no isomerization was observed when the b-anomer was
exposed to m-CPBA and NaHCO3 in CH2Cl2.40 However, the use of
CHCl3 containing 0.1% of dry HCl provided a source of activation for
either anomeric hydroxyl groups; therefore, inducing complete
isomerization to the desired a-anomer.

S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
4757
Me
14''
3.3. Allylation of aldehyde 4
Me
Me
Me
Me
18''
7''
Me18''
14''
9''
Despite the excellent 97:3 selectivity observed in the Brown
allylation, the low chemical yield, tedious reagent preparation, and
use of a stoichiometric amount of the chiral reagent warranted
investigation of another allylation protocol. Our attention focused
on the catalytic, enantioselective, Lewis-based catalyzed allylation
reaction of allyltrichlorosilanes developed in these laboratories.
Initial attempts using 0.05 equiv of (R,R)-65 with aldehyde 61 at
ꢀ78 ꢁC provided good enantioselectivity (93:7 er), unfortunately
only in 11% yield. It was determined that the Lewis-base catalyst
(R,R)-65 was not efficiently turning over. Therefore, it was antici-
pated that switching to a more Lewis-basic co-solvent such as
i-Pr2NEt instead of Et3N would facilitate a more efficient catalyst
turnover.30 With this simple modification the highest yield (76%)
and a respectable enantiomeric selectivity (94:6 er) were observed
for the desired homoallylic alcohol (S)-62. Gratifyingly, when these
conditions were applied to the synthesis of the papulacandin side-
chain, an excellent yield (88%) and diastereomeric selectivity (96:4
dr) were observed.
9''
7''
6''
6''
O
MeO
O
O
O
OMe
95
96
CF3
F3C
Ph
Ph
R
+0.051
δ 2.363
δ 2.414
Δ δH(6'')
6''
6''
O
OMe
S
S
H
H
7''
+0.106
δ 3.686
7''
δ 3.692
O
O
Δ δH(7'')
R
S
O
F3C
F3C
OMe
Me
14''
Me
14''
9''
9''
18''
Me
18''
Me
Me
Me
δ 5.941
δ 1.679 δ 6.047
δ 1.533
+0.146
–0.106
Δ δH(18'')
Δ δH(9'')
On the basis of our stereochemical analysis of the allyltri-
chlorosilane allylation the (R,R)-65 catalyst should produce the S-
configuration at the homoallylic position (Fig. 4).30 To confirm this
stereochemical outcome, the allylated product 70 was subjected to
Mosher ester analysis (Fig. 5). The Mosher ester was prepared by
the reaction of 70 with 1-methoxy-1-triflouoromethyl-phenyl-
acetyl (MTPA) chloride in pyridine/CDCl3 and was analyzed by 1H
NMR of the crude reaction mixture. Both diastereomers of the
S- and R-MTPA esters (S-MTPA-70 (95) and R-MTPA-70 (96), re-
spectively) were analyzed, and their chemical shift differences
were measured (Fig. 5).33 From the Mosher ester analysis it was
determined that the configuration at the homoallylic position was
indeed of the S-configuration, which correlated with the above
model in Figure 4.
R-MTPA-70
S-MTPA-70
Figure 5. Mosher ester analysis of MTPA-70.
balance between the protecting groups chosen. For instance, when
the resorcinol portion of the aromatic iodide contained TIPS or TBS
silyl ethers, the cross-coupling reaction did not proceed. However,
when the hydroxyl groups were protected as the benzyl ethers
productive cross-coupling was achieved. Although the benzyl
protecting groups were optimal for cross-coupling, the reductive
deprotection conditions would not be compatible with the un-
saturated side-chain 2. Therefore, these groups needed to be re-
moved and replaced before the introduction of the side-chain.
ring
(CH2)5
(CH2)5
Me
Me
ring
Me
Me
back
foward
N
N
N
N
N
N
N
N
H
H
H
H
H
H
H
H
P
P
P
P
Cl
Si
Cl
Si
O
O
O
O
N
N
N
N
ring
foward
ring
back
O
O
H3C
CH3
Cl
Cl
H
H
H
H
R
R
H
H
Si-face
attack
favored
Re-face
attack
OH
OH
R
R
H H
CH3
H H
CH3
Figure 4. Hypothetical model for the reaction promoted by (R,R)-65.
3.4. Summary of global protecting group strategy
The first attempt at the synthesis of papulacandin D employed
SEM protection because, at the time, SEM was the only protecting
group that would efficiently protect the aromatic hydroxyl groups
and the sterically hindered C(2) hydroxyl group. Unfortunately,
SEM ethers could not be cleaved in the presence of those fluoride
sources that would also allow the side-chains to emerge intact.
Thus, the related TEOC group was selected as a slightly more labile
alternative.
The sequence for the introduction of the TEOC groups was
crucial for the successful preparation of the tris-TEOC arylglyco-
pyranoside 89. If the phenolic hydroxyl groups were protected first,
then C(2)-hydroxyl group protection was very difficult, because of
One of the most challenging aspects of the total synthesis was
the successful implementation of the protecting group strategy. In
the previous section the criteria for the protecting group strategy
was discussed; however, this proved to be much more challenging
in practice that initially anticipated. Early in the synthesis it was
decided that the hydroxyl groups of papulacandin D would be
protected with silicon-based protecting groups to facilitate a global
silicon deprotection as the last step in the synthesis. This strategy
limited the choice of protecting groups to those that are easily
cleaved in the presence of fluoride and thus required a very delicate

4758
S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
Agents Chemother. 1992, 36, 1648–1657; (b) Traxler, P. U.S. Patent 4,374,129,
1983.
the additional steric encumbrance. Therefore, the following se-
quence was employed: (1) the C(2)-hydroxyl group was protected
first, through an in situ formation of a chlorocarbonate 87 and
trapping with 2-(trimethylsilyl)ethanol, (2) the benzyl groups were
removed under hydrogenolysis conditions, and (3) the phenolic
hydroxyl groups were protected using TEOC-Cl in the presence of i-
Pr2NEt. This three-step sequence proceeded in 88% overall yield
compared to the 38% yield for the three-step sequence for the SEM
protection of 55.
Finally, the successful global deprotection required extensive
optimization for the cleavage of all the TEOC groups. The C(2)-TEOC
was the most difficult to remove of all the silicon protecting groups
in 92. Manipulation of the fluoride concentration, ratio of HF to Et3N,
changing the solvent from CH3CN to DMSO, and raising the tem-
perature from 40 ꢁC to 60 ꢁC were all required to effect complete
desilylation and provide excellent yield (89%) of the natural product.
4. For L-687, 781 see: (a) VanMiddlesworth, F.; Olmstead, M. N.; Schmatz, D.;
Bartizal, K.; Fromling, R.; Bills, G.; Nollstadt, K.; Honeycutt, S.; Zweerink, M.;
Garrity, G.; Wilson, K. J. Antibiot. 1991, 44, 45–51; (b) Kaneto, R.; Chiba, H.;
Agematu, H.; Shibamoto, N.; Yoshioka, T.; Nishida, H.; Okamoto, R. J. Antibiot.
1993, 46, 247–250; For Mer-WF3010 see: (c) Chiba, H.; Kaneto, R.; Agematu, H.;
Shibamoto, N.; Yoshioka, T.; Nishida, H.; Okamoto, R. J. Antibiot. 1993, 46, 356–
358; For BU-4794F see: (d) Aoki, M.; Andoh, T.; Ueki, T.; Masuyoshi, S.; Suga-
wara, K.; Oki, T. J. Antibiot. 1993, 46, 952–960; For Saricandin see: (e) Chen, R.
H.; Tennant, S.; Frost, D.; O’Beirne, M. J.; Karwowski, J. P.; Humphrey, P. E.;
Malmberg, L. H.; Choi, W.; Brandt, K. D.; West, P.; Kadam, S. K.; Clement, J. J.;
McAlpine, J. B. J. Antibiot. 1996, 49, 596–598; For chaetiacandin see: (f) Komori,
T.; Itoh, Y. J. Antibiot. 1985, 38, 544–546; (g) Komori, T.; Yamashita, M.; Tsurumi,
Y.; Kohsaka, M. J. Antibiot. 1985, 38, 455–459; For F-10748 A1, A2, B1,B2, C1, C2,
D1, and D2 see: (h) Ohyama, T.; Iwadate-Kurihara, Y.; Hosoya, T.; Ishikawa, T.;
Miyakoshi, S.; Hamano, K.; Inukai, M. J. Antibiot. 2002, 55, 758–763; (i) Traxler,
P. U.S. Patent 4,251,517, 1981.
5. For arylglycoside synthesis see: (a) Danishefsky, S.; Phillips, G.; Ciufolini, M.
Carbohydr. Res. 1987, 171, 317–327; (b) Balachari, D.; O’Doherty, G. A. Org. Lett.
2000, 2, 863–866; (c) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 4033–
4036; (d) Ahmed, M. M.; O’Doherty, G. A. Tetrahedron Lett. 2005, 46, 4151–4155;
(e) McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem. Soc. 1995, 117,
6605–6606; (f) Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163–7169; (g)
Barrett, A. G. M.; Pen˜a, M.; Willardsen, J. A. J. Chem. Soc., Chem. Commun. 1995,
1145–1146; (h) Barrett, A. G. M.; Pen˜a, M.; Willardsen, J. A. J. Chem. Soc., Chem.
Commun. 1995, 1147–1148; (i) Rosenblum, S. B.; Bihovsky, R. J. Am. Chem. Soc.
1990, 112, 2746–2748; (j) Czernecki, S.; Perlat, M.-C. J. Org. Chem. 1991, 56,
6289–6292; (k) Parker, K. A.; Georges, A. T. Org. Lett. 2000, 2, 497–499; (l)
Friesen, R. W.; Sturnio, C. F. J. Org. Chem. 1990, 55, 2572–2574; (m) Friesen, R.
W.; Sturnio, C. F. J. Org. Chem. 1990, 55, 5808–5810; (n) Friesen, R. W.; Sturnio,
C. F.; Daljeet, A. K.; Kolaczewska, A. J. Org. Chem. 1991, 56 1944–1947; (o) Du-
bois, E.; Beau, J.-M. J. Chem. Soc., Chem. Commun. 1990, 1191–1192; (p) Dubois,
E.; Beau, J.-M. Tetrahedron Lett. 1990, 36, 5165–5168; (q) Dubois, E.; Beau, J.-M.
Carbohydr. Res. 1992, 223, 157–167; For the total synthesis of papulacandin D
see: (r) Barrett, A. G. M.; Pen˜a, M.; Willardsen, J. A. J. Org. Chem. 1996, 61, 1082–
1100; (s) Previous communication see: Denmark, S. E.; Regens, C. S.; Kobayashi,
T. J. Am. Chem. Soc. 2007, 129, 2774–2776; (t) Kobayashi, T.; Regens, C. S.;
Denmark, S. E. J. Synth. Org. Chem. Jpn 2008, 66, 616–628; (u) Hitchcock, S. A.;
Chafig, H.; Sanchez-Martinez, C.; Esteban, A. R. U.S. Patent 6,069,238 May 30, 2000.
6. Hector, R. F. Clin. Microbiol. Rev. 1993, 1–21.
4. Conclusion
The total synthesis of (þ)-papulacandin D has been accom-
plished in a convergent approach (31 steps overall, 9.2%, over
80 mg) from commercially available triacetoxyglucal and geraniol.
The synthetic strategy breaks the molecule into two nearly equal
subunits, the C-spirocyclic arylglycoside 90 and polyunsaturated
fatty acid side-chain 2. The key significant features of the synthetic
strategy are (1) the palladium-catalyzed, organosilanolate-based,
cross-coupling of a protected glucal silanol and (2) a catalytic
enantioselective allylation reaction using chiral bisphosphoramide
(R,R)-65 for the construction of the C(700) stereogenic center. Fur-
ther extension of organosilanolate-based, cross-coupling reactions
for the synthesis of other complex molecules is underway.
7. (a) Denmark, S. E.; Sweis, R. F. In Metal-Catalyzed Cross-Coupling Reactions; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; pp 163–
216; (b) Denmark, S. E.; Yang, S.-M. In Strategies and Tactics in Organic Synthesis;
Harmata, M. A., Ed.; Elsevier: Amsterdam, 2005; Vol. 6, Chapter 4; (c) Denmark,
S. E.; Baird, J. D. Chem.dEur. J. 2006, 12, 4954–4963; (d) Denmark, S. E.; Regens,
C. S. Acc. Chem. Res. 2008, 41, 1486–1499; (e) Denmark, S. E. J. Org. Chem. 2009,
74, 2915–2927.
Acknowledgements
Funding was provided by the National Institutes of Health
(Grant R01 GM63167). C.S.R. thanks Eli Lilly Research Laboratories
and Johnson & Johnson PRI for graduate fellowships. We are also
grateful to Prof. A.G.M. Barrett for providing spectra for synthetic
(þ)-papulacandin D.
8. Denmark, S. E.; Neuville, L. Org. Lett. 2000, 2, 3221–3224.
9. (a) Swindell, C. S.; Fan, W. J. Org. Chem. 1996, 61, 1109–1118; (b) Niclaou, K. C.;
Ramanjulu, J. M.; Natarajan, S.; Brase, S.; Li, H.; Boddy, C. N. C.; Rubsam, F. Chem.
Commun. 1997, 1899–1900; (c) See Supplementary data for the synthesis of 9.
10. Ferrier, R. J.; Furneaux, R. H. Carbohydr. Res. 1976, 52, 63–68.
Supplementary data
11. (a) Fernandez-Mayoralas, A.; Marra, A.; Trumtel, M.; Veyrieres, A.; Siney, P.
Tetrahedron Lett. 1989, 30, 2537–2540; (b) Fernandez-Mayoralas, A.; Marra, A.;
Trumtel, M.; Veyrieres, A.; Siney, P. Carbohydr. Res. 1989, 188, 81–95; (c) Ja¨kel, C.;
Do¨tz, K. H. J. Organomet. Chem. 2001, 624, 172–185. Although the glycal actonide
can be prepared from glucose via triacetyl glycal, but is low yielding; (d) Fraser-
Reid, B.; Walker, D. L.; Tam, S. Y.-K.; Holder, N. L. Can. J. Chem. 1973, 51, 3950–
3954; (e) Franck, R. W.; John, T. V. J. Org. Chem. 1983, 48, 3269–3276.
12. Direct formation of silanol from metalation of glucals and trapping with
hexamethylcyclotrisiloxane the yields and scale were irreproducible. (a) Butler,
C. R.; Denmark, S. E. e-EROS Encycl. Reagents Org. Synth. 2007, doi:10.1002/
047084289X.rn00785
Detailed procedures and full characterization of all synthetic
intermediates and products are provided, along with spectral
comparison of natural and synthetic (þ)-papulacandin D (215
pages). Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2010.03.093. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
13. Lee, M.; Ko, S.; Chang, S. J. Am. Chem. Soc. 2000, 122, 12011–12012.
14. For the preparation of protected aromatic iodides see Supplementary data.
15. (a) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871–4874; (b) Trost, B.
M.; Caldwell, C. D. Tetrahedron Lett. 1981, 22, 4999–5002.
References and notes
16. Roth, W.; Pigman, W. Methods Carbohydr. Chem. 1963, 2, 405–408.
17. It was found through deuterium incorporation experiments 1.0–1.5 equiv t-BuLi
was sufficient to effect the lithiation at C(1), see Supplementary data.
18. Lee, Y.; Seomoon, D.; Kim, S.; Han, H.; Chang, S.; Lee, P. J. Org. Chem. 2004, 69,
1741–1743.
19. Attempts to trap C(1)-lithio 41 with dichlorodimethylsilane, followed by hy-
drolysis of the corresponding chlorosilane, under pH 5.0 buffered aqueous
conditions, gave disiloxane as the sole product.
1. Isolation: (a) Traxler, P.; Gruner, J.; Auden, J. A. J. Antibiot. 1977, 30, 289–296;
Structural characterization: (b) Traxler, P.; Frittz, H.; Richter, W. J. Helv. Chim.
Acta 1977, 60, 578–584; (c) Traxler, P.; Fritz, H.; Fuhrer, H.; Richter, W. J. Antibiot.
1980, 33, 967–978; (d) Traxler, P.; Gruner, J.; Nuesch, J. U.S. Patent 4,278,665,
1981.
2. (a) Pe´rez, P.; Varona, R.; Garcia-Acha, I.; Dura´n, A. FEBS Lett. 1981, 129, 249–252;
´
´
(b) Varona, R.; Perez, P.; Duran, A. FEMS Microbiol. Lett. 1983, 20, 243–247; (c)
Baguley, B. C.; Rommele, G.; Gruner, J.; Wehrli, W. Eur. J. Biochem. 1979, 97, 345–
351; (d) Murgui, A.; Victoria Elorza, M.; Sentandreu, R. Biochem. Biophys. Acta
1985, 841, 215–222; (e) Pe´rez, P.; Garcia-Acha, I.; Dura´n, A. J. Gen. Microbiol.
1983, 129, 245–250; (f) Kopecka, M. Folia Microbiol. 1984, 29, 441–449; (g)
Debono, M.; Gordee, R. S. Annu. Rev. Microbiol. 1994, 48, 471–497; (h) Schmatz,
D. M.; Romancheck, M. A.; Pittarelli, L. A.; Schwartz, R. E.; Fromtling, R. A.;
Nollstadt, K. H.; Vanmiddlesworth, F. L.; Wilson, K. E.; Turner, M. J. Proc. Natl.
Acad. Sci. U.S.A. 1990, 87, 5950–5954; (i) Traxler, P.; Tosch, W.; Zak, O. J. Antibiot.
1987, 40, 1146–1164; (j) Schmatz, D. M. U.S. Patent 5,089,478, 1992.
20. This type of nonoxidative spiroketalization was observed with 57 in the
presence of acidic media.
21. The 82% yield was consistently reproducible on both 1.0–5.0 mmol scales.
22. (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661–6666; (b)
Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380–
1419; (c) For a recent review on DMDO see: Adam, W.; Saha-Mo¨ller, C. R.; Zhao,
C.-G. Org. React. 2002, 61, 219–516.
23. TMS/ethanol: (a) Mancini, M. L.; Honek, J. F. Tetrahedron Lett. 1982, 23, 3249–
3250; SEM-Cl: (b) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343–
3346; (c) Lipshutz, B. H.; Moretti, R.; Crow, R. Tetrahedron Lett. 1989, 30, 15–18.
3. (a) Bartizal, K.; Abruzzo, G.; Trainor, C.; Krupa, D.; Nollstadt, K.; Schmartz, D.;
Schwartz, R.; Hammond, M.; Balkovec, J.; Vanmiddlesworth, F. Antimicrob.

S.E. Denmark et al. / Tetrahedron 66 (2010) 4745–4759
4759
24. Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831–5834.
25. Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley-VCH: Weinheim, 2000, Chapter 10.
34. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuski, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
35. Removal of SEM from alcohols: CsF, HMPA: (a) Ireland, R. E.; Norbeck, D. W.
J. Am. Chem. Soc. 1985, 107, 3279–3285; TFA: (b) Schlessinger, R. H.; Poss, M. A.;
Richardson, S. J. Am. Chem. Soc. 1986, 108, 3112–3114; Ammonium flouride
sources in HMPA or THF: (c) Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama,
H. Tetrahedron Lett. 1988, 29, 5417–5418; TBAF, MS4 Å, DMPU: (d) Lipshutz, B.
H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 7149–7152; MgBr2, n-BuSH, Et2O: (e)
Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett 1991, 183–184; MgBr2, MeNO2,
Et2O: (f) Vakalopoulos, A.; Hoffmann, H. M. R. Org. Lett. 2000, 2, 1447–1450;
ZnBr2, MeOH, Et2O or MgBr2, MeNO2, Et2O: (g) Vakalopoulos, A.; Hoffmann, H.
M. R. Org. Lett. 2001, 3, 2185–2188; ZnX2 in CH2Cl2: (h) Kolb, H. C.; Hoffmann,
H. M. R. Tetrahedron: Asymmetry 1990, 1, 237–250; MgBr2, EtSH, Et2O: (i)
Berkowitz, D. B.; Choi, S.; Maeng, J.-H. J. Org. Chem. 2000, 65, 847–860; SEM
deprotection from phenol: (j) (TBAF, HMPA) Saimoto, H.; Hiyama, T. Tetrahedron
Lett. 1986, 27, 597–600; P2I4: (k) Saimoto, H.; Kusano, Y.; Hiyama, T. Tetrahedron
Lett. 1986, 27, 1607–1610; H2SO4: (l) Shih, T. L.; Wyvratt, M. J.; Mrozik, H. J. Org.
Chem. 1987, 52, 2029–2033; TBAF, MS4 Å, DMPU: (m) Koreeda, M.; Dixon, L. A.;
His, J. D. Synlett 1993, 555–556; HCl: (n) Graybill, T. L.; Casillas, E. G.; Pal, K.;
Townsend, C. A. J. Am. Chem. Soc. 1999, 121, 7729–7746; Anhydrous TBAF: (o)
Sugimura, T.; Paquette, L. A. J. Am. Chem. Soc. 1987, 109, 3017–3024; HF, CH3CN:
26. Denmark, S. E.; Fu, J. Chem. Rev. 2003, 123, 2208–2216.
27. (a) Grubbs’ second-generation catalysts: (1,3-bis-(2,4,6-trimethylphenyl)-2-imi-
dazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium.
(b) Lautens, M.; Maddes, M. L. Org. Lett. 2004, 6, 1883–1886; (c) BouzBouz, S.;
Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465–3467; (d) Chatterjee, A. K.;
Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783–3784;
(e) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 11360–11370.
28. (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467–8468;
(b) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827–7828; (c) Meng, D.;
Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.;
Chou, T.-C.; He, L.; Horwitz, S. B. J. Am. Chem. Soc. 1997, 119, 2733–2734.
29. (a) Jadhav, P. K.; Bhat, K. S.; Perumal, T.; Brown, H. C. J. Org. Chem. 1986, 51, 432–
439; (b) Brown, H. C.; Joshi, N. N. J. Org. Chem. 1988, 53, 4059–4062; (c) Lautens,
M.; Maddes, M. L.; Sauer, E. L. O.; Ouellet, S. G. Org. Lett. 2002, 4, 83–86; Salt free
conditions: (d) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401–404.
30. (a) Denmark, S. E.; Fu, J.; Coe, D. M.; Su, X.; Pratt, N.; Griedel, B. D. J. Org. Chem.
2006, 71, 1513–1522; (b) Denmark, S. E.; Fu, J.; Lawler, M. J. J. Org. Chem. 2006,
71, 1523–1536.
(p) White, J. D.; Kawasaki, M. J. Am. Chem. Soc. 1990, 112, 4991–4993; I2, hn: (q)
31. Commercially available geraniol was enriched by spinning band distillation (GC
analysis 99.8% geraniol/0.2% nerol)
32. (a) Takaya, H.; Ohta, T.; Inoue, S. -I.; Tokunaga, M.; Kitamura, M.; Noyori, R. Org.
Synth. 1995, 72, 74–85; (b) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Ku-
mobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori, R. J. Am. Chem. Soc. 1987,
109, 1596–1597.
Karim, S.; Parmee, E. R.; Thomas, E. J. Tetrahedron Lett. 1991, 32, 2269–2272.
36. Preparation of trialkylsilyloxymethyl chlorides: (a) Pitsch, S.; Weiss, P. A.; Wu,
X.; Ackermann, D.; Honegger, T. Helv. Chim. Acta 1999, 82, 1753–1761; (b) Pitsch,
S.; Weiss, P. A.; Jenny, L.; Stutz, A.; Wu, X. Helv. Chim. Acta 2001, 84, 3773–3795.
37. Gioeli, C.; Balgobin, N.; Joesephson, S.; Chattopadhyaya, J. B. Tetrahedron Lett.
1981, 22, 969–972.
33. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519; (b) Seco, J. M.;
Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17–117; (c) See Supplementary data
for a complete list of chemical shift data.
38. See Supplementary data for the preparation of the buffered HF solutions.
39. Brigl, P. Z. Physiol. Chem. 1922, 122, 245.
40. Liu, G.; Wurst, J. M.; Tan, D. S. Org. Lett. 2009, 11, 3670–3673.