N -Alkynyl Pyrrole Based Total Synthesis of Shensongine A

Article abstract of DOI:10.1055/s-0037-1611904

A copper-catalyzed N-alkynylation of pyrrole and a gold-catalyzed spiroketalization were key steps in the total synthesis of the pyrrole spiroketal alkaloid shensongine A. The preparation of this alkaloid is concise and amenable to the rapid synthesis of

Full text of DOI:10.1055/s-0037-1611904

SYNTHESIS
0
0
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8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–U
paper
A
en
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
N-Alkynyl Pyrrole Based Total Synthesis of Shensongine A
Brandon J. Reinusa
Sean M. Kerwin*b
OTBS
O
Cu-cat.
N-alkynylation
NH
NC
N
O
O
OBn
N
a Department of Chemistry, University of Texas at
Austin, Austin, TX 78712, USA
b Department of Chemistry & Biochemistry, Texas
State University, San Marcos, TX 78666, USA
smk89@txstate.edu
+
TIPSO
HO
Au-cat.
spiro-
ketalization
TBSO
OBn
OH
O
Key Intermediate
O
CHO
shensongine A
11 steps and 2.7% overall yield
Received: 15.05.2019
Accepted after revision: 04.07.2019
Published online: 12.08.2019
sequently, there has been significant interest in establishing
synthetic routes to these compounds.2
Our research group has been interested in the synthesis
and study of N-alkynyl azoles for more than 15 years, and
our most recent work focused on the synthesis of N-alkynyl
pyrroles.8,9 Currently established strategies for synthesizing
the PSAs rely heavily on acid-catalyzed spiroketalizations;
however, we believe a single synthetic strategy utilizing an
N-alkynyl pyrrole could allow access to both the furanose
and pyranose members of the PSAs (Scheme 1). This ap-
proach harnesses the use of alkynes as carbonyl equiva-
lents,10 and by avoiding the thermodynamic penalty of con-
version of carbonyls into their nucleophilic, enol form, pro-
vides more flexibility than alternative approaches. By
DOI: 10.1055/s-0037-1611904; Art ID: ss-2019-m0275-op
Abstract A copper-catalyzed N-alkynylation of pyrrole and a gold-cat-
alyzed spiroketalization were key steps in the total synthesis of the pyr-
role spiroketal alkaloid shensongine A. The preparation of this alkaloid
is concise and amenable to the rapid synthesis of a diverse library of
compounds.
Key words cross-coupling, alkynes, nitrogen heterocycles, spiroketal-
ization, shensongine A, pyrrole spiroketal alkaloids, total synthesis
The pyrrole spiroketal alkaloids (PSAs) are a group of
spirocyclic natural products that were recently isolated
from several different natural sources.1–3 The PSA natural
products consist of both the alpha and beta anomeric forms
of pyranose and furanose ketals derived from a common
parent ketone (Figure 1).
pyranose
furanose
O
O
It has been postulated that the underlying parent ketone
could itself be derived from two equivalents of the Maillard
reaction product 3-deoxy-D-glucosone,4 providing an ex-
planation for the seemingly large number of natural sources
for the compounds.1–5 In 2010, three separate research
groups reported the isolation of members of the PSAs, re-
sulting in several naming systems for the alkaloids. In addi-
tion, the initial misassignment of the absolute stereochem-
istry for capparasines A and B contributed to some early
confusion surrounding the natural products.6
Over the past decade, because of their association with
traditional Chinese medicine, the PSAs have maintained the
interest of the scientific community; and since their discov-
ery, several of the alkaloids have been shown to have prom-
ising biological activities.2,7 Notably, the furanose PSAs
acortatarin A (1) and acortatarin B (4) have displayed en-
couraging antioxidant activity in diabetic renal cell models.2
Unfortunately, only small amounts of the pyrrole spiroketal
alkaloids can be isolated from their natural sources; for ex-
ample, Cheng and co-workers isolated only 7.3 mg of acor-
tatarin A (1) from 50 kg of Acori tatarinowii rhizome.1 Con-
N
HO
N
O
O
α
O
O
HO
HO
X
OH
O
OH
1a (X = H):
2 (X = OH):
acortatarin A
5: pollenopyrroside A
N
X
shensongine C
O
OH
OH
O
O
HO
N
HO
N
O
O
Parent Ketone
O
O
β
HO
OH
HO
X
3b (X = H):
4 (X = OH): acortatarin B
6c: shensongine A
shensongine B
Figure 1 The pyrrole spiroketal alkaloids. a Alternative names for acor-
tatarin A: pollenopyrroside B and capparisine A. b Alternative name for
shensongine B: xylapyrroside B. c Alternative names for shensongine A:
xylapyrroside A and ent-capparisine B.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
exploiting orthogonal deprotections of a common interme-
diate (E), such a strategy could be used to rapidly generate a
large library of PSA derivatives. Since embarking on this
project, Pale and co-workers completed the synthesis of the
furanose PSA acortatarin A (1) by using an N-alkynyl pyr-
role strategy.11 In combination with our route to the pyra-
nose PSA shensongine A (6) described here, the two meth-
ods uphold the legitimacy of a single divergent synthesis of
both the pyranose and furanose PSAs from an aptly substi-
tuted N-alkynyl pyrrole intermediate (Scheme 1, E).
R2
Standard Conditionsa
R1
7ab,7bc
+
Br
O
R1
N
N
H
R2
8–17
18–27
O
O
O
O
O
NC
N
N
N
N
OEt
OEt
OEt
8/18a: 45%b
9/19b: tracec
10/20a: 0%b
11/21a: 0%b
THPO
O
O
O
O
O
N
N
N
OEt
OEt
OEt
R2
N
R2
12/22a: traceb
CO2Me
13/23a: 0%b
14/24a: traceb
N
HO
R3O
CO2Me
O
*
OR5
OR3
CN
N
O
Me
Me
TBSO
OR4
N
N
R5O
TBSO
O
R3O
HO
R1
15/25b: 8%c
16/26b: 85%c
17/27b: 60%c
A
C
OR5
N
furanose-spiroketals
Scheme 2 Screening for a pyrrole coupling partner. a Reactions were
run with pyrrole (0.2 mmol), alkynyl bromide (0.24 mmol), CuSO4·5H2O
(0.02 mmol), 1,10-phenanthroline (0.04 mmol), K2CO3 (0.4 mmol),
toluene (0.4 mL), 135 °C, 14 h; b Used 7a: R1 = -(CH2)4-OTBS; c Used
7b R1 = TIPS.
R2
Common Intermediate
E
R2
N
R2
N
HO
O
*
O
OR5
OH
R4O
OR5
hydroxy-methyl (14) also generated essentially none of the
alkynylated products (22a, 23a, 24a).
R4O
B
D
We considered a pyrrole containing an -hydroxy-
methyl as part of a lactone as a promising candidate, pre-
dicting the steric and coordinative encumbrance of the hy-
droxy-methyl would be mitigated in such a substrate. In
testing the more easily synthesized pyrrole 15, we con-
firmed our earlier inference9 that, in order to couple effec-
tively, the pyrrole partners electronics and pKa must be bal-
anced to avoid unproductive copper complexation (if the
pKa is too low) or inefficient deprotonation (if the pKa is too
high). Pyrrole 15, with a predicted low pKa (14.3), proved to
be a rather poor substrate, generating only 8% of the desired
product. Subsequently, we found that reducing the alde-
hyde 15 to a protected hydroxy-methyl afforded a much
improved coupling partner 16 that affords coupling product
26b in 85% yield (Scheme 2). From these results, it appears
a single EWG produces an electronic environment and pKa
that is optimal for N-alkynylation of pyrroles.
Continuing our search for a suitable pyrrole coupling
partner, the exceptional reactivity of pyrrole 16 led us to
implement the TBS silyl ether as our hydroxy-methyl pro-
tecting group of choice. Thus, determining how we would
introduce the -carboxaldehyde was the last step towards
establishing a pyrrole coupling partner. The easy conver-
sion of nitriles into aldehydes in conjunction with the com-
pact nature of the functional group made it a reasonable
choice. We were pleased to find that N-alkynyl pyrrole 27b
was formed in a 60% yield (Scheme 2). The ease with which
pyranose-spiroketals
Scheme 1 Proposed divergent synthesis of the pyranose and furanose
PSAs
At the start of the project, we were uncertain how much
substitution we would be able to incorporate on the pyrrole
and still achieve an efficient cross-coupling; thus, our initial
objective was to identify a suitable pyrrole coupling part-
ner. Within the PSA family of natural products, the substi-
tution on pyrrole is consistent and includes a hydroxy-
methyl in the 5-position and an aldehyde in the 2-posi-
tion.12 With this in mind, we began looking at various pyr-
roles that would only require a limited number of transfor-
mations to access this substitution pattern following N-
alkynylation (Scheme 2).
From our previous work9 we knew that 1H-pyrrole-2-
carboxylate ester (8) gave moderate yields of N-alkynyl pyr-
role 18a and that 1H-pyrrole-2,5-dicarbaldehyde (9) was
unreactive (19b, Scheme 2). Additionally, we were aware
that alkyl-alkynyl bromides and pyrroles containing -sub-
stituted aldehydes are incompatible coupling partners.13
Thus, our search began by looking into additional pyrroles
containing two electron-withdrawing groups (EWGs), pyr-
roles 10 and 11, neither of which gave the corresponding N-
alkynylated products 20a and 21a. Pyrroles substituted
with a vinyl group (12), an acetal (13), and a THP-protected
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

C
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
pyrrole 17 could be used towards the synthesis of the PSAs
led us to conclude our investigations into pyrroles and move
forward with the remainder of the project.
lylation (Scheme 3, eq. 2). We started with known pyrrole
29, which could be synthesized without silylation issues
and in excellent yields. Introducing the nitrile group using
CSI proceeded smoothly to give 30 in 95% yield. Finally, the
thermolytic cleavage of the Boc protecting group proceeded
without incident, providing gram quantities of pyrrole 17
in superb overall yield.
For our model spirocyclizations, we chose to investigate
the reactivity of N-alkynyl pyrroles with increasing chain
lengths (Scheme 4; n = 1–3). Starting with n = 1, 31a, we
anticipated only a partial cycloisomerization, due to the un-
likely formation of an oxetane spirocycle;14 thus, formation
Investigating the reactivity of N-alkynyl pyrroles under
cycloisomerization conditions became our next objective.
However, before carrying out a series of model cyclizations,
we set out to develop an efficient synthesis of pyrrole 17
(Scheme 3). Our initial synthesis of 17 was easily executed,
but suffered from low overall yields (Scheme 3, eq. 1). We
devised an alternative synthesis in which a Boc-protected
pyrrole was used to temper the reactivity of the hydroxy-
methyl group as part of an effort to improve the yield of si-
(1)
a) LAH
b) TBSCl, TEA
OH
OTBS
NC
CO2Et
NC
N
H
NC
N
H
N
H
11
28
17
(2)
c) CSI
d) 140 °C
OTBS
OTBS
OTBS
NC
NC
N
N
N
H
Boc
Boc
29
30
17
Scheme 3 Synthesis of key pyrrole intermediate 17. Reagents and conditions: (a) LAH, THF, 0 °C; (b) TBSCl, imidazole, DCM, 0 °C to r.t., 29% (two steps);
(c) CSI, THF, –78 °C, then TEA and DMF, 95%; (d) 140 °C, neat, 91%. CSI = chlorosulfonyl isocyanate.
NC
RO
AuCl (10 mol%)
N
Cyclization Products
32a–f
n
DCM
31a–f
OH
R = H or PG
NC
NC
NC
NC
NC
N
N
O
O
N
N
N
O
O
O
O
O
O
BnO
32d: 51%
n = 2, R = Bn
OBn
NC
32e: 62%
n = 3, R = H
32a: 48%
n = 1, R = H
32b: 69%
n = 1, R = Bn
32c: 39%
n = 2, R = H
NC
N
HO
CN
a
N
NC
N
N
O
b,c
+
O
O
O
TBDPSO
TBDPSO
HO
32f
31f
33
34
9%
18% td = 15 min
td = 12 h
0%
27%
Scheme 4 Model cyclization reactions. Reagents and conditions: (a) AuCl (10 mol%), DCM, r.t., 15 min, 62%; (b) TBAF, THF, r.t., 15 min, 27%; (c) CDCl3;
(d) time in CDCl3.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

D
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
the pyrrole[1,2-c]oxazole ketal derivative 32a was unex-
pected. To further understand this result, we tested the re-
activity of the n = 1 mono-benzylated diol 31b. In this case,
the 6-endo-dig product 32b was the only observed product.
Analogous reactivity was observed with the n = 2 substrate
31c, which generated the pyrrole[1,2-c]oxazole ketal deriv-
ative 32c, while the mono-benzylated diol displayed oppo-
site carbon selectivity. Interestingly, the reactivity changed
when testing the n = 3 substrate, 31e, generating the de-
sired cycoloisomerization product, spiroketal 32e, in a 62%
yield.
The model studies of Scheme 4 were a success in terms
of advancing our understanding of the reactivity of N-
alkynyl pyrrole-diols towards cycloisomerizations. It ap-
pears that cyclization proceeds preferentially from the
alkyne-tethered alcohol, and that the favored modes of cy-
clizations are 5-endo-dig, 6-endo-dig, and 6-exo-dig in this
series, with subsequent cyclization involving the pyrrole 2-
hydroxymethyl group to form the ketals. Thus, accessing
[6,6]-spiroketals (the pyranose PSA derivatives) from a suit-
able diol using this strategy should be straightforward.
However, as the 5-exo-dig cyclization mode from the more
facile alkyne-tethered alcohol is not observed, accessing the
[6,5]-spiroketals (the furanose PSA derivatives) is unlikely
to be successful in the case of a single-step spiroketalization
under these conditions, although a multistep process ap-
pears viable.
study support the probable success of a diligently planned
divergent synthesis of both the [6,5] and [6,6] PSAs from a
common intermediate.
The fewer steps involved in constructing [6,6] versus
[6,5] spirocycles using our strategy and the more favorable
formation of the [6,6] -anomer led us to choose shensong-
ine A (6) as our first synthetic target. For our retrosynthesis
of 6 we decided to use a cyclic carbonate as our protecting
group for the cis-diol; organic carbonates are easily in-
stalled and deprotected, making it an attractive choice
(Scheme 5). Through routine functional group manipula-
tions we felt that advanced intermediate 35 could provide
an easy path to shensongine A (6). A spiroketalization could
give intermediate 35 from diol 36, and 36 could come from
the corresponding silylated N-alkynyl pyrrole 37. Thus, we
were left to synthesize alkynyl bromide 38.
We began our synthesis of 38 with the known addition
of propargyl zinc to glyceraldehyde derivative 39 (Scheme
6). By utilizing routine chemistry, compound 40, the major
diastereomer of propargyl zinc addition to 39 was smoothly
transformed into silyl-ether 41 in 57% overall yield. Subse-
quent installation of the carbonate followed by bromination
of the alkyne gave 38 in 39% two-step yield. Suitably posi-
tioned to explore the key N-alkynylation step, we were un-
able to isolate the desired N-alkynyl pyrrole 37; rather, we
only isolated small amounts of the undesired elimination
product 42.
In an effort to establish a multistep synthesis of a [6,5]-
spiroketal and to conclude our model studies, we synthe-
sized N-alkynyl pyrrole 31f (Scheme 4). Cyclization of this
mono-protected diol, gave the corresponding 1H-pyrro-
lo[2,1-c][1,4]oxazine 32f in 62% yield. Subsequently, sub-
jecting 32f to a standard tetrabutylammonium fluoride
(TBAF) deprotection resulted not only in the isolation of the
expected alcohol, 33, but pyrrole spiroketal 34 as well.
While sitting in chloroform overnight, compound 33 fully
cyclized to spiroketal 34.15 Overall, the results of the model
In planning our second effort towards synthesizing 6,
we chose to protect the cis-diol as an acetonide. Our initial
strategy failed because of the carbonate serving as a leaving
group and we believed the acetonide would not suffer the
same fate. In addition, acetonides have found use in other
groups’ strategies for synthesizing the pyrrole spiroketal al-
kaloids.16 We began the synthesis with the olefination of
deoxyribopyranose 43, followed by TBS protection to give
the cis-diol (Scheme 7). Reaction with 2,2-dimethoxypro-
pane and PPTS gave 44 in 69% overall yield. Subsequently,
NC
O
O
O
O
O
N
O
N
N
O
CN
O
HO
HO
O
O
OH
O
HO
36
35
6: Shensongine A
O
NC
O
O
O
O
N
O
+
17
Br
TBSO
TBSO
38
TBSO
37
Scheme 5 Retrosynthetic analysis of shensongine A
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

E
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
ozonolysis gave aldehyde 45 in an excellent 93% yield; final-
ly, a Corey–Fuchs alkyne synthesis followed by bromination
of the resultant alkyne gave 46 in 74% yield.
Alkynyl bromide 46 reacted smoothly to form N-alkynyl
pyrrole 47 in 37% yield. Although the alkynylation did not
suffer from issues with elimination, following the removal
of the silyl ethers, diol 48 did not give the desired spiroketal
49. Instead we isolated small amounts of 50 from what ap-
pears to be the result of an initial migration of the acetonide
followed by an undesired cyclization to the pyrrole[1,2-
c]oxazole ketal. We anticipated this as a potential issue and
abandoned the strategy.
For our third attempt at synthesizing shensongine A (6),
we looked to benzyl ethers for protecting the cis-diol
(Scheme 8). Benzyl ethers should not suffer from elimina-
tion nor from rearrangement, thus they seemed aptly
H
O
O
O
O
OH
b,c
a
TBSO
OH
H
O
OH
d,e
39
40
41
OTBS
OTBS
NC
NC
N
N
TBSO
TBSO
Br
+
f
O
O
17
O
O
TBSO
O
OH
O
38
42: 8%
37: 0%
Scheme 6 Unsuccessful carbonate strategy. Reagents and conditions: (a) propargyl bromide, Zn, 0 °C, THF, (dropwise addition to glyceraldehyde deriva-
tive), –78 °C to r.t., 31%; (b) TFA, THF, H2O, r.t.; (c) TBSCl, TEA, DMAP, DCM, 0 °C to r.t., 52% for steps b and c; (d) triphosgene, pyridine, DMAP, 0 °C to
r.t., 59%; (e) NBS, cat. AgNO3, acetone, 66%; (f) CuSO4·5H2O (10 mol%), 1,10-phen (20 mol%), K2CO3 (200 mol%), toluene (0.5 M), 135 °C, 8%.
O
OMe
O
O
OH
TBSO
a,b,c
d
TBSO
HO
O
O
O
OH
O
O
Ph3P
OMe
45
44
43
e,f,g
OTBS
NC
O
O
N
Br
h
+
TBSO
17
TBSO
46
O
O
47
NC
OH
CN
N
O
i
j
NC
HO
N
N
O
O
O
O
O
+
O
O
O
O
49: 0%
50: 22%
48
Scheme 7 Unsuccessful acetonide strategy. Reagents and conditions: (a) (methoxycarbonylmethylene)triphenylphosphorane, THF, 55 °C; (b) TBSCl,
TEA, DMAP, DCM, 0 °C to r.t., 80% (two steps); (c) 2,2-dimethoxypropane, PPTS, acetone, r.t., 86%; (d) ozone, DCM, –78 °C, then PPh3, 93%; (e) CBr4,
PPh3, DCM, 0 °C, 88%; (f) n-BuLi, THF, –78 °C, 92%; (g) NBS, cat. AgNO3, acetone, 91%; (h) CuSO4·5H2O (10 mol%), 1,10-phen (20 mol%), K2CO3 (200
mol%), toluene (0.5 M), 135 °C, 37%; (i) TFA, THF, H2O, 0 °C to r.t.; 98%; (j) Ph3PAuCl (10 mol%), AgOTf (10 mol%), DCM, r.t., 22%.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

F
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
suited for the task. Starting from 39, which we could syn-
thesize from D-manitol in 40 gram lots, we were able to
perform a propargyl zinc addition at a scale large enough to
provide 35 grams of 40 in a dr of 4.4 to 1. Carrying this mix-
ture of diastereomers forward by installing the first benzyl
ether aided by TBAI gave alkyne 51 essentially as a pure di-
astereomer (dr >20:1) after chromatography in 68% yield.
Subsequently, the acid-catalyzed removal of the acetonide
followed by installation of a TIPS protecting group proceed-
ed without incident, giving alkyne 52 in a 92% overall yield.
The second benzyl ether could be introduced in 70% yield to
give alkyne 53, but some care was necessary to avoid silyl
migration. Finally, a standard bromination gave alkynyl
bromide 54 in 89% yield.
By using the sequence established in Scheme 8 we were
able to synthesize up to 2.5 grams of alkynyl bromide 54,
enabling us to optimize the subsequent N-alkynylation step
(Table 1). After significant screening, we were pleased to
Table 1 Screening the Cross-Coupling of 54 and 17
NC
N
N
N
N
OBn
OBn
N
OMe
Conditionsa
OTBS
TIPSO
+
NC
TIPSO
N
H
TBSO
OBn
54
Br
OBn
OMe
17
55
L1
L2
Entry
Precat.
Ligand
Base
Solvent
T (°C)
54 (mol%)
17 (mol%)
Yield (%)b
1
2
3
4
5
6d
7
8
9
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
L2
L2
L1
L1
L2
L2
L1
L1
L1
L1
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
K2CO3
K3PO4
K2CO3
K3PO4
K2CO3
K3PO4
K2CO3
K3PO4
K2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
115
115
115
115
135
135
135
135
115
135
115
115
115
115
115
115
115
115
115
115
115
120
120
120
120
120
120
120
120
120
100
100
100
100
120
120
120
120
120
120
120
120
100
100
100
100
100
100
100
100
100
100
100
100
120
100
100
100
100
100
100
100
100
<5
59 (51)c
30
<5
<5
14
32
<5
36
10
28
11
16c
33c
25c
42
12e
13f
14g
15h
16i
17j
18
49
41
46
22
19
C6F6
36
20k
21l
toluene
toluene
<5
<5
a Reaction conditions: pyrrole 17 (0.2 mmol), alkynyl bromide 54 (0.24 mmol), CuSO4·5H2O (0.02 mmol), ligand (0.04 mmol), base (0.4 mmol), solvent (0.4 mL),
at the indicated temperature for 14 h.
b Yields were calculated by NMR using TCE (1,1,2,2-tetrachloroethane) as internal standard.
c Isolated yield.
d Reaction was run for 36 h.
e Slow addition of alkynyl bromide over 5 h.
f Slow addition of pyrrole over 5 h.
g 5 mol% catalyst.
h 20 mol% catalyst.
i 0.8 mL toluene.
j 0.2 mL toluene.
k Used alkynyl chloride.
l Used alkynyl iodide.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

G
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
O
O
O
O
a
b
O
O
O
OH
H
OBn
H
39
from D-Mannitol
40 g
40
51
dr = 4.4:1.0
dr = >20:1
3.5 g
35 g
c,d
OH
OBn
OBn
e
f
TIPSO
TIPSO
TIPSO
OBn
H
OBn
53
H
OBn
Br
52
54
2.5 g
Scheme 8 Multigram synthesis of alkynyl bromide 54. Reagents and conditions: (a) Propargyl bromide, Zn, 0 °C, THF, (dropwise addition to glyceralde-
hyde derivative), –78 °C to r.t., 56%; (b) NaH, 0 °C, then BnBr, TBAI, 0 to 55 °C, THF, 68%; (c) 1N HCl, MeOH, r.t.; (d) TIPSCl, DMF, imidazole, 92% (two
steps); (e) NaH, 0 °C, BnBr, 0 °C to r.t., 70%; (f) NBS, cat. AgNO3, acetone, r.t., 89%.
find that we could synthesize N-alkynyl pyrrole 55 in 51%
isolated yield (entry 2). Our screens covered many parame-
ters, including base combinations with ligands (entries 1–
4), elevated temperatures (entries 5–8), extended reaction
times (entry 9), mole ratios (entries 10–13), both the slow
addition of 54 to 17 and the slow addition of 17 to 54 (en-
tries 12 and 13), catalyst loading (entries 14 and 15), con-
centration (entries 16 and 17), solvents (entries 18 and 19),
and we even looked at other alkynyl halides (entries 20 and
21).
Despite the scope of our efforts, we were unable to im-
prove the yield of the coupling beyond the results detailed
in Table 1, entry 2, which we decided must represent an op-
timal balance of the various side reactions that we ob-
served, such as homocoupling of the bromoalkyne and de-
composition of N-alkynyl pyrrole 55, and we moved for-
ward to pursue finishing the synthesis.
The TBAF deprotection of 55 proceeded without inci-
dent (93%; Scheme 9) enabling us to investigate the synthe-
sis of the [6,6]-spiroketal 57 (Table 2). We were satisfied to
find AuCl with PPTS, standard cycloisomerization condi-
tions,17,18 gave the desired spiroketal in 27% yield (entry
1).19 While investigating alternative conditions, we found
simply mixing AuCl with diol 56 in DCM gave 57 in a much
greater yield (66%; entry 2). Under similar conditions, AuCl3
gave a comparably good result, producing 57 in 59% yield
(entry 3). We found gold(I) phosphine precatalyst and
AgOTf to be poor catalysts, giving none of the desired
spiroketal (entries 4–6). Additionally, neither mercury nor
palladium catalysts, both known to catalyze alcohol
OBn
TIPSO
NC
OBn
Br
OBn
N
b
54
+
a
TIPSO
TBSO
See Table 1
OBn
17
55
NC
O
NC
N
N
O
d,e
c
OBn
N
O
O
See Table 2
O
HO
HO
HO
BnO
OBn
OH
6: Shensongine A
OBn
57
56
Scheme 9 Synthesis of shensongine A. Reagents and conditions: (a) CuSO4·5H2O (10 mol%), 4,7-dimethoxy-1,10-phenanthroline (20 mol%), K3PO4
(200 mol%), toluene (0.5 M), 115 °C, 51%; (b) TBAF, THF, 0 °C, 93%; (c) AuCl (10 mol%), DCM, r.t., 120 h, 60%; (d) DIBAL-H, DCM, 0 °C to r.t., 61%;
(e) TiCl4 (1 M in DCM), DCM, –78 to 0 °C, 70%.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

H
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
additions to alkynes, performed well (entries 7 and 8).20
Thus, by using the AuCl conditions detailed in entry 2, we
were able to isolate spiroketal 57 in 60% yield, allowing us
to complete the final steps of our shensongine A (6) synthe-
sis (Scheme 9). The reduction of nitrile 57 with DIBAL-H
gave moderate yields of aldehyde 57-1 (61%; Scheme 9). To
complete the total synthesis we employed the same condi-
tions previously reported6b for deprotection of the two ben-
zyl ethers with TiCl4 and obtained shensongine A (6) in 70%
yield.
All reactions were run under argon in round-bottom flasks or in
sealed vials using PTFE caps unless otherwise stated. All solvents and
reagents were reagent grade and used as received unless otherwise
stated. Column chromatography was carried out on SiliaFlash P60 sili-
ca gel (230–400 mesh). Reactions were monitored by TLC on Merck
silica gel 60 W F245 aluminum-backed plates. Optical rotations were
measured with a PerkinElmer 241 MC polarimeter. Melting points
were recorded with a Büchi B-540 melting point apparatus and are
uncorrected. IR spectra were obtained with a PerkinElmer Spectrum
100 FT-IR spectrophotometer using a diamond anvil ATR accessory.
High-resolution mass spectra (HRMS) were obtained with an Agilent
6530 Q-TOF spectrometer. Accurate masses are reported for the mo-
lecular ion [M + Na]+ or [M + H]+. NMR spectra were recorded at 400
MHz (1H) and 100 MHz (13C) with an Agilent MR spectrometer. NMR
spectra were recorded as parts per million (ppm) using residual sol-
vent signals as internal standards (CHCl3,  = 7.26 ppm for 1H NMR, 
= 77.00 ppm for 13C NMR). The following abbreviations are used to de-
scribe the multiplicities: s = singlet, d = doublet, dd = doublet of dou-
blets, t = triplet, q = quartet, quin. = quintet, m = multiplet, br s =
broad singlet. NMR yields were calculated using 1,1,2,2-tetrachlo-
roethane as an internal standard. Data for 1H NMR are presented as
follows: chemical shifts (, ppm), multiplicity, coupling constant (Hz),
and integration. Data for 13C NMR were presented as the chemical
shifts of peaks found.
Table 2 Screening Conditions for the Metal-Catalyzed Cycloisomeriza-
tion of 56
NC
NC
N
Conditionsa
OBn
N
O
O
HO
HO
BnO
OBn
OBn
56
57
Entry Precatalyst
Additive Solvent
T (°C)
Yield (%)b
Preparation of Pyrroles
1
2
3
4
5
6
7
8
AuCl
PPTS
THF
RT
27
All pyrroles were commercially available or synthesized by using
standard chemistry. Pyrroles purchased from suppliers were purified
by column chromatography or distillation prior to use. See the follow-
ing section for details regarding the synthesis of pyrroles that were
not commercially available.
AuCl
–
DCM
DCM
DCM
DCM
DCM
MeCN
MeCN
RT
66 (60)c
AuCl3
–
RT
59
0
Au(Ph3P)Cl
Au(Ph3P)Cl
AgOTf
–
RT
AgOTf
RT
0
Preparation of Alkynyl Bromides; General Procedure A
–
–
–
RT
0
To a solution of alkyne (1.0 equiv) in acetone (0.2 M) was added NBS
(1.2 equiv) and AgNO3 (0.1 equiv). The mixture was stirred open to
the air for 4 h. Upon completion, the acetone was removed and the
residue was taken up in hexanes, the organic solution was washed
with sat. NH4Cl, H2O (2×), and brine, and dried over Na2SO4. Removal
of the solvent under vacuum gave the pure alkynyl bromide.
Hg(OTf)2
Pd(PhCN)2Cl2
RT
0
reflux (82)
13
a Reaction conditions: 56 (0.02 mmol), cat. (0.002 mmol), solvent (0.1 mL),
at the indicated temperature for 48 h.
b Yields were calculated by NMR using TCE (1,1,2,2-tetrachloroethane) as
internal standard.
c Isolated in 60% yield at 0.3 mmol scale and run for 120 h.
Preparation of N-Alkynyl Pyrroles; General Procedure B
An 8 mL vial was charged with K2CO3 (55 mg, 0.4 mmol) and flame-
dried and allowed to cool under vacuum. Once cooled, the vial was
rapidly charged with CuSO4·5H2O (5 mg, 0.02 mmol), 1,10-phenanth-
roline (7.2 mg, 0.04 mmol), and ethyl 1H-pyrrole-2-carboxylate (8;
27.8 mg, 0.2 mmol) and an oven-dried stir bar. To the vial was then
added freshly distilled toluene (0.4 mL) and argon was bubbled
through the mixture for 10 min. Finally, alkynyl bromide ((6-bromo-
hex-5-yn-1-yl)oxy)(tert-butyl)dimethylsilane (7a; 0.24 mmol) was
added and argon was bubbled through the mixture for an additional
10 min. Following this degassing, the vial was rapidly sealed with a
Teflon cap and placed in an oil bath at 135 °C, unless otherwise noted.
After completion of the reaction, the mixture was allowed to cool to
r.t. and directly loaded onto a silica gel column and purified with hex-
anes/EtOAc.
In summary, we have developed a strategy for synthe-
sizing the pyrrole spiroketal alkaloids and demonstrated
the potential of the strategy through its application to the
synthesis of the [6,6]-spiroketal alkaloid shensongine A (6)
in 11 steps and 2.7% overall yield. Our route utilizes two key
steps: (1) a cross-coupling of an alkynyl bromide with a
pyrrole and (2) a gold-catalyzed cycloisomerization of an N-
alkynyl pyrrole. In conjuction with Pale and co-worker’s
synthesis of acortatarin A (1), this synthesis supports the
hypothesis that an N-alkynyl pyrrole strategy can be used
to access all the PSA natural products. Future work from our
lab will look to identify an appropriately protected N-
alkynyl pyrrole that can be used in the divergent synthesis
of the PSA natural products and to implement its use in the
rapid synthesis of a library of derivatives.
TBAF Deprotections; General Procedure C
A round-bottom flask containing a stir bar was charged with the sub-
strate to be deprotected and THF (0.2 M) and subsequently cooled to
0 °C. Subsequently, 1.25 equivalents of TBAF (per silyl group to be
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

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B. J. Reinus, S. M. Kerwin
Paper
Synthesis
come to r.t. Following completion of the reaction as determined by
TLC, the reaction mixture was taken up in DCM and washed with sat.
NH4Cl, H2O (2×), and brine, and dried over Na2SO4. Removal of the sol-
vent gave the crude alcohol, which was purified by flash column
chromatography.
13C NMR (100 MHz, CDCl3):  = 161.5, 135.7, 126.4, 122.7, 116.2,
113.0, 109.2, 60.4, 14.3.
HRMS (ESI): m/z [M + Na]+ calcd for C9H11NO2Na: 188.0682; found:
188.0682.
Ethyl 5-(1,3-Dioxolan-2-yl)-1H-pyrrole-2-carboxylate (13)
AuCl Cyclizations; General Procedure D
An oven-dried round-bottom flask was cooled under argon and
charged with a stir bar, pyrrole 10 (167 mg, 1 mmol), freshly distilled
toluene (4 mL), PPTS (25 mg, 0.1 mmol), and ethylene glycol (0.84 mL,
15 mmol). The mixture was then heated to 130 °C for 8 h and, after
cooling, quenched with H2O (5 mL) and extracted with DCM. The
combined organics were rinsed with brine and then dried over
Na2SO4. Residual solvents were removed and the crude compound
was purified by column chromatography (0–15% EtOAc in hexanes) to
give the product.
A vial containing a stir bar was charged with the cyclization substrate,
and DCM (0.2 M). AuCl (10 mol%) was added in one portion and the
mixture was allowed to stir until the reaction reached completion (as
determined by TLC). Note: these reactions can be very fast. Following
completion, the reaction was filtered through a plug of silica and the
solvents were removed to yield the crude cyclized product, which was
subsequently purified by flash column chromatography.
Preparation of Scheme 1 Substrates: Pyrroles
Yield: 83.3 mg (39%); yellow-orange oil; Rf = 0.35 (hexanes/EtOAc,
2:1).
1H-Pyrrole-2,5-dicarbaldehyde (9)
IR: 3275, 1705, 1657, 1594, 1575, 1510, 1317, 1258, 1217, 1095,
Prepared according to a reported procedure.21
1H NMR (400 MHz, CDCl3):  = 10.54 (br s, 1 H), 9.79 (s, 2 H), 7.01 (d,
J = 2.4 Hz, 2 H).
1017, 983, 823, 777 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.58 (br s, 1 H), 6.83 (dd, J = 4.0, 2.8 Hz,
1 H), 6.28 (dd, J = 3.6, 2.8 Hz, 1 H), 5.89 (s, 1 H), 4.30 (q, J = 7.2 Hz,
2 H), 4.02 (m, 4 H), 1.32 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 181.4, 135.7, 119.4.
13C NMR (100 MHz, CDCl3):  = 160.9, 133.1, 123.0, 115.2, 109.2, 98.0,
65.0, 60.3, 14.3.
HRMS (ESI): m/z [M + Na]+ calcd for C10H13NO4Na: 234.0737; found:
Ethyl 5-Formyl-1H-pyrrole-2-carboxylate (10)
Prepared according to a reported procedure.22
1H NMR (400 MHz, CDCl3):  = 10.30 (br s, 1 H), 9.65 (s, 1 H), 6.92 (m,
2 H), 4.37 (q, J = 7.2 Hz, 2 H), 1.36 (t, J = 7.2 Hz, 3 H).
234.0740.
13C NMR (100 MHz, CDCl3):  = 180.4, 160.4, 134.4, 128.5, 119.7,
115.5, 61.3, 14.2.
Ethyl 5-(Hydroxymethyl)-1H-pyrrole-2-carboxylate (14-1)
Prepared according to a reported procedure.24
IR: 3293, 1669, 1488, 1316, 1214, 1133, 1020, 973, 798, 761 cm–1
.
Ethyl 5-Cyano-1H-pyrrole-2-carboxylate (11)
Prepared according to a reported procedure.23
1H NMR (400 MHz, CDCl3):  = 11.22 (br s, 1 H), 6.88 (d, J = 4.0 Hz,
1 H), 6.81 (d, J = 4.0 Hz, 1 H), 4.44 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3):  = 160.8, 126.9, 119.8, 115.0, 112.8,
105.6, 62.0, 14.1.
1H NMR (400 MHz, CDCl3):  = 10.34 (br s, 1 H), 6.81 (dd, J = 3.6,
2.4 Hz, 1 H), 6.07 (dd, J = 3.6, 3.6 Hz, 1 H), 4.61 (s, 2 H), 4.27 (q, J =
7.2 Hz, 2 H), 3.65 (br s, 1 H), 1.32 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.0, 137.1, 122.3, 115.8, 108.4, 60.4,
57.4, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C8H11NO3Na: 192.0631; found:
192.0624.
Ethyl 5-Vinyl-1H-pyrrole-2-carboxylate (12)
Ethyl 5-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrole-2-
To a mixture/slurry of MePPh3Br (893 mg, 2.5 mmol) in THF (2.5 mL)
at 0 °C was added KOtBu (280.5 mg, 2.5 mmol). The mixture was al-
lowed to stir for 30 min at r.t. under argon. The mixture was placed
back on an ice bath and pyrrole 10 (334 mg, 2.0 mmol) was added
dropwise as a solution in THF (0.5 mL). The mixture was allowed to
warm to r.t. then subsequently brought to reflux for 1 h. The reaction
mixture was filtered, rinsed with EtOAc, residual solvents removed,
and the crude compound was purified by column chromatography
(0–15% EtOAc in hexanes) to give the product.
carboxylate (14)
A round-bottom flask was charged with a stir bar, 14-1 (149 mg, 0.88
mmol), DCM (3.0 mL), PPTS (12.5 mg, 0.05 mmol), and dihydropyran
(0.1 mL, 1.1 mmol). The solution was stirred under argon overnight.
The reaction was quenched with NaHCO3 solution and extracted with
DCM (×2), the organics were combine and washed with brine, then
dried over Na2SO4. The residual solvents were removed and the crude
product was purified by flash column chromatography (0–50% EtOAc
in hexanes) to yield the product.
Yield: 216.5 mg (65.5%); white solid; mp 53 °C; Rf = 0.55 (hex-
anes/EtOAc, 2:1).
Yield: 211 mg (95%); pale-yellow oil; Rf = 0.65 (hexanes/EtOAc, 1:1).
IR: 3292, 2939, 1698, 1678, 1492, 1316, 1218, 1118, 1075, 1021, 967,
903, 868, 807, 765 cm–1
.
IR: 3297, 2923, 2852, 1674, 1488, 1368, 1321, 1260, 1219, 1137,
1024, 798, 763, 713 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.85 (br s, 1 H), 6.80 (dd, J = 3.6, 2.4 Hz,
1 H), 6.12 (dd, J = 3.6, 2.8 Hz, 1 H), 4.67 (d, J = 13.2 Hz, 1 H), 4.63 (dd,
J = 4.4, 3.2 Hz, 1 H), 4.54 (d, J = 13.2 Hz, 1 H), 4.29 (q, J = 7.2 Hz, 2 H),
3.86 (m, 1 H), 3.51 (m, 1 H), 1.78 (m, 1 H), 1.68 (m, 1 H), 1.53 (m, 2 H),
1.31 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 9.95 (br s, 1 H), 6.87 (dd, J = 4.0, 2.8 Hz,
1 H), 6.58 (dd, J = 17.6, 11.2 Hz, 1 H), 6.27 (dd, J = 3.6, 2.8 Hz, 1 H),
5.65 (d, J = 17.6 Hz, 1 H), 5.21 (d, J = 11.2 Hz, 1 H), 4.34 (q, J = 7.2 Hz,
2 H), 1.36 (t, J = 7.2 Hz, 3 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

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B. J. Reinus, S. M. Kerwin
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 161.1, 133.8, 122.6, 115.1, 109.4, 98.0,
5-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-pyrrole-2-carboni-
62.4, 61.7, 60.0, 30.3, 25.1, 19.3, 14.2.
trile (17)
HRMS (ESI): m/z [M + Na]+ calcd for C13H19NO4Na: 276.1206; found:
276.1209.
1st Generation Route
A round-bottom flask was charged with a stir bar, 11 (322 mg, 2.15
mmol), and THF (30 mL), and subsequently cooled to 0 °C under ar-
gon. Following adequate cooling, LAH (121 mg, 3.2 mmol) was care-
fully added in portions. After 1 h, the reaction was carefully quenched
with a small amount of iPrOH then MeOH and diluted with NH4Cl
solution. The aqueous layer was extracted with DCM (×3) and the
combined organics were washed with brine and dried over Na2SO4.
The organics were removed to give crude 28, which was used in the
next step without further purification. Crude 28 was diluted with
DCM (10 mL) and stirred at 0 °C under argon. Imidazole (306 mg, 4.5
mmol) was added, followed by TBS-Cl (452 mg, 3.0 mmol), and the
reaction was allowed to warm to r.t. and stirred overnight. The fol-
lowing day the reaction was diluted with DCM (20 mL) and washed
with NH4Cl, water (×2), and brine. The combined organics were dried
over Na2SO4 and the residual solvent was removed. The resulting
crude product was purified by flash column chromatography (0–25%
EtOAc in hexanes) to give the product.
Methyl 5-Formyl-2-methyl-1H-pyrrole-3-carboxylate (15)
An oven-dried round-bottom flask containing a stir bar was allowed
to cool to r.t. under argon and subsequently charged with DMF (2.71
mL, 35 mmol), and then placed on an ice bath and cooled to 0 °C. PO-
Cl3 (2.83 mL, 30 mmol) was carefully added and then the mixture was
allowed to come to r.t. After 20 min, methyl 2-methyl-1H-pyrrole-3-
carboxylate (2.28 g, 20 mmol) was added in portions as a solid. Small
amounts of DCE were used to wash the sides of the flask. After 3 h, the
small amount of DCE was removed in vacuo and subsequently water
was added to the crude mixture followed by the careful addition of
NaOAc (12 g in 20 mL H2O) and Na2CO3 (5 g). The product precipitated
from the water and was filtered and rinsed with excess water and re-
crystallized from toluene.
Yield: 1.86 g (56%); white solid.
IR: 3254, 1713, 1651, 1567, 1475, 1416, 1243, 1138, 1094, 868, 776,
684 cm–1
.
Yield: 147 mg (29%); blood orange oil; Rf = 0.7 (hexanes/EtOAc, 2:1).
1H NMR (400 MHz, CDCl3):  = 10.43 (br s, 1 H), 9.42 (s, 1 H), 7.35 (d,
J = 2.8 Hz, 1 H), 3.84 (s, 3 H), 2.63 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 179.2, 164.6, 144.0, 130.4, 124.2,
IR: 3287, 2929, 2857, 2219, 1463, 1361, 1254, 1181, 1082, 834, 776,
666 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.92 (br s, 1 H), 6.79 (m, 1 H), 6.00 (m,
1 H), 4.72 (s, 2 H), 0.92 (s, 9 H), 0.10 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 137.5, 120.6, 114.6, 105.8, 99.6, 58.5,
25.8, 18.3, –5.4.
115.0, 51.1, 13.4.
HRMS (ESI): m/z [M + Na]+ calcd for C8H9NO3Na: 190.0475; found:
190.0473.
HRMS (CI): m/z [M + H]+ calcd for C12H22N2OSi: 237.1423; found:
237.1425.
Methyl 5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-methyl-1H-
pyrrole-3-carboxylate (16)
A round-bottom flask was charged with a stir bar, 15 (168 mg, 1.0
mmol), MeOH (2.0 mL), and cooled to 0 °C. Following adequate cool-
ing while stirring, NaBH4 (2 equiv) was added in portions and allowed
to warm to r.t. Following completion, as determined by TLC, the reac-
tion was diluted with water (25 mL) and extracted with DCM (3×).
The combined organics were dried with sat. NaCl and dried over Na2-
SO4 and then solvents were removed to give the crude alcohol. The
crude alcohol was then added to a round-bottom flask with DCM (5.0
mL) and charged with a stir bar. To the flask was also added TEA (0.6
mL), and a catalytic amount of DMAP. Following cooling to 0 °C, TBS-
Cl (200 mg, 1.33 mmol) was added in portions and the reaction was
allowed to cool to r.t. and stirred overnight. The following day the re-
action was diluted with DCM (20 mL) and rinsed with sat. NH4Cl (×1),
water (×2), brine (×1) and dried over Na2SO4. Following removal of re-
sidual solvents, the crude compound was purified by column chroma-
tography (0–15% EtOAc in hexanes) to give the product.
2nd Generation Route
tert-Butyl 2-Formyl-1H-pyrrole-1-carboxylate (29-1)
Prepared according to a reported procedure.25
1H NMR (400 MHz, CDCl3):  = 10.3 (s, 1 H), 7.43 (m, 1 H), 7.17 (m,
1 H), 6.27 (m, 1 H), 1.63 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 182.3, 148.3, 134.6, 127.3, 121.1,
111.6, 85.7, 27.9.
tert-Butyl 2-(Hydroxymethyl)-1H-pyrrole-1-carboxylate (29-2)
Prepared according to a reported procedure.25
1H NMR (400 MHz, CDCl3):  = 7.15 (dd, J = 3.2, 2.0 Hz, 1 H), 6.15 (m,
1 H), 6.08 (t, J = 3.6 Hz, 1 H), 4.63 (s, 2 H), 3.44 (br s, 1 H), 1.59 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 149.9, 134.7, 121.7, 113.4, 110.3, 84.3,
Yield: 123.5 mg (43%); white solid; Rf = 0.3 (hexanes/EtOAc, 5:1); mp
55–58 °C.
57.5, 27.8.
IR: 3302, 2951, 2856, 1675, 1596, 1450, 1339, 1224, 1134, 1060,
tert-Butyl 2-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-pyrrole-1-
carboxylate (29)
1001, 834, 776 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.51 (br s, 1 H), 6.31 (d, J = 2.8 Hz, 1 H),
Prepared according to a reported procedure.25
4.58 (s, 2 H), 3.77 (s, 3 H), 2.48 (s, 3 H), 0.89 (s, 9 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 166.0, 135.3, 129.1, 111.1, 107.1, 58.3,
1H NMR (400 MHz, CDCl3):  = 7.19 (m, 1 H), 6.23 (m, 1 H), 6.13 (t, J =
3.0 Hz, 1 H), 4.89 (s, 2 H), 1.59 (s, 9 H), 0.94 (s, 9 H), 0.09 (s, 6 H).
50.6, 25.8, 18.3, 13.1, –5.3.
HRMS (ESI): m/z [M + H]+ calcd for C14H26NO3Si: 284.1676; found:
13C NMR (100 MHz, CDCl3):  = 149.2, 135.3, 120.9, 111.0, 110.2, 83.4,
60.1, 27.9, 25.8, 18.3, –5.3.
284.1677.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

K
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
tert-Butyl 2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-cyano-1H-
Methyl 5-Formyl-2-methyl-1-((triisopropylsilyl)ethynyl)-1H-
pyrrole-1-carboxylate (30)
pyrrole-3-carboxylate (25b)
An oven-dried round-bottom flask was charged with a stir bar and
cooled under argon. The flask was then charged with 29 (10.0 g, 32.1
mmol) and freshly distilled THF (100 mL). The mixture was then
cooled to –78 °C and CSI (chlorosulfonyl isocyanate, 3.33 mL, 37
mmol) was added dropwise. Following addition of the CSI, the reac-
tion was stirred for 1.75 h and maintained at –78 °C. After the appro-
priate time had passed, anhydrous TEA (19 mL) was added slowly fol-
lowed by the slow addition of anhydrous DMF (8.0 mL). The reaction
was then allowed to warm to 0 °C and then r.t. After 15 min at r.t., the
reaction mixture was poured into a seperatory funnel with sat. NH4Cl
and extracted with EtOAc (×3). The combined organics were then
washed with H2O (×3), brine, and dried over Na2SO4, removal of resid-
ual solvents gave the crude product, which was then purified by flash
column chromatography (0–25% EtOAc in hexanes) to give the desired
product.
Prepared according to General Procedure B.
Yield: 5.6 mg (8%); clear oil; Rf = 0.7 (hexanes/EtOAc, 4:1).
IR: 2944, 2865, 2186, 1718, 1682, 1568, 1502, 1440, 1234, 1134,
1072, 881, 773, 676 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.77 (s, 1 H), 7.31 (s, 1 H), 3.84 (s, 3 H),
2.68 (s, 3 H), 1.14 (m, 21 H).
13C NMR (100 MHz, CDCl3):  = 178.2, 163.8, 146.5, 132.7, 120.5,
114.8, 90.0, 76.2, 51.5, 18.5, 12.1, 11.2.
HRMS (ESI): m/z [M + Na]+ calcd for C19H29NO3SiNa: 370.1809; found:
370.1815.
Methyl 5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-methyl-1-((tri-
isopropylsilyl)ethynyl)-1H-pyrrole-3-carboxylate (26b)
Prepared according to General Procedure B.
Yield: 10.23 g (95%); clear oil.
Yield: 78.9 mg (85%); pale yellow oil; Rf = 0.65 (hexanes/EtOAc, 4:1).
IR: 2944, 2864, 2185, 1714, 1593, 1544, 1462, 1224, 1070, 882, 835,
IR: 2955, 2931, 2858, 2224, 1752, 1410, 1306, 1253, 1166, 1105, 835,
776 cm–1
.
774, 676 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.90 (d, J = 4.0 Hz, 1 H), 6.33 (m, 1 H),
4.88 (d, J = 1.2 Hz, 2 H), 1.64 (s, 9 H), 0.93 (s, 9 H), 0.10 (s, 6 H).
1H NMR (400 MHz, CDCl3):  = 6.40 (s, 1 H), 4.66 (s, 2 H), 3.79 (s, 3 H),
2.59 (s, 3 H), 1.12 (m, 21 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 165.0, 140.0, 134.1, 112.3, 109.2, 91.7,
13C NMR (100 MHz, CDCl3):  = 147.4, 142.3, 124.9, 113.4, 110.7,
104.1, 87.1, 60.3, 27.7, 25.8, 18.2, –5.4.
73.6, 57.2, 51.0, 25.8, 18.6, 18.3, 12.0, 11.2, –5.2.
HRMS (ESI): m/z [M + Na]+ calcd for C25H45NO3Si2Na: 486.2830;
HRMS (ESI): m/z [M + Na]+ calcd for C17H28N2O3SiNa: 359.1761;
found: 359.1763.
found: 486.2827.
5-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-pyrrole-2-carboni-
trile (17)
5-(((tert-Butyldimethylsilyl)oxy)methyl)-1-((triisopropylsi-
lyl)ethynyl)-1H-pyrrole-2-carbonitrile (27b)
An oven-dried round-bottom flask was cooled under argon and
charged with a stir bar and 30 (9.08 g, 27 mmol). The compound was
then heated neat to 142 °C with sufficient stirring. After 45 min, the
reaction was removed from the oil bath and allowed to cool for 5 min.
After briefly cooling, hexanes (100 mL) were added to the round-bot-
tom flask and the mixture was allowed to continue to stir overnight.
The following day the hexanes were removed and the crude product
was purified by column chromatography (0–25% EtOAc in hexanes) to
give the product.
Prepared according to General Procedure B.
Yield: 29.5 mg (60%); pale oil; Rf = 0.6 (hexanes/EtOAc, 10:1).
IR: 2943, 2865, 2225, 2188, 1462, 1423, 1370, 1254, 1198, 1122,
1075, 997, 835, 779 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.76 (d, J = 3.6 Hz, 1 H), 6.17 (d, J =
3.6 Hz, 1 H), 4.73 (s, 2 H), 1.13 (s, 21 H), 0.90 (s, 9 H), 0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 141.6, 120.7, 112.1, 109.0, 108.0, 90.0,
74.3, 57.6, 25.7, 18.5, 18.3, 11.1, –5.4.
HRMS (CI): m/z [M + H]+ calcd for C23H41N2OSi2: 417.2757; found:
417.2754.
Yield: 5.79 g (91%); while solid; mp 39 °C.
Gave matching spectral data as above.
N-Alkynyl Pyrroles
Preparation of Scheme 4 Substrates
Ethyl 1-(6-((tert-Butyldimethylsilyl)oxy)hex-1-yn-1-yl)-1H-pyr-
role-2-carboxylate (18a)
(But-3-yn-1-yloxy)(tert-butyl)dimethylsilane (31a-1)
Data consistent with reported data.26
Prepared according to General Procedure B.
1H NMR (400 MHz, CDCl3):  = 3.74 (t, J = 7.2 Hz, 2 H), 2.40 (td, J = 7.2,
2.8 Hz, 2 H), 1.95 (t, J = 2.8 Hz, 1 H), 0.89 (s, 9 H), 0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 81.5, 69.2, 61.7, 25.8, 22.8, 18.3, –5.3.
Yield: 794 mg (45%); pale oil; Rf = 0.75 (hexanes/EtOAc, 2:1).
IR: 2930, 2274, 1721, 1465, 1422, 1259, 1104, 835, 733 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.00 (dd, J = 2.8, 2.0 Hz, 1 H), 6.90 (dd,
J = 3.6, 1.6 Hz, 1 H), 6.15 (dd, J = 4.0, 2.8 Hz, 1 H), 4.30 (q, J = 7.2 Hz,
2 H), 3.65 (t, J = 5.6 Hz, 2 H), 2.43 (m, 2 H), 1.67 (m, 4 H), 1.34 (t, J =
7.2 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 159.6, 131.5, 125.5, 117.6, 109.8, 72.6,
69.2, 62.6, 60.2, 31.9, 25.9, 25.1, 18.3, 18.1, 14.3, –5.3.
((4-Bromobut-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane (31a-2)
Prepared according to General Procedure A; data consistent with re-
ported data.27
1H NMR (400 MHz, CDCl3):  = 3.72 (t, J = 7.2 Hz, 2 H), 2.40 (t, J =
7.2 Hz, 2 H), 0.89 (s, 9 H), 0.06 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 77.4, 61.4, 39.0, 25.8, 23.9, 18.2, –5.3.
HRMS (CI): m/z [M + H]+ calcd for C19H32NO3Si: 350.2151; found:
350.2145.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

L
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
1-(4-((tert-Butyldimethylsilyl)oxy)but-1-yn-1-yl)-5-(((tert-butyl-
dimethylsilyl)oxy)methyl)-1H-pyrrole-2-carbonitrile (31a-3)
1-(4-(Benzyloxy)but-1-yn-1-yl)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-1H-pyrrole-2-carbonitrile (31b-3)
Prepared according to General Procedure B.
Prepared according to General Procedure B.
Yield: 69.6 mg (35%); pale oil.
Yield: 68.8 mg (33%); clear oil.
IR: 2954, 2929, 2857, 2225, 1440, 1254, 1104, 835, 775 cm–1
.
IR: 2929, 2857, 2224, 1440, 1362, 1311, 1254, 1212, 1097, 1005, 836,
778, 736, 697 cm–1
1H NMR (400 MHz, CDCl3):  = 7.41–7.26 (m, 5 H), 6.74 (d, J = 4.4 Hz,
1 H), 6.15 (d, J = 4.4 Hz, 1 H), 4.68 (s, 2 H), 4.59 (s, 2 H), 3.70 (t, J =
6.8 Hz, 2 H), 2.75 (t, J = 7.2 Hz, 2 H), 0.91 (s, 9 H), 0.08 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 141.3, 137.8, 128.3, 127.6, 127.6,
120.3, 112.3, 109.0, 108.0, 73.0, 72.9, 69.4, 68.0, 57.3, 25.7, 20.6, 19.7,
–5.4.
.
1H NMR (400 MHz, CDCl3):  = 6.73 (d, J = 3.6 Hz, 1 H), 6.14 (d, J =
3.6 Hz, 1 H), 4.67 (s, 2 H), 3.80 (t, J = 7.2 Hz, 2 H), 2.64 (t, J = 7.2 Hz,
2 H), 0.90 (s, 9 H), 0.90 (s, 9 H), 0.08 (s, 12 H).
13C NMR (100 MHz, CDCl3):  = 141.3, 120.3, 112.3, 109.0, 107.9, 71.9,
69.4, 61.5, 57.4, 25.8, 25.7, 22.7, 18.2, –5.3, –5.3.
HRMS (ESI): m/z [M + Na]+ calcd for C22H38N2O2Si2Na: 441.2364;
found: 441.2378.
HRMS (ESI): m/z [M + Na]+ calcd for C23H30N2O2SiNa: 417.1969;
found: 417.1977.
1-(4-Hydroxybut-1-yn-1-yl)-5-(hydroxymethyl)-1H-pyrrole-2-
carbonitrile (31a)
1-(4-(Benzyloxy)but-1-yn-1-yl)-5-(hydroxymethyl)-1H-pyrrole-
2-carbonitrile (31b)
Prepared according to General Procedure C.
Yield: 20.3 mg (65%); pale oil.
IR: 3358, 2924, 2223, 1440, 1311, 1208, 1026, 792, 753 cm–1
1H NMR (400 MHz, CDCl3):  = 6.72 (d, J = 4.0 Hz, 1 H), 6.17 (d, J =
4.0 Hz, 1 H), 4.62 (s, 2 H), 3.81 (t, J = 6.0 Hz, 2 H), 3.29 (br s, 2 H), 2.67
(t, J = 6.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 141.1, 120.2, 112.3, 110.0, 108.0, 72.8,
70.2, 60.7, 56.0, 22.5.
HRMS (ESI): m/z [M + Na]+ calcd for C10H10N2O2Na: 213.0634; found:
213.0628.
Prepared according to General Procedure C.
.
Light orange oil that despite careful chromatographic purification
contained ca. 5% of the alkyne homo-coupling side product (28.8 mg,
60%).
Rf = 0.45 (hexanes/EtOAc, 1:1).
IR: 3428, 2868, 2222, 1440, 1311, 1207, 1098, 1027, 791, 747,
699 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.40–7.27 (m, 5 H), 6.72 (d, J = 4.0 Hz,
1 H), 6.16 (d, J = 4.4 Hz, 1 H), 4.59 (s, 2 H), 4.58 (s, 2 H), 3.69 (t, J =
6.4 Hz, 2 H), 2.78 (br s, 1 H), 2.74 (t, J = 6.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 141.4, 137.4, 128.4, 127.9, 127.8,
120.2, 112.1, 109.7, 107.9, 73.1, 72.6, 69.6, 67.9, 56.2, 19.7.
4,5-Dihydro-1′H,3H-spiro[furan-2,3′-pyrrolo[1,2-c]oxazole]-
5′-carbonitrile (32a)
Prepared according to General Procedure D.
HRMS (ESI): m/z [M + Na]+ calcd for C17H16N2O2Na: 303.1104; found:
303.1105.
Yield: 13.3 mg (48%); pale-yellow oil.
IR: 3268, 3140, 2944, 2216, 1169, 1035, 989, 792 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.93 (d, J = 3.6 Hz, 1 H), 5.88 (dt, J = 4.0,
0.8 Hz, 1 H), 5.04 (dd, J = 12.4, 0.8 Hz, 1 H), 4.90 (dd, J = 12.4, 0.8 Hz,
1 H), 4.23 (dt, J = 8.0, 6.8 Hz, 1 H), 4.12 (dt, J = 5.6, 8.0 Hz, 1 H), 2.75
(m, 1 H), 2.48 (m, 1 H), 2.33 (m, 1 H), 2.24 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 138.4, 126.5, 118.9, 112.9, 99.5, 94.8,
69.4, 65.5, 35.0, 24.8.
3-(2-(Benzyloxy)ethyl)-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbo-
nitrile (32b)
Prepared according to General Procedure D.
Yield: 11.3 mg (69%); pale oil; Rf = 0.65 (hexanes/EtOAc, 2:1).
IR: 3386, 2899, 2862, 2216, 1678, 1450, 1359, 1314, 1188, 1096,
1069, 1028, 738, 699 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C10H10N2O2Na: 213.0634; found:
213.0635.
1H NMR (400 MHz, CDCl3):  = 7.38–7.26 (m, 5 H), 6.76 (d, J = 4.0 Hz,
1 H), 6.55 (q, J = 0.8 Hz, 1 H), 5.95 (dd, J = 3.6, 0.8 Hz, 1 H), 5.02 (d, J =
0.8 Hz, 2 H), 4.55 (s, 2 H), 3.65 (t, J = 6.0 Hz, 2 H), 2.49 (td, J = 6.4,
0.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 144.8, 137.9, 128.4, 127.7, 125.9,
119.3, 112.8, 104.5, 102.7, 100.0, 73.0, 66.6, 63.3, 32.0.
((But-3-yn-1-yloxy)methyl)benzene (31b-1)
Data consistent with reported data.28
1H NMR (400 MHz, CDCl3):  = 7.40–7.27 (m, 5 H), 4.57 (s, 2 H), 3.61
(t, J = 6.8 Hz, 2 H), 2.52 (td, J = 6.8, 2.8 Hz, 2 H), 2.01 (t, J = 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 137.9, 128.3, 127.6, 81.2, 72.9, 69.2,
HRMS (ESI): m/z [M + Na]+ calcd for C17H16N2O2Na: 303.1104; found:
303.1104.
68.1, 19.8.
tert-Butyldimethyl(pent-4-yn-1-yloxy)silane (31c-1)
Data consistent with reported data.26
1H NMR (400 MHz, CDCl3):  = 3.69 (t, J = 6.0 Hz, 2 H), 2.26 (td, J = 7.2,
2.8 Hz, 2 H), 1.91 (t, J = 2.8 Hz, 1 H), 1.71 (m, 2 H), 0.88 (s, 9 H), 0.05 (s,
6 H).
13C NMR (100 MHz, CDCl3):  = 84.2, 68.2, 61.3, 31.4, 25.9, 18.2, 14.8,
–5.3.
(((4-Bromobut-3-yn-1-yl)oxy)methyl)benzene (31b-2)
Prepared according to General Procedure A.
1H NMR (400 MHz, CDCl3):  = 7.42–7.29 (m, 5 H), 4.57 (s, 2 H), 3.60
(t, J = 6.8 Hz, 2 H), 2.54 (t, J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 137.7, 128.2, 127.4, 127.4, 76.5, 72.7,
67.6, 39.0, 20.8.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

M
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
((5-Bromopent-4-yn-1-yl)oxy)(tert-butyl)dimethylsilane (31c-2)
13C NMR (100 MHz, CDCl3):  = 138.3, 128.2, 127.5, 127.4, 83.8, 72.8,
68.5, 68.4, 28.5, 15.2.
Prepared according to General Procedure A.
1H NMR (400 MHz, CDCl3):  = 3.67 (t, J = 6.0 Hz, 2 H), 2.29 (t, J =
7.2 Hz, 2 H), 1.70 (m, 2 H), 0.88 (s, 9 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 79.9, 61.3, 37.6, 31.2, 25.8, 18.2, 16.0, –
(((5-Bromopent-4-yn-1-yl)oxy)methyl)benzene (31d-2)
Prepared according to General Procedure A.
Yield: 1.36 g (93%); clear oil.
5.4.
IR: 3031, 2859, 1702, 1453, 1364, 1273, 1203, 1102, 1075, 1027, 908,
5-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(5-((tert-butyldimeth-
ylsilyl)oxy)pent-1-yn-1-yl)-1H-pyrrole-2-carbonitrile (31c-3)
735, 696 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.44–7.28 (m, 5 H), 4.54 (s, 2 H), 3.58
(t, J = 6.4 Hz, 2 H), 2.37 (t, J = 7.6 Hz, 2 H), 1.84 (m, 2 H).
Prepared according to General Procedure B.
13C NMR (100 MHz, CDCl3):  = 138.3, 128.2, 127.4, 127.4, 79.6, 72.8,
68.4, 37.9, 28.3, 16.4.
HRMS (ESI): m/z [M + Na]+ calcd for C12H13BrONa: 275.0042; found:
Yield: 71.4 mg (33%); pale oil; Rf = 0.8 (hexanes/EtOAc, 4:1).
IR: 2953, 2929, 2857, 2224, 1440, 1308, 1254, 1212, 1102, 834,
775 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.72 (d, J = 4.0 Hz, 1 H), 6.13 (d, J =
4.0 Hz, 1 H), 4.67 (s, 2 H), 3.74 (t, J = 5.6 Hz, 2 H), 2.52 (t, J = 7.2 Hz,
2 H), 1.81 (quint., J = 6.4 Hz, 2 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.08 (s,
6 H), 0.06 (s, 6 H).
275.0040.
1-(5-(Benzyloxy)pent-1-yn-1-yl)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-1H-pyrrole-2-carbonitrile (31d-3)
13C NMR (100 MHz, CDCl3):  = 141.1, 120.2, 112.4, 108.9, 108.0, 74.5,
Prepared according to General Procedure B.
68.6, 61.3, 57.4, 31.5, 25.8, 25.7, 18.2, 14.7, –5.3, –5.3.
HRMS (ESI): m/z [M + Na]+ calcd for C23H40N2O2Si2Na: 455.2521;
found: 455.2525.
Yield: 70.1 mg (34%); pale oil; Rf = 0.45 (hexanes/EtOAc, 4:1).
IR: 2929, 2856, 2223, 1440, 1363, 1309, 1255, 1212, 1078, 836, 779,
735, 697 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.38–7.24 (m, 5 H), 6.74 (d, J = 4.0 Hz,
1 H), 6.15 (d, J = 4.0 Hz, 1 H), 4.66 (s, 2 H), 4.55 (s, 2 H), 3.65 (t, J =
6.0 Hz, 2 H), 2.58 (t, J = 7.0 Hz, 2 H), 1.93 (m, 2 H), 0.92 (s, 9 H), 0.09 (s,
6 H).
5-(Hydroxymethyl)-1-(5-hydroxypent-1-yn-1-yl)-1H-pyrrole-
2-carbonitrile (31c)
Prepared according to General Procedure C.
13C NMR (100 MHz, CDCl3):  = 141.1, 138.3, 128.2, 127.6, 127.4,
120.2, 112.4, 108.9, 108.0, 74.2, 73.0, 68.9, 68.4, 57.3, 28.6, 25.7, 18.2,
15.2, –5.4.
HRMS (ESI): m/z [M + Na]+ calcd for C24H32N2O2SiNa: 431.2125;
found: 431.2135.
Yield: 21 mg (62%); pale-oil; Rf = 0.15 (hexanes/EtOAc, 2:1).
IR: 3370, 2936, 2223, 1440, 1309, 1209, 1024, 791 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.73 (d, J = 3.6 Hz, 1 H), 6.18 (d, J =
3.6 Hz, 1 H), 4.62 (s, 2 H), 3.80 (t, J = 6.0 Hz, 2 H), 2.79 (br s, 2 H), 2.57
(t, J = 6.8 Hz, 2 H), 1.84 (quint., J = 6.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 140.9, 120.2, 112.3, 109.7, 108.2, 74.5,
68.9, 61.1, 56.1, 30.5, 14.9.
HRMS (ESI): m/z [M + Na]+ calcd for C11H12N2O2Na: 227.0791; found:
227.0789.
1-(5-(Benzyloxy)pent-1-yn-1-yl)-5-(hydroxymethyl)-1H-pyrrole-
2-carbonitrile (31d)
Prepared according to General Procedure C.
Yield: 33.1 mg (66%); clear oil; Rf = 0.5 (hexanes/EtOAc, 1:1).
IR: 3423, 2865, 2222, 1440, 1365, 1310, 1208, 1104, 1076, 1026, 790,
3,4,5,6-Tetrahydro-1′H-spiro[pyran-2,3′-pyrrolo[1,2-c]oxazole]-
5′-carbonitrile (32c)
740, 699 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.38–7.24 (m, 5 H), 6.73 (d, J = 4.0 Hz,
1 H), 6.17 (d, J = 4.0 Hz, 1 H), 4.58 (s, 2 H), 4.54 (s, 2 H), 3.64 (t, J =
6.0 Hz, 2 H), 2.58 (t, J = 6.8 Hz, 2 H), 2.29 (br s, 1 H), 1.92 (m, 2 H).
13C NMR (100 MHz, CDCl3):  = 140.8, 138.2, 128.3, 127.7, 127.6,
120.2, 112.2, 109.5, 108.3, 74.6, 73.0, 68.7, 68.5, 56.3, 28.4, 15.3.
Prepared according to General Procedure D.
Yield: 8.1 mg (39%); pale oil; Rf = 0.56 (hexanes/EtOAc, 2:1).
IR: 3284, 3181, 2956, 2219, 1654, 1547, 1493, 1329, 1185, 1055,
791 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.90 (d, J = 4.0 Hz, 1 H), 5.89 (d, J =
4.0 Hz, 1 H), 5.01 (dd, J = 12.8, 1.2 Hz, 1 H), 4.91 (dd, J = 12.8, 1.2 Hz,
1 H), 4.03–3.90 (m, 2 H), 2.54 (m, 1 H), 2.06 (m, 1 H), 1.96 (m, 2 H),
1.80 (m, 1 H), 1.62 (m, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H18N2O2Na: 317.1260; found:
317.1264.
3-(3-(Benzyloxy)propyl)-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboni-
trile (32d)
13C NMR (100 MHz, CDCl3):  = 138.2, 125.8, 112.5, 109.8, 99.3, 94.9,
65.1, 64.8, 32.4, 23.7, 19.8.
Prepared according to General Procedure D.
HRMS (ESI): m/z [M + Na]+ calcd for C11H12N2O2Na: 227.0791; found:
Yield: 7.0 mg (51%); pale oil; Rf = 0.8 (hexanes/EtOAc, 2:1).
227.0785.
IR: 3408, 2860, 2215, 1677, 1475, 1311, 1173, 1100, 739, 699 cm–1
.
((Pent-4-yn-1-yloxy)methyl)benzene (31d-1)
Data consistent with reported data.28
1H NMR (400 MHz, CDCl3):  = 7.42–7.28 (m, 5 H), 4.54 (s, 2 H), 3.60
(t, J = 6.2 Hz, 2 H), 2.35 (td, J = 6.8, 2.4 Hz, 2 H), 1.97 (t, J = 2.4 Hz, 1 H),
1.86 (m, 2 H).
1H NMR (400 MHz, CDCl3):  = 7.38–7.26 (m, 5 H), 6.76 (d, J = 4.0 Hz,
1 H), 6.45 (d, J = 0.8 Hz, 1 H), 5.94 (d, J = 4.0 Hz, 1 H), 5.00 (s, 2 H), 4.51
(s, 2 H), 3.51 (t, J = 6.0 Hz, 2 H), 2.29 (td, J = 7.2, 0.8 Hz, 2 H), 1.86 (m,
2 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

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B. J. Reinus, S. M. Kerwin
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 147.2, 138.3, 128.3, 127.7, 127.6,
125.9, 119.3, 112.8, 104.5, 101.7, 99.9, 73.0, 69.0, 63.3, 28.1, 26.7.
HRMS (ESI): m/z [M + Na]+ calcd for C18H18N2O2Na: 317.1260; found:
317.1264.
1H NMR (400 MHz, CDCl3):  = 6.78 (d, J = 3.6 Hz, 1 H), 5.90 (d, J =
3.6 Hz, 1 H), 4.77, 4.73 (ABq, J = 14.8 Hz, 2 H), 4.02 (d, J = 12.4 Hz, 1 H),
3.76 (d, J = 12.4 Hz, 1 H), 3.71 (m, 2 H), 2.02–1.55 (m, 6 H).
13C NMR (100 MHz, CDCl3):  = 130.9, 119.6, 113.5, 103.3, 101.8, 93.6,
62.0, 57.4, 51.4, 32.3, 24.5, 18.1.
HRMS (ESI): m/z [M + Na]+ calcd for C12H14N2O2Na: 241.0947; found:
241.0951.
tert-Butyl(hex-5-yn-1-yloxy)dimethylsilane (31e-1)
Data consistent with reported data.29
1H NMR (400 MHz, CDCl3):  = 3.62 (t, J = 6.0 Hz, 2 H), 2.20 (td, J = 6.8,
2.8 Hz, 2 H), 1.93 (t, J = 2.4 Hz, 1 H), 1.60 (m, 4 H), 0.88 (s, 9 H), 0.04 (s,
6 H).
((5-Bromopent-4-yn-1-yl)oxy)(tert-butyl)diphenylsilane (31f-2)
Prepared according to General Procedure A.
13C NMR (100 MHz, CDCl3):  = 84.5, 68.2, 62.5, 31.8, 25.9, 24.9, 18.3,
18.1, –5.3.
1H NMR (400 MHz, CDCl3):  = 7.68 (m, 4 H), 7.42 (m, 6 H), 3.76 (t, J =
6.0 Hz, 2 H), 2.39 (t, J = 7.1 Hz, 2 H), 1.77 (m, 2 H), 1.07 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 135.5, 133.7, 129.5, 127.6, 79.9, 62.0,
37.7, 31.1, 26.8, 19.2, 16.2.
((6-Bromohex-5-yn-1-yl)oxy)(tert-butyl)dimethylsilane (31e-2)
Prepared according to General Procedure A.
1H NMR (400 MHz, CDCl3):  = 3.62 (t, J = 6.0 Hz, 2 H), 2.23 (t, J =
6.8 Hz, 2 H), 1.59 (m, 4 H), 0.89 (s, 9 H), 0.04 (s, 6 H).
5-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(5-((tert-butyldiphe-
nylsilyl)oxy)pent-1-yn-1-yl)-1H-pyrrole-2-carbonitrile (31f-3)
Prepared according to General Procedure B.
13C NMR (100 MHz, CDCl3):  = 80.1, 62.4, 37.7, 31.7, 25.9, 24.7, 19.4,
18.2, –5.3.
Pale oil with co-eluting impurities.
IR: 3310, 3071, 2954, 2929, 2856, 2224, 1589, 1471, 1427, 1389,
1308, 1255, 1212, 1106, 1006, 982, 837, 779, 738, 700 cm–1
.
1-(6-((tert-Butyldimethylsilyl)oxy)hex-1-yn-1-yl)-5-(((tert-butyl-
dimethylsilyl)oxy) methyl)-1H-pyrrole-2-carbonitrile (31e-3)
1H NMR (400 MHz, CDCl3):  = 7.67 (m, 4 H), 7.39 (m, 6 H), 6.73 (d, J =
4.0 Hz, 1 H), 6.14 (d, J = 4.0 Hz, 1 H), 4.63 (s, 2 H), 3.79 (t, J = 6.0 Hz,
2 H), 2.59 (t, J = 7.2 Hz, 2 H), 1.86 (m, 2 H), 1.06 (s, 9 H), 0.90 (s, 9 H),
0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 141.1, 135.5, 133.6, 129.5, 127.6,
120.2, 112.4, 108.9, 108.0, 74.5, 68.2, 62.2, 57.4, 31.4, 26.8, 25.7, 19.2,
18.2, 14.9, –5.3.
Prepared according to General Procedure B.
Pale oil isolated with some dialkyne impurity (110 mg, 49%).
IR: 2952, 2929, 2857, 2225, 1471, 1439, 1386, 1310, 1253, 1213,
1089, 1005, 833, 774 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.72 (d, J = 4.0 Hz, 1 H), 6.14 (d, J =
4.0 Hz, 1 H), 4.67 (s, 2 H), 3.65 (t, J = 6.0 Hz, 2 H), 2.46 (t, J = 6.8 Hz,
2 H), 1.68 (m, 4 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.08 (s, 6 H), 0.05 (s,
6 H).
HRMS (ESI): m/z [M + Na]+ calcd for C33H44N2O2Si2Na: 579.2834;
found: 579.2831.
13C NMR (100 MHz, CDCl3):  = 141.1, 120.2, 112.5, 108.9, 108.0, 74.7,
68.8, 62.4, 57.4, 31.8, 25.9, 25.7, 25.0, 24.7, 19.4, 18.3, –5.3, –5.3.
HRMS (ESI): m/z [M + Na]+ calcd for C24H42N2O2Si2Na: 469.2677;
1-(5-((tert-Butyldiphenylsilyl)oxy)pent-1-yn-1-yl)-5-(hydroxy-
methyl)-1H-pyrrole-2-carbonitrile (31f)
A round-bottom flask was charged with 31f-3 (with impurities from
cross-coupling), a stir bar, and a mixture of THF/H2O/TFA in a 1:1:1
ratio (3 mL). After completion, as determined by TLC, the reaction was
carefully quenched with NaHCO3, extracted with DCM (3×), and the
combined organics were rinsed with brine and dried over Na2SO4. The
solvents were removed to give the crude oil, which was further puri-
fied by flash column chromatography to give the title compound.
found: 469.2678.
1-(6-Hydroxyhex-1-yn-1-yl)-5-(hydroxymethyl)-1H-pyrrole-2-
carbonitrile (31e)
Prepared according to General Procedure C.
Yield: 69.7 mg (32% over two steps); clear oil.
IR: 3343, 2937, 2867, 2222, 1438, 1310, 1208, 1061, 1023, 789,
Yield: 50.5 mg (29% over two steps); clear oil.
752 cm–1
.
IR: 3445, 3071, 2930, 2857, 2222, 1472, 1440, 1427, 1308, 1208,
1H NMR (400 MHz, CDCl3):  = 6.72 (d, J = 4.0 Hz, 1 H), 6.17 (d, J =
4.0 Hz, 1 H), 4.61 (s, 2 H), 3.63 (t, J = 6.4 Hz, 2 H), 3.08 (br s, 2 H), 2.47
(t, J = 6.4 Hz, 2 H), 1.69 (m, 4 H).
13C NMR (100 MHz, CDCl3):  = 140.9, 120.2, 112.4, 109.6, 108.0, 74.8,
68.8, 61.9, 55.9, 31.3, 24.4, 17.9.
1106, 1026, 982, 823, 789, 701 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.67 (m, 4 H), 7.37 (m, 6 H), 6.74 (d, J =
4.0 Hz, 1 H), 6.19 (d, J = 4.0 Hz, 1 H), 4.57 (s, 2 H), 3.81 (t, J = 6.0 Hz,
2 H), 2.61 (t, J = 7.2 Hz, 2 H), 1.86 (m, 2 H), 1.85 (br s, 1 H), 1.07 (s,
9 H).
HRMS (ESI): m/z [M + Na]+ calcd for C12H14N2O2Na: 241.0947; found:
13C NMR (100 MHz, CDCl3):  = 140.6, 135.5, 133.6, 129.6, 127.6,
241.0954.
120.2, 112.2, 109.5, 108.4, 74.8, 68.5, 62.1, 56.4, 31.2, 26.8, 19.2, 14.8.
HRMS (ESI): m/z [M + Na]+ calcd for C27H30N2O2SiNa: 465.1969;
found: 465.1970.
3,4,5,6-Tetrahydro-1′H,4′H-spiro[pyran-2,3′-pyrrolo[2,1-c][1,4]-
oxazine]-6′-carbonitrile (32e)
Prepared according to General Procedure D.
3-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-1H-pyrrolo-
[2,1-c][1,4]oxazine-6-carbonitrile (32f)
Yield: 27.2 mg (62%); pale oil; Rf = 0.3 (hexanes/EtOAc, 10:1).
IR: 2945, 2870, 2210, 1436, 1380, 1317, 1279, 1188, 1160, 1077,
Prepared according to General Procedure D.
Yield: 28 mg (62%); pale oil.
1056, 1031, 942, 758 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

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B. J. Reinus, S. M. Kerwin
Paper
Synthesis
IR: 3071, 2928, 2856, 2218, 1680, 1472, 1448, 1428, 1363, 1315,
1191, 1110, 822, 738, 702 cm–1
1H NMR (400 MHz, CDCl3):  = 7.67 (m, 4 H), 7.39 (m, 6 H), 6.77 (d, J =
4.0 Hz, 1 H), 6.43 (d, J = 0.8 Hz, 1 H), 5.94 (dd, J = 4.0, 0.8 Hz, 1 H), 4.97
(d, J = 0.8 Hz, 2 H), 3.71 (t, J = 6.0 Hz, 2 H), 2.31 (td, J = 7.6, 0.8 Hz, 2 H),
1.80 (m, 2 H), 1.07 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 147.3, 135.5, 134.7, 133.6, 129.6,
127.6, 127.6, 125.9, 119.2, 112.9, 104.4, 101.6, 99.8, 63.2, 62.7, 29.6,
29.4, 27.7, 26.8, 26.5, 19.1, 18.9.
DMAP. The mixture was stirred under argon and cooled to 0 °C, sub-
sequently TBS-Cl (180 mg, 1.2 mmol) was added portionwise and the
reaction was allowed to warm to r.t. and stirred overnight. After the
reaction reached completion, the mixture was diluted with DCM (10
mL), rinsed with sat. NH4Cl (×1), H2O (×1), brine, and dried over
MgSO4. The solvents were removed and the crude oil was purified by
flash chromatography (0–50% EtOAc in hexanes) to give the product.
.
Yield: 125 mg (52% overall from 40); clear oil; Rf = 0.65 (hexanes/EtOAc,
1:1); []D +6.0 (c = 1.0, CH2Cl2).
IR: 3413, 3312, 2953, 2929, 2858, 1471, 1463, 1361, 1253, 1055, 834,
HRMS (ESI): m/z [M + H]+ calcd for C27H31N2O2Si: 443.2149; found:
443.2150.
776 cm–1
.
1H NMR (400 MHz, CDCl3):  = 3.78 (m, 3 H), 3.64 (dt, J = 6.8, 4.4 Hz,
1 H), 2.55 (m, 2 H), 2.48 (br m, 2 H), 2.05 (t, J = 2.8 Hz, 1 H), 0.90 (s,
9 H), 0.09 (s, 6 H).
3-(3-Hydroxypropyl)-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbo-
nitrile (33)
13C NMR (100 MHz, CDCl3):  = 80.3, 72.3, 71.0, 70.6, 63.8, 25.8, 23.6,
Prepared according to General Procedure C.
18.2, –5.4, –5.5.
1H NMR (400 MHz, CDCl3):  = 6.76 (d, J = 3.6 Hz, 1 H), 6.49 (d, J =
0.8 Hz, 1 H), 5.95 (dd, J = 3.6, 0.8 Hz, 1 H), 5.05 (s, 2 H), 3.71 (t, J =
6.4 Hz, 2 H), 2.31 (td, J = 7.2, 0.8 Hz, 2 H), 1.82 (m, 2 H), 1.59 (br s,
1 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H24O3Si: 245.1567; found:
245.1570.
(4R,5S)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(prop-2-yn-1-
yl)-1,3-dioxolan-2-one (38-1)
4,5-Dihydro-1′H,3H,4′H-spiro[furan-2,3′-pyrrolo[2,1-c][1,4]-
oxazine]-6′-carbonitrile (34)
A solution of DCM (30 mL) and triphosgene (1.42 g, 4.77 mmol) was
cooled to –10 °C, after which pyridine (1.6 mL, 19.1 mmol), and
DMAP (one crystal) were added. Compound 41 (1.11 g, 4.54 mmol) in
DCM (30 mL) was added dropwise and the resulting mixture was
stirred for 2 h at r.t. The mixture was then diluted with DCM (30 mL)
and washed with sat. NH4Cl (×1), sat. NaHCO3 (×1), brine (×1), and
dried over Na2SO4. The solvent was then removed and the crude com-
pound was purified by column chromatography (0–50% EtOAc in hex-
anes) to give the product.
Prepared according to General Procedure C (note: spontaneously cy-
clized in CDCl3).
Yield: 7.6 mg (27%); oily solid.
IR: 3121, 2956, 2891, 2211, 1486, 1430, 1398, 1307, 1258, 1189,
1163, 1100, 1050, 1018, 899, 762 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.79 (d, J = 3.2 Hz, 1 H), 5.90 (d, J =
3.2 Hz, 1 H), 4.87 (d, J = 12 Hz, 1 H), 4.73 (d, J = 12 Hz, 1 H), 4.14 (d, J =
10 Hz, 1 H), 4.08 (d, J = 10 Hz, 1 H), 4.04 (m, 2 H), 2.19 (m, 2 H), 2.04
(m, 1 H), 1.93 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 131.2, 119.8, 113.6, 103.4, 103.0,
101.9, 68.7, 58.1, 49.2, 35.7, 23.3.
Yield: 730 mg (59%); off-white solid; mp 52 °C; Rf = 0.45 (hexanes/
EtOAc, 2:1); []D +39.7 (c = 1.0, DCM).
IR: 3295, 2930, 2858, 1798, 1471, 1365, 1255, 1172, 1146, 1074,
1003, 836, 770 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H13N2O2: 205.0972; found:
205.0976.
1H NMR (400 MHz, CDCl3):  = 4.85 (m, 1 H), 4.69 (m, 1 H), 4.06 (dd,
J = 12, 2.0 Hz, 1 H), 3.97 (dd, J = 12, 3.6 Hz, 1 H), 2.97 (ddd, J = 17, 8.4,
2.8 Hz, 1 H), 2.86 (ddd, J = 17, 5.6, 2.8 Hz, 1 H), 2.09 (t, J = 2.8 Hz, 1 H),
0.89 (s, 9 H), 0.10 (s, 6 H).
Preparation of Scheme 6 Substrates
13C NMR (100 MHz, CDCl3):  = 153.9, 77.8, 77.5, 76.1, 71.9, 60.3, 25.6,
19.0, 17.9, –5.7, –5.7.
HRMS (ESI): m/z [M + Na]+ calcd for C13H22O4SiNa: 293.1180; found:
293.1182.
(S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)but-3-yn-1-ol (40)
Prepared according to a reported procedure30 using commercially
available 39.
Yield: 1.88 g (31%); clear oil; []D +6.5 (c = 1.08, DCM).
IR: 3285, 2921, 1708, 1420, 1194, 1063, 1037, 860 cm–1
.
(4S,5R)-4-(3-Bromoprop-2-yn-1-yl)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)-1,3-dioxolan-2-one (38)
1H NMR (400 MHz, CDCl3):  = 4.07 (m, 2 H), 3.96 (m, 1 H), 3.76 (m,
1 H), 2.57–2.41 (m, 2 H), 2.23 (br s, 1 H), 2.06 (t, J = 2.8 Hz, 1 H), 1.40
(s, 3 H), 1.34 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 109.3, 79.8, 77.2, 71.2, 70.0, 65.8, 26.6,
25.1, 23.5.
Prepared according to General Procedure A.
Yield: 625 mg (66%); white solid; mp 68 °C; Rf = 0.45 (hexanes/EtOAc,
2:1); []D +45.0 (c = 1.0, CHCl3).
IR: 3491, 2954, 2858, 1797, 1471, 1176, 1074, 838, 770 cm–1
.
HRMS (CI): m/z [M + H]+ calcd for C9H15O3: 171.1021; found:
171.1024.
1H NMR (400 MHz, CDCl3):  = 4.83 (m, 1 H), 4.68 (m, 1 H), 4.00 (dd,
J = 12, 2.0 Hz, 1 H), 3.94 (dd, J = 12, 3.6 Hz, 1 H), 2.97 (dd, J = 16.8,
8.4 Hz, 1 H), 2.88 (dd, J = 16.8, 5.6 Hz, 1 H), 0.88 (s, 9 H), 0.09 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 153.8, 77.7, 75.9, 73.5, 60.3, 42.3, 25.5,
(2R,3S)-1-((tert-Butyldimethylsilyl)oxy)hex-5-yne-2,3-diol (41)
A round-bottom flask was charged with a stir bar, 40 (172 mg, 1.0
mmol), THF (2.0 mL), H2O (2.0 mL), and TFA (2.0 mL) and the reaction
was stirred overnight. All solvents were then removed and the crude
product was purified by column chromatography (DCM/EtOH, 10:1).
To the triol was added DCM (3.6 mL), TEA (0.3 mL), and a crystal of
20.2, 17.9, –5.7.
HRMS (ESI): m/z [M + Na]+ calcd for C13H21BrO4SiNa: 371.0285; found:
371.0286.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

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B. J. Reinus, S. M. Kerwin
Paper
Synthesis
(S,E)-1-(6-((tert-Butyldimethylsilyl)oxy)-5-hydroxyhex-3-en-1-yn-
1-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrrole-2-car-
bonitrile (42)
1H NMR (400 MHz, CDCl3):  = 7.02 (dt, J = 15.6, 7.2 Hz, 1 H), 5.91 (dt,
J = 15.6, 1.6 Hz, 1 H), 4.25 (m, 1 H), 4.12 (q, J = 6.0 Hz, 1 H), 3.72 (s,
3 H), 3.65 (m, 2 H), 2.50 (m, 2 H), 1.41 (s, 3 H), 1.33 (s, 3 H), 0.87 (s,
9 H), 0.06 (s, 3 H), 0.05 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 166.7, 145.8, 122.7, 108.2, 77.3, 75.9,
61.5, 51.4, 32.3, 28.0, 25.7, 25.4, 18.1, –5.4, –5.5.
Prepared according to General Procedure B.
Yield: 7.7 mg (8%); pale oil; Rf = 0.5 (hexanes/EtOAc, 2:1); []D +3.0 (c
= 0.08, DCM).
HRMS (ESI): m/z [M + H]+ calcd for C17H33O5Si: 345.2092; found:
345.2098.
IR: 3499, 2929, 2857, 2225, 1811, 1438, 1255, 1109, 1005, 956, 837,
778 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.77 (d, J = 4.0 Hz, 1 H), 6.22 (dd, J = 16,
5.2 Hz, 1 H), 6.18 (d, J = 4.0 Hz, 1 H), 6.02 (dd, J = 16, 1.6 Hz, 1 H), 4.68
(s, 2 H), 4.29 (m, 1 H), 3.71 (dd, J = 10, 4.0 Hz, 1 H), 3.47 (dd, J = 10,
7.6 Hz, 1 H), 2.64 (d, J = 4.0 Hz, 1 H), 0.91 (s, 9 H), 0.90 (s, 9 H), 0.09 (s,
6 H), 0.08 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 142.6, 141.3, 120.9, 112.2, 109.5,
109.0, 108.1, 77.5, 72.6, 72.0, 66.4, 57.3, 25.8, 25.7, 18.2, –5.3, –5.3.
2-((4S,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)acetaldehyde (45)
To a round-bottom flask was added a stir bar, 44 (9.45 g, 27.4 mmol),
and DCM (150 mL) and the mixture was then cooled to –78 °C. Subse-
quently, O3 was bubbled through the solution until the solvent turned
blue (ca. 1.5 h), indicating reaction completeness. O2 was then bub-
bled through until the solution returned to clear and then the mixture
was charged with PPh3 (8.26 g, 31.5 mmol). The reaction was allowed
to warm to r.t. and stirred overnight. The following day the solvent
was removed and the residue was purified by flash column chroma-
tography to yield the aldehyde.
HRMS (ESI): m/z [M + Na]+ calcd for C24H40N2O3Si2Na: 483.2470;
found: 483.2468.
Preparation of Scheme 7 Substrates
Yield: 7.38 g (93%); clear oil; []D –10.5 (c = 1.11, DCM).
Methyl (5S,6R,E)-7-((tert-Butyldimethylsilyl)oxy)-5,6-dihydroxy-
hept-2-enoate (44-1)
IR: 2859, 1731, 1223, 1095, 838, 776, 670 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.78 (t, J = 1.6 Hz, 1 H), 4.69 (dt, J = 8.0,
6.0 Hz, 1 H), 4.16 (dt, J = 8.0, 5.6 Hz, 1 H), 3.59 (m, 2 H), 2.85 (ddd, J =
17.2, 6.0, 1.2 Hz, 1 H), 2.74 (ddd, J = 17.2, 8.0, 2.0 Hz, 1 H), 1.40 (s,
3 H), 1.34 (s, 3 H), 0.86 (s, 9 H), 0.04 (s, 3 H), 0.04 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 200.0, 108.2, 71.9, 61.4, 43.6, 27.8,
25.8, 25.3, 18.1, –5.4, –5.5.
To deoxyribopyranose (10.6 g, 80 mmol) in THF (200 mL) was added
methyl (triphenylphosphoranylidene)acetate (32.5 g, 96 mmol). The
reaction was heated to reflux until completion, then the mixture was
cooled and the solvent was removed. The crude residue was then tak-
en up in DCM (5 mL) and cooled in an ice bath. To the cooled solution
was added TEA (16.7 mL, 120 mmol), DMAP (one scoop), and TBS-Cl
(7.2 g, 48 mmol). The reaction was allowed to warm to r.t. and stirred
overnight. The following day the solvents were removed and the resi-
due was purified by column chromatography (0–50% EtOAc in hex-
anes) to yield the product.
HRMS (ESI): m/z [M + Na]+ calcd for C14H28O4SiNa: 311.1649; found:
311.1650.
tert-Butyl(((4R,5S)-5-(3,3-dibromoallyl)-2,2-dimethyl-1,3-dioxol-
Yield: 9.75 g (80%); clear oil; Rf = 0.1 (hexanes/EtOAc, 4:1); []D –4.9 (c
an-4-yl)methoxy) dimethylsilane (46-1)
= 1.0, DCM).
A round-bottom flask was charged with a stir bar, DCM (10 mL), CBr4
(3.3 g, 10 mmol), and cooled in an ice bath. Subsequently PPh3 (5.2 g,
20 mmol) was added and the solution was allowed to warm to r.t. Al-
dehyde 45 (1.43 g, 4.9 mmol) in CH2Cl2 (15 mL) was added dropwise
and the reaction was allowed to continue to stir until complete (10
min). Following reaction completion, the reaction was diluted with
petroleum ether and the solvents were removed. The crude material
was again taken up in petroleum ether and filtered. Following filtra-
tion, the solvent was again removed and the residue was purified by
column chromatography (short column; 0–10% EtOAc in hexanes) to
give the dibromide.
IR: 3387, 2924, 1704, 1657, 1438, 1275, 1215, 1170, 1066, 1036, 985,
877, 822 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.02 (dt, J = 15.6, 7.6 Hz, 1 H), 5.94 (d,
J = 15.6 Hz, 1 H), 3.81 (m, 1 H), 3.77 (d, J = 4.8 Hz, 2 H), 3.73 (s, 3 H),
3.55 (q, J = 4.8 Hz, 1 H), 2.54 (m, 1 H), 2.41 (m, 1 H), 2.22 (br s, 2 H),
0.90 (s, 9 H), 0.09 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 166.7, 145.3, 123.5, 72.8, 71.7, 63.9,
51.5, 36.1, 25.8, 18.1, –5.4, –5.5.
Methyl (E)-4-((4S,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (44)
Yield: 1.93 g (88%); []D –33.2 (c = 0.98, CH2Cl2).
IR: 3463, 2953, 2929, 2857, 1471, 1380, 1251, 1217, 1068, 835, 775,
A round-bottom flask was charged with a stir bar, 44-1 (9.75 g, 32
mmol), acetone (100 mL), 2,2-dimethoxypropane (15 mL, 120 mmol),
and PPTS (2.0 g). The reaction was allowed to stir until completion as
determined by TLC (generally 4–6 h). Following completion, a small
amount of Na2CO3 was added and the solvent was removed. The crude
compound was then purified by flash column chromatography (0–
15% EtOAc in hexanes) to give the product.
667 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.55 (dd, J = 7.2, 6.4 Hz, 1 H), 4.20 (m,
1 H), 4.12 (dt, J = 7.6, 5.6 Hz, 1 H), 3.65 (m, 2 H), 2.47 (ddd, J = 15.2,
7.2, 4.4 Hz, 1 H), 2.34 (ddd, J = 15.2, 9.2, 6.4 Hz, 1 H), 1.41 (s, 3 H), 1.33
(s, 3 H), 0.88 (s, 9 H), 0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 135.4, 108.2, 90.0, 77.2, 75.4, 61.3,
33.6, 28.0, 25.8, 25.4, 18.1, –5.4.
HRMS (ESI): m/z [M + Na]+ calcd for C15H28Br2O3SiNa: 465.0067;
Yield: 9.45 g (86%); clear oil; Rf = 0.45 (hexanes/EtOAc, 6:1); []D –40.9
(c = 0.98, DCM).
found: 465.0072.
IR: 2987, 2952, 2930, 2858, 1726, 1660, 1436, 1380, 1322, 1251,
1216, 1166, 1087, 835, 775, 666 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

Q
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
tert-Butyl(((4R,5S)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolan-
4-yl)methoxy)dimethylsilane (46-2)
5-(Hydroxymethyl)-1-(3-((4S,5R)-5-(hydroxymethyl)-2,2-dimeth-
yl-1,3-dioxolan-4-yl)prop-1-yn-1-yl)-1H-pyrrole-2-carbonitrile
(48)
To an oven-dried round-bottom flask cooled under argon was added a
stir bar, 46-1 (1.93 g, 4.34 mmol), THF (22 mL), and then subsequently
the mixture was cooled to –78 °C. Once thoroughly cooled, n-BuLi
(8.15 mL, 13 mmol) was added dropwise down the side of the flask
and then the mixture was stirred for 3 h. After reaction completion,
the mixture was quenched with sat. NH4Cl and extracted with EtOAc.
The combined organics were washed with brine and dried over
Na2SO4. Removal of the solvent gave an oil, which was purified by col-
umn chromatography (0–15% EtOAc in hexanes) to give the alkyne.
A round-bottom flask was charged with 47 (195 mg, 0.37 mmol) a stir
bar, and a mixture of THF/H2O/TFA in a 10:1:1 ratio (1.2 mL). After
completion, as determined by TLC, the reaction was carefully
quenched with NaHCO3 extracted with EtOAc (3×), and the combined
organics were dried over MgSO4. The solvents were removed to give
the crude oil, which was further purified by flash column chromatog-
raphy (50–100% EtOAc in hexanes) to give the title compound.
Yield: 105 mg (98%); Rf = 0.3 (EtOAc); clear oil; []D –16.8 (c = 0.63,
Yield: 1.14 g (92%); clear oil; Rf = 0.55 (hexanes/EtOAc, 5:1); []D –16.7
CH2Cl2).
(c = 0.98, DCM).
IR: 3446, 2939, 2222, 1439, 1381, 1211, 1071, 793 cm–1
.
IR: 3314, 2929, 2857, 1463, 1380, 1251, 1216, 1075, 833, 776 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.73 (d, J = 4.0 Hz, 1 H), 6.19 (d, J =
4.0 Hz, 1 H), 4.67 (d, J = 14 Hz, 1 H), 4.62 (d, J = 14 Hz, 1 H), 4.45 (q, J =
6.7 Hz, 1 H), 4.32 (q, J = 5.6 Hz, 1 H), 3.88 (dd, J = 11.6, 4.8 Hz, 1 H),
3.83 (dd, J = 11.6, 5.6 Hz, 1 H), 2.83 (dd, J = 16.8, 7.2 Hz, 1 H), 2.74 (dd,
J = 16.8, 6.8 Hz, 1 H), 1.81 (br s, 2 H), 1.51 (s, 3 H), 1.39 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 4.33 (dt, J = 8.0, 5.6 Hz, 1 H), 4.16 (q, J =
6.1 Hz, 1 H), 3.72 (m, 2 H), 2.59 (ddd, J = 16.8, 5.6, 2.8 Hz, 1 H), 2.48
(ddd, J = 16.8, 8.0, 2.8 Hz, 1 H), 2.02 (t, J = 2.8 Hz, 1 H), 1.46 (s, 3 H),
1.36 (s, 3 H), 0.89 (s, 9 H), 0.06 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 108.5, 81.1, 75.6, 69.6, 61.5, 27.8, 25.8,
13C NMR (100 MHz, CDCl3):  = 141.4, 120.3, 112.2, 110.1, 108.9,
25.3, 20.0, 18.2, –5.4, –5.4.
108.1, 75.3, 71.6, 70.3, 60.9, 56.1, 27.7, 25.2, 20.4.
HRMS (ESI): m/z [M + Na]+ calcd for C15H28O3SiNa: 307.1700; found:
HRMS (ESI): m/z [M + Na]+ calcd for C15H18N2O4Na: 313.1159; found:
307.1705.
313.1162.
(((4R,5S)-5-(3-Bromoprop-2-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-
4-yl)methoxy)(tert-butyl)dimethylsilane (46)
(5S)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4,5-dihydro-1′H,3H-
spiro[furan-2,3′-pyrrolo[1,2-c]oxazole]-5′-carbonitrile (50)
Prepared according to General Procedure A.
Prepared according to General Procedure D.
Yield: 1.34 g (91%); pale-yellow oil; []D –2.9 (c = 1.01, DCM).
IR: 2930, 2884, 2857, 1471, 1463, 1380, 1370, 1251, 1215, 1075,
Yield: 24.1 mg (22%); oily white solid; []D +6.3 (c = 0.22, DCM).
IR: 3267, 2987, 2936, 2218, 1774, 1457, 1373, 1263, 1183, 1057, 998,
1005, 836, 776, 667 cm–1
.
843, 794, 671 cm–1
.
1H NMR (400 MHz, CDCl3):  = 4.28 (dt, J = 7.2, 6.0 Hz, 1 H), 4.13 (dt,
J = 7.2, 5.6 Hz, 1 H), 3.72 (dd, J = 10.8, 7.2 Hz, 1 H), 3.68 (dd, J = 10.8,
5.6 Hz, 1 H), 2.60 (dd, J = 16.8, 6.0 Hz, 1 H), 2.48 (dd, J = 16.8, 7.2 Hz,
1 H), 1.42 (s, 3 H), 1.33 (s, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 108.5, 77.2, 76.8, 75.3, 61.4, 39.5, 27.7,
25.8, 25.3, 21.1, 18.1, –5.4, –5.5.
1H NMR (400 MHz, CDCl3):  = 6.93 (d, J = 3.2 Hz, 1 H), 5.88 (m, 1 H),
5.03 (m, 1 H), 4.88 (m, 1 H), 4.34 (m, 0.5 H), 4.22 (m, 0.5 H), 4.18–4.05
(m, 2 H), 3.87 (m, 1 H), 2.84–2.75 (m, 1 H), 2.54–2.26 (m, 3 H), 2.22–
2.12 (m, 0.5 H), 1.42 (s, 1.5 H), 1.41 (s, 1.5 H), 1.35 (s, 1.5 H), 1.35 (s,
1.5 H).
13C NMR (100 MHz, CDCl3):  = 138.7, 138.3, 126.7, 126.6, 118.8,
118.6, 112.8, 112.7, 109.6, 109.5, 99.6, 99.5, 94.9, 94.9, 81.6, 80.8,
77.5, 76.5, 67.2, 65.6, 65.4, 35.1, 34.0, 27.5, 27.2, 26.7, 26.6, 25.2, 25.1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H27BrO3SiNa: 385.0805; found:
385.0812.
HRMS (ESI): m/z [M + Na]+ calcd for C15H18N2O4Na: 313.1159; found:
313.1173.
5-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(3-((4S,5R)-5-(((tert-
butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)prop-1-yn-1-yl)-1H-pyrrole-2-carbonitrile (47)
Preparation of Shensongine A
Prepared according to General Procedure B.
(1S,2S)-1,2-Bis((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol
(39-1)
Prepared according to a reported procedure from D-mannitol.31
1H NMR (400 MHz, CDCl3):  = 4.10 (m, 4 H), 3.96 (m, 2 H), 3.71 (m,
Yield: 74.5 mg (37%); clear oil; Rf = 0.75 (hexanes/EtOAc, 2:1); []D
–6.4 (c = 0.67, DCM).
IR: 2953, 2930, 2857, 2224, 1471, 1440, 1379, 1253, 1214, 1077,
1005, 836, 777 cm–1
.
2 H), 2.85 (br s, 2 H), 1.39 (s, 6 H), 1.33 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 109.3, 76.0, 71.0, 66.6, 26.6, 25.1.
1H NMR (400 MHz, CDCl3):  = 6.73 (d, J = 4.0 Hz, 1 H), 6.14 (d, J =
4.0 Hz, 1 H), 4.69 (s, 2 H), 4.39 (dt, J = 8.4, 5.6 Hz, 1 H), 4.19 (q, J =
6.0 Hz, 1 H), 3.76 (d, J = 6.0 Hz, 2 H), 2.85 (dd, J = 16.8, 5.2 Hz, 1 H),
2.72 (dd, J = 16.8, 8.0 Hz, 1 H), 1.46 (s, 3 H), 1.36 (s, 3 H), 0.90 (s, 9 H),
0.88 (s, 9 H), 0.08 (s, 6 H), 0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 141.4, 120.4, 112.3, 108.9, 108.5,
107.9, 77.2, 75.5, 71.8, 69.6, 61.4, 57.4, 27.8, 25.8, 25.7, 25.3, 19.9,
18.2, 18.1, –5.3, –5.4.
(R)-2,2-Dimethyl-1,3-dioxolane-4-carbaldehyde (39)
Prepared according to a reported procedure.31
1H NMR (400 MHz, CDCl3):  = 9.71 (d, J = 2.0 Hz, 1 H), 4.37 (ddd, J =
7.2, 4.4, 2.0 Hz, 1 H), 4.16 (dd, J = 8.8, 7.2 Hz, 1 H), 4.09 (dd, J = 8.8,
4.8 Hz, 1 H), 1.48 (d, J = 0.8 Hz, 3 H), 1.41 (d, J = 0.8 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C27H46N2O4Si2Na: 541.2888;
found: 541.2887.
13C NMR (100 MHz, CDCl3):  = 201.7, 111.2, 79.8, 65.5, 26.2, 25.1.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

R
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
(S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)but-3-yn-1-ol (40)
Prepared according to a reported procedure, with freshly made 39.30
Yield: 35.13 g (56%).
The combined organics were then washed with water (×2), brine (×1),
and dried over Na2SO4. Removal of the solvent and purification by col-
umn chromatography gave the title compound.
Yield: 4.73 g (92%; two steps); clear oil; Rf = 0.55 (hexanes/EtOAc,
6:1); []D +32.2 (c = 1.04, DCM).
Data matches our previous samples and reported data.30
IR: 3469, 3312, 2942, 2866, 1462, 1384, 1366, 1247, 1207, 1090,
(R)-4-((S)-1-(Benzyloxy)but-3-yn-1-yl)-2,2-dimethyl-1,3-dioxol-
ane (51)
1064, 1013, 995, 881, 792, 735, 679 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.38–7.25 (m, 5 H), 4.78 (d, J = 11.2 Hz,
1 H), 4.54 (d, J = 11.2 Hz, 1 H), 3.87 (m, 1 H), 3.76 (m, 2 H), 3.58 (m,
1 H), 2.71 (ddd, J = 17.2, 4.4, 2.8 Hz, 1 H), 2.59 (ddd, J = 17.2, 5.2,
2.8 Hz, 1 H), 2.09 (br s, 1 H), 2.03 (t, J = 2.8 Hz, 1 H), 2.05 (m, 21 H).
13C NMR (100 MHz, CDCl3):  = 137.9, 128.3, 127.9, 127.7, 81.1, 76.9,
72.2, 72.0, 69.9, 63.8, 20.4, 17.9, 11.8.
An oven-dried round-bottom flask was cooled under argon and
charged with a stir bar, 40 (3.4 g, 20 mmol), and freshly distilled THF
(80 mL), and cooled in an ice bath. Once sufficiently cool, NaH (960
mg, 24 mmol) was added in one portion. After 30 min, BnBr (2.87 mL,
24 mmol), and TBAI (370 mg, 1.0 mmol) were added and the reaction
was allowed to warm to r.t. and stirred at 50 °C overnight. The reac-
tion was then quenched with NH4Cl, extracted with EtOAc (×3), and
the combined organics were then rinsed with brine and dried over
Na2SO4. Removing the solvent and purification of the crude material
by column chromatography (0–50% EtOAc in hexanes) gave the title
compound.
HRMS (ESI): m/z [M + Na]+ calcd for C22H36O3SiNa: 399.2326; found:
399.2334.
(((2R,3S)-2,3-Bis(benzyloxy)hex-5-yn-1-yl)oxy)triisopropylsilane
(53)
Yield: 3.54 g (68%); clear oil; []D +43.7 (c = 1.11, DCM).
An oven-dried round-bottom flask was cooled under argon and
charged with a stir bar, 52 (2.72 g, 7.2 mmol), THF (40 mL), and then
cooled to 0 °C. After adequate cooling, NaH (347 mg, 8.6 mmol) was
carefully added in portions and, after 5 min, the reaction was allowed
to warm to r.t. and stirring was continued for an additional 30 min.
Subsequently, the reaction was cooled to 0 °C and BnBr (1.2 mL, 10.1
mmol) was added. The reaction was then allowed to warm to r.t. and
stirred overnight. The reaction was then quenched with sat. NH4Cl
and the mixture was extracted with EtOAc (×3). The combined organ-
ics were washed with brine and dried over Na2SO4, removal of the sol-
vents and purification by column chromatography (0–25% EtOAc in
hexanes) gave the title compound.
IR: 3290, 2882, 1959, 1454, 1380, 1272, 1212, 1073, 1027, 860, 741,
698 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.39–7.26 (m, 5 H), 4.79 (d, J = 11.2 Hz,
1 H), 4.59 (d, J = 11.2 Hz, 1 H), 4.20 (dd, J = 12.4, 6.8 Hz, 1 H), 4.07 (dd,
J = 8.4, 6.4 Hz, 1 H), 3.90 (dd, J = 8.4, 5.6 Hz, 1 H), 3.56 (dt, J = 7.2,
4.8 Hz, 1 H), 2.64 (ddd, J = 17.2, 4.8, 2.8 Hz, 1 H), 2.52 (ddd, J = 17.2,
5.2, 2.8 Hz, 1 H), 2.04 (t, J = 2.8 Hz, 1 H), 1.40 (s, 3 H), 1.35 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 137.8, 128.3, 127.9, 127.8, 109.2, 80.4,
77.4, 76.3, 72.3, 70.3, 66.6, 26.7, 25.2, 20.9.
(2R,3S)-3-(Benzyloxy)hex-5-yne-1,2-diol (52-1)
Yield: 2.36 g (70%); clear oil; []D –2.2 (c = 1.0, DCM).
A round-bottom flask was charged with a stir bar, 51 (3.54 g, 13.6
mmol), MeOH (50 mL), and 1N HCl (10 mL) and allowed to stir until
completion (TLC). Following reaction completion, K2CO3 (1.9 g) was
added and the mixture was stirred for 10 min. Solvents were removed
and then the diol was taken up in water and extracted back out with
DCM (×3), the combined organics were rinsed with brine (×1), and
dried over MgSO4. Removing the solvents gave the desired diol, which
was used without further purification.
IR: 3310, 3031, 2944, 2866, 2130, 1495, 1457, 1386, 1270, 1205,
1095, 1069, 1029, 882, 745, 695 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.39–7.25 (m, 10 H), 4.80 (d, J =
11.2 Hz, 1 H), 4.73 (d, J = 11.6 Hz, 1 H), 4.65 (d, J = 11.2 Hz, 1 H), 4.58
(d, J = 11.6 Hz, 1 H), 3.95 (dd, J = 10.6, 4.0 Hz, 1 H), 3.81 (dd, J = 10.6,
5.6 Hz, 1 H), 3.75 (q, J = 5.6 Hz, 1 H), 3.70 (m, 1 H), 2.60 (m, 2 H), 1.98
(t, J = 2.8 Hz, 1 H), 1.05 (m, 21 H).
[]D +47.5 (c = 1.48, DCM).
13C NMR (100 MHz, CDCl3):  = 138.5, 138.2, 128.2, 128.2, 127.9,
127.9, 127.6, 127.5, 81.5, 80.5, 73.2, 72.3, 69.8, 63.2, 20.4, 18.0, 11.8.
HRMS (ESI): m/z [M + Na]+ calcd for C29H42O3SiNa: 489.2795; found:
IR: 3291, 2921, 1956, 1453, 1344, 1271, 1209, 1070, 859, 739, 713,
698 cm–1
.
489.2791.
1H NMR (400 MHz, CDCl3):  = 7.39–7.26 (m, 5 H), 4.74 (d, J = 11.2 Hz,
1 H), 4.53 (d, J = 11.2 Hz, 1 H), 3.83 (m, 1 H), 3.75 (dd, J = 11.6, 3.6 Hz,
1 H), 3.70 (dd, J = 11.6, 5.6 Hz, 1 H), 3.63 (q, J = 5.6 Hz, 1 H), 2.73 (br s,
2 H), 2.58 (dd, J = 5.6, 2.8 Hz, 2 H), 2.04 (t, J = 2.8 Hz, 1 H).
(((2R,3S)-2,3-Bis(benzyloxy)-6-bromohex-5-yn-1-yl)oxy)triiso-
propylsilane (54)
13C NMR (100 MHz, CDCl3):  = 137.5, 128.4, 127.9, 80.4, 77.9, 72.3,
Prepared according to General Procedure A.
721, 70.5, 63.1, 20.3.
Yield: 2.45 g (89%); []D –15.5 (c = 1.1, DCM).
HRMS (ESI): m/z [M + Na]+ calcd for C13H16O3Na: 243.0992; found:
243.0984.
IR: 3065, 3032, 2943, 2867, 1454, 1268, 1094, 1068, 1026, 882, 782,
735, 695 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.41–7.26 (m, 10 H), 4.79 (d, J =
11.6 Hz, 1 H), 4.70 (d, J = 11.6 Hz, 1 H), 4.64 (d, J = 11.6 Hz, 1 H), 4.58
(d, J = 11.6 Hz, 1 H), 3.95 (dd, J = 10.8, 4.0 Hz, 1 H), 3.83 (dd, J = 10.8,
5.6 Hz, 1 H), 3.76 (m, 1 H), 3.68 (m, 1 H), 2.65 (dd, J = 17.2, 4.8 Hz,
1 H), 2.60 (dd, J = 17.2, 5.6, 1 H), 1.08 (m, 21 H).
13C NMR (100 MHz, CDCl3):  = 138.3, 138.0, 128.3, 128.2, 128.0,
127.9, 127.6, 127.5, 80.3, 77.5, 76.6, 73.1, 72.3, 63.0, 39.1, 21.6, 18.0,
11.8.
(2R,3S)-3-(Benzyloxy)-1-((triisopropylsilyl)oxy)hex-5-yn-2-ol (52)
A round-bottom flask was charged with a stir bar, 52-1 (crude from
previous step), DMF (50 mL), imidazole (3.7 g, 54 mmol), and cooled
to 0 °C. TIPS-Cl (3.1 mL, 13.6 mmol), was then added dropwise and
the reaction was warmed to r.t. and stirred overnight. The reaction
was then diluted with NH4Cl (200 mL) and extracted with Et2O (×3).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

S
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C29H42BrO3Si: 545.2081; found:
545.2092.
1H NMR (400 MHz, CDCl3):  = 7.41–7.21 (m, 10 H), 6.74 (d, J = 4.0 Hz,
1 H), 6.15 (dd, J = 4.0, 0.8 Hz, 1 H), 4.81 (d, J = 11.6 Hz, 1 H), 4.77 (d, J =
11.6 Hz, 1 H), 4.69 (d, J = 11.6 Hz, 1 H), 4.64 (s, 2 H), 4.63 (d, J =
11.6 Hz, 1 H), 4.00 (dd, J = 10.8, 4.0 Hz, 1 H), 3.87 (m, 2 H), 3.73 (m,
1 H), 2.84 (m, 2 H), 1.08 (m, 21 H), 0.89 (s, 9 H), 0.05 (s, 6 H).
(((2R,3S)-2,3-Bis(benzyloxy)-6-chlorohex-5-yn-1-yl)oxy)triiso-
propylsilane (54-1)
13C NMR (100 MHz, CDCl3):  = 141.5, 138.5, 138.2, 128.2, 128.2,
127.9, 127.8, 127.5, 127.5, 120.3, 112.5, 108.7, 107.8, 80.5, 76.9, 73.1,
72.5, 72.3, 69.5, 63.0, 57.6, 25.7, 20.4, 18.2, 18.0, 11.9, –5.3.
HRMS (ESI): m/z [M + H]+ calcd for C41H60N2O4Si2Na: 701.4164; found:
701.4179.
To an oven-dried round-bottom flask was added a stir bar, 53 (233.4
mg, 0.5 mmol) and freshly distilled THF (2.0 mL). The mixture was
cooled to –10 °C and n-BuLi (0.6 mmol) was added dropwise. The re-
action was then allowed to come to 0 °C and stirred for 45 min, after
which NCS (106 mg, 0.8 mmol) was added in one portion. The reac-
tion was then allowed to come to r.t. and stirred for an additional 1.5
h. After reaction completion, the mixture was quenched with sat.
NH4Cl, extracted with EtOAc (×3), washed with brine, and dried over
Na2SO4. The solvents were removed and the residue was purified by
column chromatography (0–10% EtOAc in hexanes) to give the title
compound.
1-((4S,5R)-4,5-Bis(benzyloxy)-6-hydroxyhex-1-yn-1-yl)-5-
(hydroxymethyl)-1H-pyrrole-2-carbonitrile (56)
Prepared according to General Procedure C.
Yield: 139.8 mg (93%); clear oil; []D +7.1 (c = 1.01, DCM).
IR: 3420, 3030, 2875, 2222, 1439, 1319, 1208, 1094, 1024, 791, 747,
Yield: 117.3 mg (47%); clear oil; Rf = 0.4 (hexanes/EtOAc, 15:1); []D
–17.3 (c = 0.62, DCM).
698 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.39–7.24 (m, 10 H), 6.72 (d, J = 4.0 Hz,
1 H), 6.15 (d, J = 4.0 Hz, 1 H), 4.72 (d, J = 11.2 Hz, 1 H), 4.69 (d, J =
11.6 Hz, 1 H), 4.64 (d, J = 11.6 Hz, 1 H), 4.62 (d, J = 11.2 Hz, 1 H), 4.50
(d, J = 13.6 Hz, 1 H), 4.45 (d, J = 13.6 Hz, 1 H), 3.93–3.78 (m, 3 H), 3.73
(m, 1 H), 2.88 (dd, J = 17.2, 4.8 Hz, 1 H), 2.83 (dd, J = 17.2, 4.0 Hz, 1 H),
2.36 (br s, 2 H).
13C NMR (100 MHz, CDCl3):  = 141.2, 137.5, 137.2, 128.5, 128.4,
128.1, 128.0, 127.9, 120.2, 112.3, 109.8, 107.9, 79.1, 76.1, 72.5, 72.3,
71.4, 70.3, 60.5, 56.0, 20.2.
IR: 3055, 3022, 2943, 2866, 1455, 1270, 1098, 1067, 882, 784, 734,
696 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.40–7.25 (m, 10 H), 4.79 (d, J =
11.6 Hz, 1 H), 4.68 (d, J = 11.6 Hz, 1 H), 4.63 (d, J = 11.6 Hz, 1 H), 4.57
(d, J = 11.6 Hz, 1 H), 3.94 (dd, J = 10.8, 4.0 Hz, 1 H), 3.83 (dd, J = 10.8,
5.2 Hz, 1 H), 3.74 (q, J = 5.6 Hz, 1 H), 3.66 (m, 1 H), 2.59 (m, 2 H), 1.07
(m, 21 H).
13C NMR (100 MHz, CDCl3):  = 138.4, 138.1, 128.3, 128.2, 128.0,
127.9, 127.6, 127.5, 80.3, 73.1, 72.3, 66.9, 63.0, 58.3, 20.7, 18.0, 11.8.
HRMS (ESI): m/z [M + Na]+ calcd for C26H26N2O4: 453.1785; found:
453.1789.
HRMS (ESI): m/z [M + Na]+ calcd for C29H41ClO3SiNa: 523.2406; found:
523.2397.
(2S,4S,5R)-4,5-Bis(benzyloxy)-3,4,5,6-tetrahydro-1′H,4′H-
spiro[pyran-2,3′-pyrrolo[2,1-c][1,4]oxazine]-6′-carbonitrile (57)
(((2R,3S)-2,3-Bis(benzyloxy)-6-iodohex-5-yn-1-yl)oxy)triiso-
propylsilane (54-2)
Prepared according to General Procedure D.
By following the procedure described for 54-1 (using I2 in place of
Yield: 84.2 mg (60%); pale oil; []D –117.5 (c = 0.56, DCM).
NCS) the title compound was isolated.
IR: 3031, 2922, 2215, 1453, 1374, 1166, 1183, 1050, 742, 695 cm–1
.
Yield: 174.1 mg (59%); clear oil; Rf = 0.45 (hexanes/toluene, 1:1); []D
–19.4 (c = 1.08, CH2Cl2).
1H NMR (400 MHz, CDCl3):  = 7.44–7.26 (m, 10 H), 6.79 (d, J = 4.0 Hz,
1 H), 5.90 (d, J = 4.0 Hz, 1 H), 4.85–4.59 (m, 4 H), 4.58 (d, J = 12 Hz,
1 H), 4.55 (d, J = 12 Hz, 1 H), 4.21 (d, J = 12.6 Hz, 1 H), 3.99 (ddd, J =
11.6, 4.8, 2.8 Hz, 1 H), 3.93 (dd, J = 12.4, 2.4 Hz, 1 H), 3.84 (d, J = 12.6,
1 H), 3.76 (m, 1 H), 3.56 (dd, J = 12.4, 0.8 Hz, 1 H), 2.27 (t, J = 12 Hz,
1 H), 2.06 (dd, J = 12.8, 4.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 138.2, 138.0, 130.2, 128.4, 128.3,
127.7, 127.6, 127.6, 127.3, 119.7, 113.3, 103.5, 101.9, 95.7, 72.5, 71.4,
70.7, 70.2, 62.6, 57.8, 50.7, 33.6.
IR: 3031, 2943, 2863, 1463, 1365, 1271, 1070, 1013, 883, 808, 735,
696 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.39–7.25 (m, 10 H), 4.77 (d, J =
11.2 Hz, 1 H), 4.68 (d, J = 11.6 Hz, 1 H), 4.62 (dd, J = 11.2 Hz, 1 H), 4.57
(dd, J = 11.6 Hz, 1 H), 3.93 (dd, J = 10.8, 4.4 Hz, 1 H), 3.81 (dd, J = 10.8,
5.6 Hz, 1 H), 3.75 (m, 1 H), 3.66 (m, 1 H), 2.79 (dd, J = 17.2, 4.8 Hz,
1 H), 2.74 (dd, J = 17.2, 6.0 Hz, 1 H), 1.06 (m, 21 H).
13C NMR (100 MHz, CDCl3):  = 138.4, 138.1, 128.3, 128.2, 128.0,
127.9, 127.6, 127.5, 91.7, 80.4, 76.9, 73.1, 72.3, 63.1, 22.7, 18.0, 11.8.
HRMS (ESI): m/z [M + Na]+ calcd for C26H26N2O4Na: 453.1785; found:
453.1783.
HRMS (ESI): m/z [M + Na]+ calcd for C29H41IO3SiNa: 615.1762; found:
615.1761.
(2S,4S,5R)-4,5-Bis(benzyloxy)-3,4,5,6-tetrahydro-1′H,4′H-
spiro[pyran-2,3′-pyrrolo[2,1-c][1,4]oxazine]-6′-carbaldehyde (6-1)
1-((4S,5R)-4,5-Bis(benzyloxy)-6-((triisopropylsilyl)oxy)hex-1-yn-
1-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrrole-2-car-
bonitrile (55)
A flame-dried vial was allowed to cool under argon and subsequently
charged with a stir bar, 57 (78.4 mg, 0.18 mmol), and anhydrous DCM
(1.0 mL). The solution was cooled to 0 °C and 1 M DIBAL-H in hexanes
(0.45 mmol, 2.5 equiv) was added dropwise over 5 min. Immediately
following the addition of DIBAL-H, the reaction was allowed to warm
and stirred for 45 min. Following completion, the reaction was
quenched with EtOAc and allowed to stir for 15 min. After quenching,
a Fieser workup was performed (7 L H2O, followed by 7 L 15%
NaOH, followed by 18 L H2O). The reaction was further diluted with
Prepared according to General Procedure B, using 4,7-dimethoxy-
1,10-phenanthroline as the ligand, K3PO4 as the base and 115 °C for
the temperature.
Yield: 71.5 mg (51%); pale oil; []D –10.0 (c = 1.0, DCM).
IR: 3032, 2929, 2864, 2224, 1496, 1460, 1441, 1362, 1321, 1255,
1212, 1091, 1004, 836, 737, 695 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

T
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
EtOAc and washed with sat. NH4Cl, brine, and dried over Na2SO4. Re-
moval of the solvents and purification of the residue by column chro-
matography (0–50% EtOAc in hexanes) gave the title compound.
HRMS (ESI): m/z [M + Na]+ calcd for C12H15NO5Na: 276.0842; found:
276.0852.
Yield: 47.7 mg (61%); clear oil; []D –134.6 (c = 0.43, DCM).
Funding Information
IR: 2869, 1655, 1453, 1317, 1188, 1051, 741, 698 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.45 (s, 1 H), 7.41–7.26 (m, 10 H), 6.90
(d, J = 4.0 Hz, 1 H), 5.99 (d, J = 4.0 Hz, 1 H), 4.83–4.66 (m, 5 H), 4.59 (d,
J = 12 Hz, 1 H), 4.56 (d, J = 12 Hz, 1 H), 4.03 (d, J = 14.4 Hz, 1 H), 3.99
(ddd, J = 11.6, 4.8, 2.4 Hz, 1 H), 3.93 (dd, J = 12.4, 2.4 Hz, 1 H), 3.75 (br
s, 1 H), 3.57 (d, J = 12 Hz, 1 H), 2.30 (t, J = 12 Hz, 1 H), 2.05 (dd, J = 12.6,
4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 178.5, 138.3, 138.2, 134.2, 131.1,
128.3, 128.3, 127.6, 127.5, 127.5, 127.3, 123.8, 104.6, 95.6, 72.7, 71.3,
71.0, 70.1, 62.4, 57.6, 52.3, 33.6.
We gratefully acknowledge the William and Ella Owens Medical Re-
search Foundation, the Robert Welch Foundation, and Texas State
University for support.
W
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l
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h
F
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n
d
ati
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(A
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2
9
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611904.
S
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p
orti
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gInformati
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n
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p
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o
n
HRMS (ESI): m/z [M + H]+ calcd for C26H28NO5: 434.1962; found:
434.1964.
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An oven-dried round-bottom flask was charged with a stir bar and al-
lowed to cool under argon. The flask was then charged with 6-1 (44.4
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Yield: 18.1 mg (70%); white solid; mp 105 °C (decomp.); []D –186.5
(c = 0.37, MeOH).
IR: 3397, 1648, 1501, 1408, 1319, 1184, 1082, 1045, 975, 849,
728 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.42 (s, 1 H), 6.91 (d, J = 4.0 Hz, 1 H),
6.00 (d, J = 4.0 Hz, 1 H), 4.81 (d, J = 15.6 Hz, 1 H), 4.71 (m, 2 H), 4.15
(m, 1 H), 4.00 (d, J = 14 Hz, 1 H), 3.88 (m, 2 H), 3.79 (dd, J = 12.8,
1.2 Hz, 1 H), 2.19 (br s, 2 H), 2.04 (dd, J = 12.8, 5.4 Hz, 1 H), 1.92 (m,
1 H).
13C NMR (100 MHz, CDCl3):  = 178.7, 134.2, 130.9, 124.2, 104.8, 95.3,
67.3, 65.0, 64.5, 57.7, 52.1, 35.6.
1H NMR (400 MHz, CD3OD):  = 9.36 (s, 1 H), 7.01 (d, J = 4.0 Hz, 1 H),
6.06 (d, J = 4.0 Hz, 1 H), 4.83 (d, J = 15.6 Hz, 1), 4.73 (dd, J = 15.6,
0.8 Hz, 1 H), 4.59 (dd, J = 14 Hz, 1 H), 4.07 (ddd, J = 11.6, 5.6, 2.8 Hz,
1 H), 3.96 (d, J = 14 Hz, 1 H), 3.80 (dd, J = 11.6, 1.2 Hz, 1 H), 3.78 (m,
1 H), 3.75 (dd, J = 11.6, 1.6 Hz, 1 H), 1.98 (dd, J = 12.8, 11.6 Hz, 1 H),
1.89 (dd, J = 12.8, 5.2 Hz, 1 H).
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96.9, 68.9, 66.5, 66.3, 58.8, 53.7, 36.3.
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1 H), 6.04 (d, J = 3.2 Hz, 1 H), 4.85 (d, J = 12.8 Hz, 1 H), 4.74 (d, J =
12.8 Hz, 1 H), 4.55 (d, J = 11.2 Hz, 1 H), 4.06 (m, 1 H), 3.94 (d, J =
11.2 Hz, 1 H), 3.88–3.72 (m, 3 H), 1.98 (m, 1 H), 1.91 (dd, J = 10,
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U

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Paper
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–U