The vinylogous aldol reaction of N-Sulfinyl metallodienamines

Article abstract of DOI:10.1016/j.tet.2019.130901

The discovery and development of the vinylogous aldol reaction of N-sulfinyl metallodienamines with aldehydes and ketones is described. The diastereoselectivity of the reaction, first reported in 2017 as a key step in the total asymmetric synthesis of (?)-albocycline, has been corrected by Mosher ester analysis. The reaction has been optimized and the scope investigated, with yields ranging from 68–89% and diastereomeric ratios as high as 5.9:1. Extensive investigation into the mechanisms affecting stereoselectivity revealed that two stereochemical erosion pathways are operative when using LiHMDS and SnCl₄. A transition state supported by DFT calculations has been advanced to rationalize the stereochemical course of the reaction.

Full text of DOI:10.1016/j.tet.2019.130901

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The vinylogous aldol reaction of N-Sulfinyl metallodienamines
Po-Cheng Yu, Vijay K. Chatare, Harsh Patel, Charles DeBrosse, Rodrigo B. Andrade
PII:
S0040-4020(19)31318-3
https://doi.org/10.1016/j.tet.2019.130901
TET 130901
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 November 2019
Revised Date: 16 December 2019
Accepted Date: 19 December 2019
Please cite this article as: Yu P-C, Chatare VK, Patel H, DeBrosse C, Andrade RB, The vinylogous
aldol reaction of N-Sulfinyl metallodienamines, Tetrahedron (2020), doi: https://doi.org/10.1016/
j.tet.2019.130901.
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Graphical Abstract:
1

The Vinylogous Aldol Reaction of N-Sulfinyl Metallodienamines
Po-Cheng Yu,a Vijay K. Chatare,a Harsh Patel,a Charles DeBrosse,a and
Rodrigo B. Andradea*
aDepartment of Chemistry, Temple University, Philadelphia, PA 19122, United States
* Corresponding author: tel: +1-215-204-7155; fax: +1-215-204-9851; e-mail:
randrade@temple.edu
Abstract: The discovery and development of the vinylogous aldol reaction of N-sulfinyl
metallodienamines with aldehydes and ketones is described. The diastereoselectivity of
the reaction, first reported in 2017 as a key step in the total asymmetric synthesis of (−)-
albocycline, has been corrected by Mosher ester analysis. The reaction has been
optimized and the scope investigated, with yields ranging from 68−89% and
diastereomeric ratios as high as 5.9:1. Extensive investigation into the mechanisms
affecting stereoselectivity revealed that two stereochemical erosion pathways are
operative when using LiHMDS and SnCl4. A transition state supported by DFT
calculations has been advanced to rationalize the stereochemical course of the reaction.
Key words: vinylogous aldol, N-sulfinyl metallodienamine, albocycline, methodology
2

1. Introduction
Structurally complex natural products are unrivaled in their ability to inspire
novel synthetic strategies and/or tactics.1-2 In 2017, we published a concise total synthesis
of the macrolactone antibiotic albocycline (1) wherein we targeted the C6−C7 bond for
disconnection in precursor 2 (Figure 1).3 We envisioned this goal could be realized by the
regio- and stereoselective addition of N-sulfinyl metallodienamine (NSMD) 3 derived
from sulfinimine 5 to aldehyde 4. While Ellman had demonstrated that N-sulfinyl
metalloenamines stereoselectively add to aldehydes in analogy to the aldol reaction,4-5 the
vinylogous variant of this reaction had not been explored prior to our report.3 In 2013, we
first demonstrated the synthetic utility of 2,3-indole fused NSMDs in annulation reactions
for the concise syntheses of Aspidosperma indole alkaloids.6-7 Herein, we describe the
optimization and scope of the vinylogous aldol reaction (VAR) of NSMDs. In addition,
we correct and update the diastereoselectivity of the reaction as was previously reported
and posit a stereochemical model to rationalize observed diastereoselectivity supported
by DFT calculations.3
Figure 1. Inspiration for and discovery of the VAR of N-sulfinyl metallodienamines.
3

The vinylogous Mukaiyama aldol reaction (VMAR) has found widespread use in
the chemical synthesis of polyketide natural products owing to its high regioselectivity
(i.e., reaction at the γ- versus the α-position), stereoselectivity, and a priori inclusion of
at least two additional carbons in the product vis-à-vis the standard aldol reaction, thus
enhancing overall efficiency.8-9 In 2004, Kobayashi reported that the VMAR of
vinylketene silyl N,O-acetals bearing the Evans oxazolidinone auxiliary with aldehydes
proceeds with high levels of remote 1,7- and 1,6,7-asymmetric induction under the
agency of TiCl4.10 The Kalesse11 and particularly Hosokawa12-15 groups have made
improvements to the Kobayashi aldol reaction that have been extensively employed in
many total syntheses.16
Upon completion of our synthesis of albocycline enabled by new methodology,
we turned our attention toward developing the scope of the VAR of N-sulfinyl
metallodienamines with aldehydes.
2. Results and Discussion
Much like the reported reaction of NSMD 3 with aldehyde 4, we found the former
smoothly reacted with aliphatic, aromatic, and other α,β-unsaturated aldehydes in high
yields (70−85%) and exclusive γ-regioselectivity to furnish what appeared to be a single
1
diastereomer (dr > 95:5) of the vinylogous aldol product as determined by H and 13C
NMR analysis.17 However, when we employed the NSMD derived from N-sulfinyl imine
6 bearing a prochiral γ-carbon in the VAR with propionaldehyde, we were surprised to
isolate what appeared to be a ~4:1 ratio of inseparable diastereomers. In principle, the
VAR of prochiral NSMDs can produce up to four diastereomers (i.e., two syn- and two
4

anti-stereoisomers). Protection of the newly formed carbinol as its TBS ether allowed for
separation of the major isomer derived from 7a (Scheme 1). Rigorous characterization of
the relative and absolute stereochemistry of aldols 7a−d was accomplished by correlation
with known compounds (Scheme S1).18-19 Moreover, the diastereomeric ratio (dr) of
1
products 7a−d as determined by integrating H-3 (Scheme 1, red sphere) in 7a−d by H
NMR spectroscopy wherein the dr was found to be 8:4:2:1 (see Scheme S2 for details). In
other words, the dr of major anti-7a aldol versus the sum of minor aldols 7b−d was ~1:1.
Scheme 1. VAR of prochiral NSMD derived from 6 with propionaldehyde.
The results of the VAR prompted us to revisit the key step in our albocycline
synthesis wherein NSMD 3 derived from N-sulfinyl imine 5 was reacted with aldehyde 4
complexed with SnCl4 to furnish aldol 2 (Scheme 2). To confirm the dr of this reaction,
we employed two methods. First, we prepared Mosher ester 9 in 82% yield by treating 2
with excess (R)-Mosher acid (8) in the presence of DCC and DMAP to ensure complete
1
consumption of starting material. H NMR analysis of 9 revealed a mixture of
diastereomers in a 2.9:1 ratio (Figure S1). Second, we employed HPLC analysis, which
5

gave the same ratio, thus ultimately confirming the reported VAR did not proceed in
>95:5 dr but rather a ~3:1 ratio (Figure S2).3
Scheme 2. Revisiting the diastereoselectivity of the VAR in the albocycline synthesis.
The absolute stereochemistry of the newly formed (7S)-chiral center in
intermediate 2 was originally assigned by correlation with albocycline, whose structure
had been unambiguously established by single crystal X-ray analysis.20-21 Accordingly,
Mosher ester analysis of the major diastereomer in 9 was fully consistent with an (S)
configuration at the C7 stereocenter (Figure S1).22 In retrospect, the minor (7R)-
diastereomer unknowingly carried forward in the albocycline synthesis was therefore
removed by iterative chromatography en route to the target, which required eight
additional operations.3
Having corrected the diastereoselectivity of the VAR, we sought to optimize this
reaction with the goal of increasing the modest dr. To that end, we screened a variety of
conditions including the base (e.g., NaHMDS, KHMDS), additive (e.g., HMPA, LiCl),
solvent (e.g., toluene, Et2O, THF), and Lewis acid (e.g., BF3•OEt2, TiCl4) to compare
with the original procedure (entry 1) as determined by HPLC, and the results are shown
6

in Table 1. The use of HMPA and LiCl (entries 2−3) slightly decreased the yield;
however, the former eroded dr. The requirement of a Lewis acid was demonstrated by a
control experiment (entry 4) where no Lewis acid was used; accordingly, no reaction took
place at -78 °C after 2 h. While the reaction proceeded in the presence of BF3•OEt2 (entry
5), no diastereoselectivity was observed. Replacing LiHMDS with NaHMDS (entry 6)
led to an improvement in yield and dr, the latter of which went from 2.7:1 to 4.7:1.
KHMDS (entry 7) proved to be the optimal base by providing the highest yield (89%) of
VAR product while maintaining the same dr as NaHMDS (4.7:1). Entries 8−11 probed
the role of solvent and Lewis acid when using KHMDS as the base, which were all
inferior to the best conditions (entry 7).
7

Lewis
acid
SnCl4
SnCl4
SnCl4
Yield
(%)
81
75
77
dra
Entry
Base
Additive Solvent 1 Solvent 2
1
2
3
4
5
6
7
8
9
LiHMDS
THF
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2.7:1b
1.9:1
2.6:1
−
1:1
4.7:1
4.7:1
4.0:1
3.3:1
4.7:1
4.1:1
−
HMPA
LiCl
THF
−
−
−
−
−
−
−
−
−
−
THF
CH2Cl2 BF3•OEt2
87
85
89
43
79
64
63
NaHMDS
KHMDS
THF
THF
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
THF
SnCl4
SnCl4
TiCl4
SnCl4
SnCl4
SnCl4
10
11
Toluene
Et2O
CH2Cl2
CH2Cl2
a Diastereomeric ratio (dr) was determined by HPLC. b Absolute configuration of the new
stereocenter was confirmed by Mosher analysis (see SI for details).
Table 1. Optimization of VAR of NSMD derived from 5 and tiglaldehyde.
With optimal reaction conditions for the VAR of NSMDs with aldehydes in hand,
we turned our attention to determining the scope of this transformation. To this end, we
investigated two NSMDs: one derived from tiglaldehyde 5, which was used in the total
synthesis of albocycline, and the other derived from crotonaldehyde 11. Five aldehydes
were selected including α,β-unsaturated, aromatic, aliphatic, and alicyclic. The results are
shown in Table 2. Diastereomeric ratios and assignment of absolute stereochemistry were
accomplished by Mosher ester analysis (Tables S1−2). Overall, yields for all VARs were
very good (70−89%). Both NSMDs derived from 5 and 11 retained good
diastereoselectivity when reacted with α,β-unsaturated aldehydes tiglaldehyde (10, 13a)
and crotonaldehyde (12b, 13b), with aldol 13b displaying the highest selectivity (dr =
8

5.9:1). Erosion of diastereoselectivity was observed when benzaldehyde was employed
(12c, 13c) wherein the dr dropped to 1.4:1 for the NSMD derived from 5 and 1.2:1 for the
NSMD derived from 11. The VARs with aliphatic (12d, 13d) and alicyclic (12e, 13e)
aldehydes showed little to no diastereoselectivity.
a Diastereomeric ratio (dr) was determined by Mosher analysis (see SI for details).
Table 2. Scope of VAR with NSMD derived from tiglaldehyde 5 or crotonaldehyde 11
and α,β-unsaturated, aromatic, aliphatic and alicyclic aldehydes.
To probe nucleophilicity and expand the scope of the VAR, we reacted the
NSMD derived from 5 with ketones. Specifically, we chose methyl pyruvate (Scheme
3A) in addition to acetophenone and benzophenone (Scheme 3B). While the reaction
with the methyl pyruvate proceeded in high yield (91%), it was not particularly
diastereoselective (dr = 1.1:1). Both aromatic ketones (Scheme 3B) failed to react in the
VAR.
9

O
S
O
S
A
B
i) KHMDS, THF
-20 ºC, 1 h
N
t-Bu
N
t-Bu
Me OH
Me
H
MeO2C
H
*
ii) SnCl4, CH2Cl2
-78 ºC, 2 h
methyl pyruvate
91%
Me
Me
5
14
dr = 1.1:1
O
S
O
S
i) KHMDS, THF
-20 ºC, 1 h
N
t-Bu
N
t-Bu
R
OH
Me
H
Ph
H
*
ii) SnCl4, CH2Cl2
-78 ºC, 2 h
acetophenone or
benzophenone
Me
Me
5
15: R = Me
16: R = Ph
Scheme 3. Reaction of NSMD derived from 5 with (A) methyl pyruvate, (B)
acetophenone, and benzophenone.
To better understand the difference in diastereoselectivity between Li- and K-
derived N-sulfinyl metallodienamines in the vinylogous aldol reaction, we carried out
additional experiments to identify the source of stereochemical erosion (Table 3). Entries
1−3 were performed under optimal reaction conditions (i.e., KHMDS); however, instead
of quenching the reaction, an additional equivalent of HMDS base was added to the
reaction mixture, followed by stirring at -78 °C for 2 h prior to quenching. Results from
the experiment with LiHMDS (entry 1) revealed the dr eroded to 2.7:1, which was
consistent with the original NSMD-mediated VAR conditions using LiHMDS (entry 1,
Table 1). The use of NaHMDS (entry 2) and KHMDS (entry 3) had no effect on the dr,
demonstrating the role of Li in the stereochemical erosion pathway. A plausible
explanation for the erosion in dr is that Li promotes a retro-aldol reaction under
thermodynamic control. To test this hypothesis, we carried out a crossover experiment
with benzaldehyde (entry 4) and employed d4-methanol (entry 5). In both cases, no
evidence of reversibility was detected. To rule out the role of Li+ in promoting a retro-
10

aldol pathway, 12-crown-4 was added to the reaction mixture following metalation with
LiHMDS to sequester the cation. In the event, a dr of 2.7:1 was observed (entry 6).
dra
Entry
Base
Additive 1
Additive 2
KHMDS
KHMDS
KHMDS
LiHMDS
LiHMDS
LiHMDS
NaHMDS
KHMDS
PhCHO, SnCl4
CD3OD
2.7:1
4.7:1
4.7:1
2.7:1b
2.7:1c
2.7:1
1
2
3
4
5
6
−
−
−
−
−
LiHMDS 12-crown-4
−
a Diastereomeric ratio (dr) was determined by 13C NMR analysis (see SI for details).
b Crossover product with benzaldehyde 12c was not detected. c γ-deutero N-sulfinyl imine
5 was not detected.
Table 3. Role of LiHMDS in the erosion of diastereoselectivity.
To probe the Li-mediated epimerization pathway further, we took vinylogous
aldol product 10 prepared under optimized conditions (dr = 4.7:1) and subjected it to
various reaction conditions (Table 4). Not surprisingly, stoichiometric deprotonation of
10 with LiHMDS to generate the lithium alkoxide and additional stirring at -78 °C for 2 h
resulted in no change in dr (entry 1). Alternatively, the addition of SnCl4 following the
deprotonation event—conditions that recapitulate the previously observed LiHMDS-
mediated epimerization pathway (entry 1, Table 3)—resulted in an erosion of dr to 2.7:1
(entry 2). Erosion was not observed when BF3•OEt2 was added to the lithium alkoxide
(entry 3), therefore strongly implicating the role of tin and lithium salts in combination.
11

Further evidence of this was obtained by sequestering Li+ with 12-crown-4 prior to
adding SnCl4 (entry 4) wherein no erosion in dr was observed (Table 4, entry 4).
Altogether, these results suggest the modest dr associated with LiHMDS-mediated
vinylogous aldol reactions of NSMDs can arise either from C−C bond formation in the
stereochemistry-determining VAR or an epimerization pathway, both of which are
unique to Li vis-à-vis Na or K and reminiscent of the roles of alkali metal salts in
determining the diastereoselectivity (i.e., E/Z ratios) in the venerable Wittig reaction.23
dra
Entry Additive
Lewis acid
4.7:1
2.7:1
4.7:1
4.7:1
1
2
3
4
−
−
−
−
SnCl4
BF3•OEt2
SnCl4
12-crown-4
a Diastereomeric ratio (dr) was determined by
13C NMR analysis (see SI for details).
Table 4. Effects of Lewis acids and Li+ on the dr of VAR product 10.
To rationalize the stereochemical course of the NSMD-mediated VAR reaction,
we employed DFT calculations at the B3LYP/6-31G(d) level of theory (see SI for
details).24 All NSMDs irrespective of metal counterion preferred the (Z)-NSMD
geometry by approximately 1 kcal/mol (Figure 2A, see SI for details). Furthermore, we
advance the synclinal transition state in Figure 2B as a stereochemical model for the
observed diastereoselectivity wherein a tin species serves as a linchpin between the
12

aldehyde and the NSMD.3,9-10 At this stage, it is unclear why α,β-unsaturated aldehydes
emerged as the most stereoselective substrates in the vinylogous aldol reactions whereas
aliphatic and aromatic aldehydes were not. Additional experiments are currently
underway to explore this interesting transformation that despite its dr served admirably in
the concise total asymmetric synthesis of macrolactone antibiotic (−)-albocycline.
A
B
Figure 2. (A) Optimized structure of (Z)-NSMD 3 (M=K) from DFT calculations.
(B) Stereochemical model for the SnCl4-mediated VAR of NSMD 3
and aldehydes invoking a synclinal transition state.
3. Conclusion
Complex natural products offer unlimited sources of inspiration for the creation of
novel synthetic methods. We have described the discovery and development of the
vinylogous aldol reaction of N-sulfinyl metallodienamines (NSMDs) with aldehydes and
ketones. Our first disclosure of this reaction in the total asymmetric synthesis of (−)-
albocycline reported it proceeded with high diastereoselectivity (dr = >95:5). However, in
the process of expanding reaction scope we found the dr was in fact ~3:1. Reaction
optimization found that KHMDS was superior to LiHMDS. The reaction proceeded in
synthetically useful yields (68−89%) with α,β-unsaturated aldehydes providing the
13

highest dr (5.9:1). While electrophilic methyl ketones (e.g., methyl pyruvate) reacted in
high yields with KHMDS, no diastereoselectivity was observed. Owing to the modest
natural of the VAR of NSMDs, we did not explore the reaction of these chiral synthons
with chiral aldehydes to probe the diastereofacial preference of the former over the latter.
Mechanistic invesigations revealed that two stereochemical erosion pathways are
operative when using LiHMDS and SnCl4 but not with NaHMDS or KHMDS. A
transition state supported by DFT calculations has been advanced to rationalize the
stereochemical course of the reaction.
4. Experimental Section
4.1. General information
All reactions containing moisture or air-sensitive reagents were performed in flame-
dried glassware under nitrogen or argon. Tetrahydrofuran, toluene, diethyl ether and
dichloromethane were passed through two columns of neutral alumina prior to use.
Anhydrous dimethyl sulfoxide (DMSO) was purchased from Sigma-Aldrich and
subjected to three cycles of freeze-pump-thaw before use. Diisopropylamine and
trimethylamine were distilled from CaH2 prior to use. Solutions of LiHMDS, NaHMDS,
and KHMDS in THF (Sigma-Aldrich) were titrated with diphenylacetic acid
(recrystallized from toluene and dried in vacuo prior to use) with the titre being the
average of three runs. Tiglaldehyde-derived N-sulfinyl imine 5 and albocycline
intermediates 2 and 4 were prepared by known methods.3 Crotonaldehyde-derived N-
sulfinyl imine 11 was prepared using the procedure of Ellman.25 All other reagents were
purchased from commercial sources and used without further purification. All solvents
14

for work-up procedures were used as received. Flash column chromatography was
performed with ICN Silitech 32-63 D 60Å silica gel with the indicated solvents. Thin
layer chromatography was performed on Merck 60 F254 silica gel plates. Detection was
performed using UV light, KMnO4 stain, iodine chamber, PMA stain and subsequent
1
13
heating. H and C NMR spectra were recorded at the indicated field strength in CDCl3
at rt. Chemical shifts are indicated in parts per million (ppm) downfield from
tetramethylsilane (TMS, δ = 0.00) and referenced to the CDCl3. Splitting patterns are
abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet).
Diastereomeric ratios and assignment of absolute stereochemistry for compounds 2, 10,
12b-e and 13a-e were accomplished by Mosher ester analysis (Figure S1, Tables S1−2).
4.2. General procedure
4.2.1. General procedure for N-sulfinyl imine aldol products
To a solution of N-sulfinyl imine (1.0 mmol) in anhydrous THF (3 mL) at -20 °C
was added LiHMDS, NaHMDS, or KHMDS (1.2 mL, 1.2 mmol, 1.0 M in THF)
dropwise and stirred for 1 h, and then cool to -78 °C. In a separate flask, SnCl4 (1.1 mL,
1.1 mmol, 1.0 M in CH2Cl2) was added dropwise to a solution of aldehyde (1.1 mmol) in
CH2Cl2 (3 mL) at -78 °C and stirred for 30 min. At this time, previously generated
metallodienamine was cannulated to the Lewis acid-complexed aldehyde containing flask
at -78 °C over 5 min and the reaction mixture was stirred for 2 h at -78 °C. The reaction
was quenched with saturated NH4Cl (3 mL) and extracted with EtOAc (3 mL × 3). The
combined organic layers were dried over Na2SO4 and concentrated under reduced
15

pressure. The residue was purified by flash column chromatography to afford aldol
product as a viscous oil.
4.2.2. (R)-N-((1E,2E)-2-methylpent-2-en-1-ylidene)-2-methylpropane-2-sulfinamide (6)
To a solution of 2-methyl-2-pentenal (1.00 g, 10.2 mmol) and (R)-tert-
butanesulfinamide (1.35 g, 11.22 mmol) in THF (5 mL) at rt were added Ti(OEt)4 (4.28
mL, 20.4 mmol) dropwise with stirring overnight. The reaction was quenched with water
(5 mL), and the resulting suspension was filtered through a short pad of Celite. The filter
cake was washed with EtOAc (20 mL × 3). The aqueous layer was removed and the
organic layer was washed with brine (20 mL). The organic layer was dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified
by flash column chromatography eluting with EtOAc/hexanes (2:8) to afford 6 as a clear
20
oil (1.63 g, 79%). [α]D −463 (
c
1.0, CHCl3); IR (neat) 2965, 2874, 1636, 1579, 1456,
1362, 1084, 1045, 729 cm-1; 1H NMR (500 MHz) δ 8.10 (s, 1H), 6.22 (t, J = 7.3 Hz, 1H),
13
2.30 (qd, J = 7.5, 7.5 Hz, 2H), 1.87 (s, 3H), 1.19 (s, 9H), 1.07 (t, J = 7.6 Hz, 3H); C
NMR (126 MHz) δ 167.0, 150.1, 134.7, 57.4, 22.8, 22.6, 13.5, 11.5; HRMS (ESI) calcd
for C10H19NOSNa [M + Na]+ 224.1085, found 224.1091.
4.2.3. (R)-N-((1E,2E)-5-hydroxy-2,4-dimethylhept-2-en-1-ylidene)-2-methylpropane-2-
sulfinamide (7a
Following general procedure 4.2.1 above, 179 mg (69% yield) of inseparable
mixture 7a d were obtained as a yellowish oil after purification by flash column
−d)
−
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3357, 2963, 2928, 2874,
1682, 1634, 1577, 1456, 1364, 1060, 974, 908, 731 cm-1; 1H NMR (500 MHz) δ 8.14 (s,
1H), 6.26−6.12 (dq, J = 10.0, 1.4 Hz, 0.53H,7a; dq, J = 10.0, 1.4 Hz, 0.27H, 7b; dq, J =
16

10.1, 1.5 Hz, 0.13H, 7c; dq, J = 10.1, 1.5 Hz, 0.07H, 7d), 3.48 (dt, J = 8.8, 4.7 Hz, 1H),
2.84−2.65 (m, 1H), 1.91 (s, 3H), 1.57−1.35 (m, 2H), 1.20 (s, 9H), 1.11−1.05 (m, 3H),
0.99−0.94 (m, 3H); 13C NMR (126 MHz) δ 166.8, 149.5, 135.5, 76.6, 57.1, 39.1, 27.7,
22.5, 16.6, 11.7, 10.1; HRMS (ESI) calcd for C13H26NO2S [M + H]+ 260.1684, found
260.1673.
4.2.4. (S)-N-((S,1E,2E,6E)-5-hydroxy-2,6-dimethylocta-2,6-dien-1-ylidene)-2-
methylpropane-2-sulfinamide (10)
Following general procedure 4.2.1 above, 241 mg (89% yield) of inseparable
diastereomers 10 were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3387, 2980, 2923, 1635,
1579, 1455, 1364, 1056, 751 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 6.20 (t, J
= 7.0 Hz, 1H), 5.49 (m, 1H), 4.13 (dd, J = 12.1, 6.0 Hz, 1H), 2.64−2.44 (m, 2H), 2.07 (s,
1H), 1.87 (s, 3H), 1.60 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H), 1.17 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 166.5, 144.1, 137.0, 136.2, 121.6, 76.6, 57.1, 34.5, 22.4, 13.1, 11.6, 11.1;
HRMS (ESI) calcd for C14H25NO2SNa [M + Na]+ 294.1504, found 294.1496.
4.2.5. (S)-N-((S,1E,2E,6E)-5-hydroxy-2-methylocta-2,6-dien-1-ylidene)-2-
methylpropane-2-sulfinamide (12b)
Following general procedure 4.2.1 above, 180 mg (70% yield) of inseparable
diastereomers 12b were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3395, 2962, 2920, 1635,
1579, 1455, 1364, 1060, 966, 748 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 6.23
(t, J = 7.2 Hz, 1H), 5.66−5.58 (m, 1H), 5.44 (ddd, J = 15.3, 7.1, 1.6 Hz, 1H), 4.13 (q, J =
6.6 Hz, 1H), 2.90−2.63 (s, 1H), 2.57−2.39 (m, 2H), 1.82 (s, 3H), 1.62 (d, J = 6.3 Hz, 3H),
17

1.12 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 166.4, 143.8, 136.2, 133.2, 127.2, 71.6,
57.0, 36.7, 22.3, 17.5, 11.5; HRMS (ESI) calcd for C13H23NO2SNa [M + Na]+ 280.1347,
found 280.1334.
4.2.6. (S)-N-((S,1E,2E)-5-hydroxy-2-methyl-5-phenylpent-2-en-1-ylidene)-2-
methylpropane-2-sulfinamide (12c)
Following general procedure 4.2.1 above, 220 mg (75% yield) of inseparable
diastereomers 12c were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (2:8). IR (neat) 3389, 2960, 2923, 1635,
1
1580, 1454, 1364, 1052, 757, 701 cm-1; H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H),
7.42−7.21 (m, 5H), 6.29 (m, 1H), 4.84 (dd, J = 12.7, 5.7 Hz, 1H), 2.90−2.67 (m, 3H),
1.82 (m, 3H), 1.18 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 166.4, 143.8, 143.4, 136.8,
128.6, 127.8, 125.8, 73.3, 57.2, 38.7, 22.4, 11.5; HRMS (ESI) calcd for C16H23NO2SNa
[M + Na]+ 316.1347, found 316.1338.
4.2.7. (S)-N-((R,1E,2E)-5-hydroxy-2-methylhept-2-en-1-ylidene)-2-methylpropane-2-
sulfinamide (12d)
Following general procedure 4.2.1 above, 176 mg (72% yield) of inseparable
diastereomers 12d were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3419, 2961, 2925, 1635,
1579, 1456, 1363, 1059, 981, 743 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 6.29
(t, J = 7.4 Hz, 1H), 3.72−3.54 (m, 1H), 2.47−2.31 (m, 2H), 1.94 (s, 1H), 1.84 (s, 3H),
1.55−1.37 (m, 2H), 1.13 (s, 9H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
166.5, 144.1, 136.7, 72.4, 57.1, 36.5, 30.1, 22.4, 11.6, 10.0; HRMS (ESI) calcd for
C12H23NO2SNa [M + Na]+ 268.1347, found 268.1338.
18

4.2.8. (S)-N-((S,1E,2E)-5-cyclohexyl-5-hydroxy-2-methylpent-2-en-1-ylidene)-2-
methylpropane-2-sulfinamide (12e)
Following general procedure 4.2.1 above, 236 mg (79% yield) of inseparable
diastereomers 12e were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3423, 2970, 2925, 1634,
1
1575, 1456, 1363, 1060, 981, 743 cm-1; H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H),
6.39−6.34 (m, 1H), 3.55−3.49 (m, 1H), 2.55−2.39 (m, 2H), 1.90 (s, 3H), 1.88−1.82 (m,
1H), 1.81−1.73 (m, 2H), 1.70−1.64 (m, 2H), 1.41−1.33 (m, 1H), 1.28−1.20 (m, 2H), 1.20
(m, 9H), 1.16−1.09 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 166.5, 144.9, 136.5, 75.3,
57.1, 43.5, 33.9, 29.2, 27.8, 26.4, 26.2, 26.0, 22.4, 11.6; HRMS (ESI) calcd for
C16H29NO2SNa [M + Na]+ 322.1817, found 322.1806.
4.2.9. (S)-N-((S,1E,2E,6E)-5-hydroxy-6-methylocta-2,6-dien-1-ylidene)-2-
methylpropane-2-sulfinamide (13a)
Following general procedure 4.2.1 above, 218 mg (85% yield) of inseparable
diastereomers 13a were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3394, 2923, 1639, 1581,
1363, 1056, 1000, 753, 720 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.18 (m, 1H), 6.49 (d, J
= 4.7 Hz, 2H), 5.53 (d, J = 6.4 Hz, 1H), 4.18 (t, J = 6.4 Hz, 1H), 2.65−2.46 (m, 2H), 1.87
(s, 1H), 1.64 (s, 3H), 1.63 (d, J = 7.7 Hz, 3H), 1.21 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 164.0, 147.5, 136.9, 130.4, 121.6, 76.5, 57.3, 38.6, 22.4, 13.0, 11.2; HRMS (ESI) calcd
for C13H23NO2SNa [M + Na]+ 280.1347, found 280.1330.
4.2.10. (S)-N-((S,1E,2E,6E)-5-hydroxyocta-2,6-dien-1-ylidene)-2-methylpropane-2-
sulfinamide (13b)
19

Following general procedure 4.2.1 above, 192 mg (79% yield) of inseparable
diastereomers 13b were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3393, 2980, 2921, 1639,
1
1581, 1456, 1364, 1060, 964, 752, 721 cm-1; H NMR (500 MHz, CDCl3) δ 8.17 (d, J =
8.6 Hz, 1H), 6.51 (m, 2H), 5.70 (dd, J = 14.8, 6.7 Hz, 1H), 5.51 (dd, J = 15.0, 6.5 Hz,
1H), 4.22 (d, J = 6.3 Hz, 1H), 2.51 (d, J = 5.9 Hz, 2H), 2.48−2.25 (m, 1H), 1.70 (d, J =
6.1 Hz, 3H), 1.19 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 164.0, 147.2, 133.0, 130.7,
127.8, 71.7, 57.3, 40.8, 22.4, 17.7; HRMS (ESI) calcd for C12H21NO2SNa [M + Na]+
266.1191, found 266.1179.
4.2.11. (S)-N-((S,1E,2E)-5-hydroxy-5-phenylpent-2-en-1-ylidene)-2-methylpropane-2-
sulfinamide (13c)
Following general procedure 4.2.1 above, 215 mg (77% yield) of inseparable
diastereomers 13c were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (2:8). IR (neat) 3393, 2981, 2925, 2359,
1
1638, 1581, 1456, 1363, 1052, 701 cm-1; H NMR (500 MHz, CDCl3) δ 8.13 (m, 1H),
7.41−7.24 (m, 5H), 6.58–6.39 (m, 2H), 4.84 (dd, J = 12.1, 5.1 Hz, 1H), 2.83−2.64 (m,
3H), 1.19 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 163.9, 147.0, 143.6, 130.9, 128.6,
127.9, 125.8, 73.2, 57.3, 42.6, 22.4; HRMS (ESI) calcd for C15H21NO2SNa [M + Na]+
302.1191, found 302.1178.
4.2.12. (S)-N-((R,1E,2E)-5-hydroxyhept-2-en-1-ylidene)-2-methylpropane-2-sulfinamide
13d
Following general procedure 4.2.1 above, 187 mg (81% yield) of inseparable
diastereomers 13d were obtained as a yellowish oil after purification by flash column
20

chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3419, 2962, 1640, 1581,
1458, 1363, 1081, 1062, 999, 719 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.14 (m, 1H), 6.48
(dddd, J = 15.5, 9.9, 8.7, 2.6 Hz, 2H), 3.72−3.58 (m, 1H), 2.50−2.28 (m, 2H), 1.60 (s,
1H), 1.52−1.38 (m, 2H), 1.14 (s, 9H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 163.9, 147.4, 130.9, 72.1, 57.3, 40.5, 30.1, 22.5, 9.8; HRMS (ESI) calcd for
C11H21NO2SNa [M + Na]+ 254.1191, found 254.1179.
4.2.13. (S)-N-((S,1E,2E)-5-cyclohexyl-5-hydroxypent-2-en-1-ylidene)-2-methylpropane-
2-sulfinamide (13e)
Following general procedure 4.2.1 above, 208 mg (73% yield) of inseparable
diastereomers 13d were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3427, 2970, 2925, 1636,
1
1575, 1456, 1363, 1059, 981, 743 cm-1; H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 9.2
Hz, 1H), 6.73−6.41 (m, 2H), 3.56 (dd, J = 8.4, 3.6 Hz, 1H), 2.62−2.34 (m, 2H),
1.91−1.74 (m, 3H), 1.66 (dd, J = 37.3, 10.0 Hz, 3H), 1.47−1.33 (m, 1H), 1.27−1.24 (m,
2H), 1.21 (s, 9H), 1.11 (dddd, J = 25.1, 21.9, 15.5, 7.7 Hz, 3H);13C NMR (125 MHz,
CDCl3) δ 164.0, 148.5, 130.5, 74.8, 57.2, 43.4, 37.9, 29.0, 27.9, 27.8, 26.3, 26.0, 22.4;
HRMS (ESI) calcd for C15H27NO2SNa [M + Na]+ 308.1660, found 308.1650.
4.2.14. (4E,6E)-methyl 6-(((S)-tert-butylsulfinyl)imino)-2-hydroxy-2,5-dimethylhex-4-
enoate (14)
Following general procedure 4.2.1 above, 263 mg (91% yield) of inseparable
diastereomers 14 were obtained as a yellowish oil after purification by flash column
chromatography eluting with EtOAc/hexane (3:7). IR (neat) 3395, 2980, 2954, 2925,
2869, 1737, 1636, 1581, 1455, 1364, 1083, 984 cm-1; 1H NMR (500 MHz) δ 8.12 (s, 1H),
21

6.23 (t, J = 7.4 Hz, 1H), 3.78 (s, 3H), 2.81−2.62 (m, 2H), 1.90 (s, 3H), 1.47 (s, 3H), 1.19
13
(s, 9H); C NMR (126 MHz) δ 176.6, 166.3, 140.8, 137.7, 74.3, 57.2, 53.0, 39.3, 25.9,
22.5, 11.6; HRMS (ESI) calcd for C13H24NO4S [M + H]+ 290.1426, found 290.1417.
Acknowledgements
The NSF (CHE-1665145) supported this research. Support for the NMR facility at
Temple University by a CURE grant (Pennsylvania Department of Health) is gratefully
acknowledged. We thank Prof. Graham E. Dobereiner for valuable dissussions and kind
assistance with DFT calculations, in addition to Prof. Sarah Wengryniuk for access to
HPLC instrumentation.
Supporting Information
Stereochemical assignments by Mosher ester analysis and HPLC including
experimental details, 1H and 13C NMR spectra for all new compounds, DFT calculations
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24

Temple University
A Commonwealth University
Rodrigo B. Andrade, Ph.D.
Professor
Department of Chemistry
Philadelphia, PA 19122
Voice: 215-204-7155
Fax: 215-204-9851
http://www.chem.temple.edu
Highlights for “The Vinylogous Aldol Reaction of N-Sulfinyl Metallodienamines”
•
development and optimization of the reaction of N-sulfinyl metallodienamines with
aldehydes and ketones.
•
•
key step employed in total synthesis of (−)-albocycline
update and correct the diastereoselectivity of the reaction employing both HPLC
and Mosher ester analysis
•
•
yields ranging from 68−89% and diastereomeric ratios as high as 5.9:1.
A transition state supported by DFT calculations has been advanced to rationalize
the stereochemical course of the reaction.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: