Group-Assisted Purification Chemistry for Asymmetric Mannich-type Reaction of Chiral N-Phosphonyl Imines with Azlactones Leading to Syntheses of α-Quaternary α,β-Diamino Acid Derivatives ?

Article abstract of DOI:10.1021/acs.joc.7b02556

An asymmetric Mannich-type reaction between chiral N-phosphonyl imines and azlactones [oxazol-5(4H)-ones] has been established under convenient conditions at room temperature. The reaction was performed without using any bases, additives, or catalysts to achieve up to excellent chemical yields and diastereoselectivity for 32 examples. The α-quaternary syn-α,β-diamino acid products were purified simply by washing the crude mixtures with cosolvents, following the group-assisted purification chemistry/technology, without involving traditional chromatography or recrystallization methods. The auxiliary can be readily removed and recycled for reuse. The absolute configuration was unambiguously assigned by X-ray structural analysis.

Full text of DOI:10.1021/acs.joc.7b02556

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Article
Group-Assisted Purification (GAP) chemistry for Asymmetric
Mannich-type reaction of chiral N-phosphonyl imines with azlactones
leading to syntheses of #-quaternary #, #-diamino acid derivatives
Haowei Zhang, Zhen Yang, Brian Nlong Zhao, and Guigen Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02556 • Publication Date (Web): 13 Dec 2017
Downloaded from http://pubs.acs.org on December 13, 2017
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Group-Assisted Purification (GAP) chemistry for Asymmetric
Mannich-type reaction of chiral N-phosphonyl imines with azlactones
leading to syntheses of α-quaternary α, β-diamino acid derivatives†
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Haowei Zhang‡, Zhen Yang‡, Brian Nlong Zhao‡,$ and Guigen Li*‡,#
‡Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing, 210093, China
#Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas
79409ꢀ1061, USA
*Eꢀmail: guigen.li@ttu.edu.
† We would like to dedicate this work to Professor Albert Padwa on occasion of his 80th birthday.
ABSTRACT: Asymmetric Mannichꢀtype reaction between chiral Nꢀphosphonyl imines and
azlactones (oxazolꢀ5(4H)ꢀones) has been established under convenient conditions at room
temperature. The reaction was performed without using any bases, additives or catalysts to
achieve up to excellent chemical yields and diastereoselectivity for 32 examples. The αꢀquaternary
synꢀα, βꢀdiamino acid products were purified simply by washing the crude mixtures with
coꢀsolvents, following the groupꢀassisted purification (GAP) chemistry/technology, without
involving traditional chromatography or recrystallization methods. The auxiliary can be readily
removed and recycled for reꢀuse. The absolute configuration was unambiguously assigned by
Xꢀray structural analysis.
KEY WORDS: Nꢀphosphonyl imine, azlactone, oxazolones, α, βꢀdiamino acid, quaternary chiral
center.
INTRODUCTION
α, βꢀDiamino acids are important common structural building blocks found in natural products,
peptides, peptidomimetics, antibiotics and many other medicinally valuable compounds.1ꢀ2 These
diamino acids containing two vicinal nitrogenꢀbearing and αꢀquaternary chiral centers have
represented a challenging task for synthetic organic community, especially when their enantiopure
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forms need to be controlled efficiently. As so, a variety of methodologies have been devised for
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their preparation in enantiomeric selective manners.1,
One of the most straightforward
approaches to chiral α, βꢀdiamino acids is to perform direct Mannich reaction between αꢀamino
acid equivalents and imines, in which CꢀC bonds and two stereogenic centers are created in a
single synthetic operation.4ꢀ6 To approach asymmetric synthesis of α, βꢀdiamino acid derivatives,
several chiral enolates4 and chiral sulfinyl imines3a, 5 were ultilized in these Mannich reactions.
However, these reactions often suffered from strong bases (such as LDA or LiꢀHMDS) and low
temperature (often lowered to ꢀ78 oC).
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Among different nucleophilic αꢀamino acid equivalents, azlactones (also known as oxazolones
or oxazolꢀ5(4H)ꢀones) have been wellꢀknown alternatives, since their scaffold basically consists of
“masked” amino acids, which can be used in the synthesis of natural and biomedical molecules,
and in the construction of quaternary αꢀamino acids.7 Several studies have been conducted in
regards to the efficient syntheses of α, βꢀdiamino acid equivalents via asymmetric Mannichꢀtype
reaction between sulfonylꢀimines and azlactones.7ꢀ8 TMS quinine8b, gold complexes8c, chiral
ionꢀpair catalysts9, phosphoric acid derivatives8f and chiral thioureas10 were also utilized in these
reactions to obtain good to excellent yields and stereoselectivities. However, quite complex
catalysts or high catalyst loadings are usually required, and in some cases, the stereoselectivities
were poorly controlled. Sometimes, their substrate scope also limits their applications on large
scales. As far as we are concerned, except for sulfonylꢀimines, chiral sufinyl imines and
Nꢀphosphonyl imines have not been applied into the Mannich reaction with azlactones so far.
Over the past few years, we have made many efforts on designing new chiral Nꢀphosphonyl
imines for asymmetric reactions. Many asymmetric reactions have been successfully conducted,
including azaꢀMBH reaction12, borylation13, the umpolung reaction14 and several others.15 In
addition to wellꢀcontrolling stereoselectivities, these auxiliaries have extra bonus effects on
simplifying the purification progress. With Nꢀphosphonyl containing groups are attached, the
resulting products can often be obtained simply by washing the crude mixture with common
solvents without recourse to chromatography or recrystallization,12ꢀ16 leading to a new concept
called groupꢀassisted purification (GAP) chemistry/technology. GAP chemistry is generally
defined as the chemistry for organic synthesis and chemical production that can avoid classical
purification processes, such as chromatography and recrystallization, by purposely introducing
wellꢀfunctionalized groups in starting materials, followed by being transferred into final products.
This strategy can amazingly convert liquid products into corresponding solid ones, for further
enabling their purification simply by washing with common solvents. Indeed, GAP chemistry is
the first such a concept in chemical sciences that combines all four aspects of reagent, reaction,
separation and purification. Due to its hybrid characteristics, GAP chemistry has to meet the
requirements of chemical and physical aspects, such as chemical reactivity and stability of GAP
starting materials, adequate solubility of GAP products for washing and for further reactions,
asymmetric control by chiral GAP groups for both asymmetric synthesis and asymmetric catalysis,
extensive substrate scopes, and deprotection of GAP auxiliaries for recycle and reꢀuse.
During our continuing research on this topic, we are eager to expand GAP chemistry scope by
developing more diversities of asymmetric reactions by involving Nꢀphosphonyl imines as GAP
starting materials. Following the previous studies in our laboratory,15b, 17 here we would like to
report that the asymmetric Mannichꢀtype reactions between Nꢀphosphonyl imines and azlactones
leads to the efficient formation of αꢀquaternary synꢀα, βꢀdiamino acid analogs, without the use of
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any bases, additives and catalysts (Scheme 1). Azlactones derived from several natural and
unnatural αꢀamino acids were successfully apllied in this reaction with good to high yields and
excellent diastereoselectivities. This reaction follows the GAP chemistry process in which pure
products can be obtained simply by washing crude mixtures with coꢀsolvents of DCM and hexane.
Scheme 1 Asymmetric synthesis of α-quaternary α, β-diamino acid derivatives
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RESULTS AND DISCCUTION
Initially, we conducted the Mannichꢀtype reaction between Nꢀphosphonyl imine 1a and
4ꢀmethylꢀ2ꢀphenylꢀoxazolꢀ5(4H)ꢀone 2a. The reaction conditions were carefully optimized, and
the results were summarized in Table 1. Considering the acidity of the αꢀhydrogen of the
azlactone (pKa≈9), some organic and inorganic bases were utilized to form nucleophilic enolates
(entries 1ꢀ4). However, except DABCO gave a modest yield (55%), other stronger bases gave
only trace amounts of products, because the azlactones can be decomposed to amino esters.
Giving the fact that imines can be activated by the BronstedꢀLowry acids, we then added several
acids into the reaction mixture (entries 5ꢀ8). Surprisingly, when imine and azlactone were reacted
in DCM with no additives (entry 5), we got excellent conversion rate (92%) and
diastereoselectivities (only syn isomers were observed, dr of syn 12:1). Notably, after
concentration, precipitating with hexane and washing the crude mixture with coꢀsolvents of DCM
and hexane, the major product can be obtained in 83% yield and >20:1 dr, following the GAP
chemistry workꢀup procedure. Acetic acid or benzoic acid (10% mol) can accelerate the reaction,
allowing the completion within 8 hours (entries 6, 7), as well as increasing the diastereoselectivity
slightly. However, stronger acid TFA can cause the decomposition of the imine, thus lower the
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yield. Then, decreasing the temperature to 0 C led to >20:1 dr but an inferior conversion rate
(entry 9). Finally, the optimization of solvents revealed that all five solvents THF, toluene, ether,
acetonitrile and acetone deliver lower yields and diastereoselectivity than DCM (entries 10ꢀ14). In
order to compare the reactivity with the Nꢀphosphonyl imine, we introduced the chiral sulfinyl
imine 1a’ into the reaction (entries 15, 16), which led to no product but the recovery of the starting
materials.
Table 1. Screening of reaction conditions
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entrya
imine
1a
additive
DABCO
KOH
solvent
DCM
DCM
DMF
yield
55%
19%
<5%
trace
syn:antie
dr of syne
1b
2
>20:1
8.8:1
1a
>20:1
1:3.2
3
1a
K2CO3
LDA
/
/
/
/
4
1a
DCM
92%
(83%e)
12:1
(>20:1e)
5
1a
/
DCM
>20:1
6c
7c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a’
1a’
AcOH (10% mol)
DCM
DCM
DCM
DCM
THF
89%
93%
29%
82%d
54%
84%
81%
83%
63%
0%f
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
/
17:1
16:1
2.6:1
>20:1
6.8:1
11:1
9.1:1
8.8:1
10:1
/
PhCOOH (10% mol)
8
TFA (10% mol)
9d
10
11
12
13
14
15
16
/
/
/
Et2O
/
toluene
MeCN
acetone
DCM
DCM
/
/
DABCO
0%f
/
/
aReactions were performed with imine (0.4 mmol), azlactone (0.48 mmol) in 10 mL solvent under N2 at room
temperature for 18h. Reaction time 48h.cReaction time 8h. Temperature decreased to 10 C. isolated yield by
GAP washing. Other conversion rates were determined by 31P NMR analysis of the crude mixture. eThe
diastereoisomer ratio were determined by crude 31P NMR. syn:anti>20:1 means only syn isomers were observed.
dr represents the ratio of two syn isomers. fThe starting materials were maintained.
b
d
o
e
With the optimized reaction conditions established, the substrate scope of azlactones 2 was
evaluated, and the results were summarized in Scheme 2. We got good to high yields, as well as
complete syn selectivity and good diastereoselectivity in all the cases. The substituent on the
aromatic ring (R2 group) did not have significant effect on asymmetric induction (3aaꢀ3ai), but
4ꢀnitro substituent (3ad) showed that the electronꢀwithdrawing group has a negative effect on the
diastereoselectivity. The heteroꢀaryl groups were also bearable in the reactions (3ah, 3ai). Then,
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azlactones derived from several natural αꢀamino acids (including Ala, Val, Phe, Leu, Met, Tyr and
Trp) and some unnatural cases were conducted into the reactions (3ajꢀ3aq). The isopropyl group
seriously diminished the yield (3ak, 44%) maybe due to the steric hindrance. The hetero
atomꢀcontaining groups on the side chain were also tolerable (3aoꢀ3aq), leading to high yields
(80%ꢀ89%) and dr (95:5).
Scheme 2. Substrate scope of the azlactonesa
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aReactions were performed with imine (0.4 mmol), azlactone (0.48 mmol) in dry DCM at room temperature for
b
c
18h. Isolated yields after GAP washing. the syn:anti ration and dr were determined from 31P NMR of crude
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d
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reaction mixture, see Support Information for details. The reaction was conducted on 2g scale. The absolute
stereochemistries of 3ah were determined by Xꢀray crystallography, and those of the other products were assigned
by analogy. fFurther recrystallization was conducted after GAP washing to afford the single isomer.
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Subsequently, the substrate scope of Nꢀphosphonyl imines 1 was evaluated, and the results
were listed in Scheme 3. Various aromatic imines containing either electronꢀwithdrawing or
electronꢀdonating groups could be used in the reaction. Good yields and excellent
diastereoselectivities were obtained in most cases, except the 4ꢀmethyloxyl, 2ꢀbromo, 2ꢀfuryl,
2ꢀthienyl cases (3fa, 3ka, 3pa, 3oa), in which the dr were lower than 90:10. In most of the cases ,
the pure products were obtained simply by washing the crude mixture with hexane/DCM once or
twice without the use of chromatography. However, due to the low dr value, further
recrystallization was needed in cases 3fa, 3ka and 3oa to afford the single isomer. Besides the
aromatic Nꢀphosphonyl imines (R3=aryl), the aliphatic imines (R3= cyclohexyl, iꢀPr, Et, etc.) were
unstable and inseparable, which failed to participate in these reactions.
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Scheme 3. Substrate scope of the N-phosphonyl iminesa
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aReactions were performed with imine (0.4 mmol), azlactone (0.48 mmol) in dry DCM at room temperature for
b
c
18h. Isolated yields after GAP washing. the syn:anti ration and dr were determined from 31P NMR of crude
mixture. dFurther recrystallization was conducted after GAP washing to afford the single isomer.
The absolute configuration of 3h was determined by Xꢀray structural analysis (see Supporting
Information), revealing the two vicinal chiral centers retaining a (2S, 3R) configuration, which is
in contrast with our previous work18. According to the literature report19, this reaction seems to
follow an azaꢀene reaction. The transition state shown in Figure 1 revealed that the PꢀO bond of
the Nꢀphosphonyl imine activated the enol intermediate of the azlactone through a hydrogen
bond8e, 8f, 19c, followed by an azaꢀene type reaction to form the observed stereochemistry, which
was controlled by the chiral auxiliary.
Figure 1 Plausible activation mode for the stereoselective reaction between chiral
N-phosphonyl imines and azlactones
To expand the synthetic utility of the present system, the chiral auxiliary was cleaved (Scheme
4A). The Mannich product 3aa was dissolved in MeOH and treated with 48% aqueous HBr,
followed by Boc protection, to form quaternary synꢀα, βꢀdiamino ester 4 in 60% overall yield,
with 72% of the chiral amine recycled. Adduct 4 was subsequently converted to other derivatives,
including fully deprotected α, βꢀdiamino acid 5 and dipeptide 6 in one or two operations (Scheme
4B). These compounds are crucial fragments of some bioactive peptides and medicinally valuable
compounds.
Scheme 4 Derivatization of the Mannich product 3aaa
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aConditions: (a) 10 eq. HBr, MeOH, rt; (b) (Boc)2O, TEA, DCM, rt; (c) PhOH, AcOH, 6M HCl, reflux; (d)
TFA, DCM, rt; (e) BocꢀValꢀOH, EDC, HOBt, TEA, DCM, 0 oC to rt.
In summary, asymmetric Mannichꢀtype reaction between chiral Nꢀphosphonyl imines and
azlactones has been presented. Without the use of any additives, bases or catalysts, the reaction
went smoothly to form αꢀquaternary synꢀα, βꢀdiamino acid derivatives in good to excellent
chemical yields and diastereoselectivity. The pure products can be obtained simply by GAP
workꢀup procedure, and can be further transformed into valuable Bocꢀprotected α, βꢀdiamino
esters, fully deprotected α, βꢀdiamino acids and dipeptides. The absolute stereochemistry was
determined by Xꢀray analysis, which was in contrast with our previous work. Our further studies
will be focused on new asymmetric reactions of Nꢀphosphonyl imines, enamines and hemiaminals.
EXPERIMENTAL SECTION
General Method
All commercially available chemicals were used as received without further purification.
Solvents were delivered from Innovation Technology solvent system. All reactions were carried
out in flame dried flask under nitrogen atmosphere. The 1H and 13C NMR spectra were recorded in
CDCl3 on a 400 MHz instrument with TMS as internal standard. Chemical shifts (δ) were reported
in ppm with respect to TMS. Data are represented as follows: chemical shift, mutiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet), coupling constant (J, Hz) and integration. HRMS
analyses were carried out using a TOFꢀMS instrument with an ESI source.
Synthesis and Characterization of N-Phosphonyl Imines 1a-1p
These compounds were synthesized according to our published procedures.20 Into a dried and
nitrogen flushed roundꢀbottomed flask, chiral phosphoramide (259 mg, 1.00 mmol), aldehyde
(1.50 mmol) and DCM (5 mL) were loaded. The resulting mixture was protected by nitrogen and
o
was cooled to 0 C prior to the addition of DIEA (0.50 mL, 3 mmol). Into the above mixture, a
solution of TiCl4 in DCM (1 M, 0,60 mmol) was added in drops. The reaction was stirred at 0 oC
for 30 min and at room temperature for 24 h. The clear solution of the crude reaction mixture was
directly transferred to silica gel (200–300 mesh) packed in a column for chromatography and
1
eluted by mixed solvents of PE/EA (v/v,7:3 to 1:1) to give imine products. The H , 13C and 31P
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NMR data for these compounds agree with the published data.20 Some newly synthesized imines
were characterized as follows.
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(3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀ((E)ꢀ(2ꢀ(trifluoromethyl)benzylidene)amino)octahydr
oꢀ1Hꢀbenzo[d][1,3ꢀ,2]diazaphosphole 2ꢀoxide(1m):
20
1
Yellow solid, 305 mg, 74% yield; [α]D = +41.8 (c = 0.78, CHCl3); H NMR
(400 MHz, CDCl3) δ 9.28 (dd, J = 31.9, 2.0 Hz, 1H), 8.38 (d, J = 7.6 Hz, 1H),
7.75 (d, J = 7.6 Hz, 1H), 7.69ꢀ7.59 (m, 2H), 3.61ꢀ3.39 (m, 2H), 3.12ꢀ3.01 (m, 1H),
2.55 (td, J = 10.8, 2.9 Hz, 1H), 2.16ꢀ1.98 (m, 2H), 1.82 (d, J = 11.4 Hz, 2H), 1.40ꢀ1.23 (m, 13H),
1.07 (d, J = 6.6 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ 164.7, 134.0 (d, J = 28.1 Hz), 132.3,
131.9, 130.8 (q, J = 31.3 Hz), 129.1, 125.9 (d, J = 5.5 Hz), 124.2 (q, J = 274.3 Hz), 59.9 (d, J =
7.8 Hz), 58.9 (d, J = 10.4 Hz), 45.4 (d, J = 2.5 Hz), 44.8 (d, J = 2.5 Hz), 30.0 (d, J = 9.2 Hz), 29.5
(d, J = 10.2 Hz), 24.4, 24.3, 21.9 (d, J = 2.8 Hz), 21.5 (d, J = 4.1 Hz), 20.8, 20.5; 31P NMR (162
MHz, CDCl3) δ 25.92; HRMS (ESIꢀTOF) m/z [C20H29F3N3OP+Na]+ calcd for 438.1893, found
438.1896.
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(3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀ((E)ꢀ(naphthalenꢀ1ꢀylmethylene)amino)octahydroꢀ1
Hꢀbenzo[d][1,3,2]diazaphosphole 2ꢀoxide(1n):
White solid, 317 mg, 80% yield; [α]D = +4.1 (c = 0.73, CHCl3); 1H NMR (400
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MHz, CDCl3) δ 9.73 (d, J = 33.8 Hz, 1H), 9.09 (d, J = 8.5 Hz, 1H), 8.21 (d, J =
6.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.67ꢀ7.62 (m, 1H), 7.61ꢀ7.54 (m,
2H), 3.56ꢀ3.40 (m, 2H), 3.20ꢀ3.08 (m, 1H), 2.93 (s, 1H), 2.12 (d, J = 11.4 Hz, 2H), 1.84 (d, J = 4.6
Hz, 2H), 1.44ꢀ1.28 (m, 13H), 1.14 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.0 (d, J
= 6.9 Hz), 134.0, 133.7, 132.2, 131.7, 128.9, 128.0, 126.5, 125.4, 124.1, 60.1 (d, J = 8.3 Hz), 59.6
(d, J = 9.1 Hz), 45.4 (d, J = 2.8 Hz), 44.8 (d, J = 3.1 Hz), 29.9 (d, J = 9.8 Hz), 29.8 (d, J = 9.0 Hz),
24.53, 24.49, 22.2 (d, J = 3.3 Hz), 21.4 (d, J = 3.2 Hz), 20.9, 20.7; 31P NMR (162 MHz, CDCl3) δ
25.21; HRMS (ESIꢀTOF) m/z [C20H29F3N3OP+Na]+ calcd for 438.1893, found 438.1896.
(3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀ((E)ꢀ(furanꢀ2ꢀylmethylene)amino)octahydroꢀ1Hꢀbenz
o[d][1,3,2]diazaphosphole 2ꢀoxide(1o):
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White solid, 182 mg, 52% yield; [α]D = ꢀ52.7 (c = 1.02, CHCl3); H NMR (400
MHz, CDCl3) δ 8.85 (d, J = 33.7 Hz, 1H), 7.67 (s, 1H), 7.12 (s, 1H), 6.63ꢀ6.55 (m,
1H), 3.46ꢀ3.28 (m, 2H), 3.13ꢀ3.04 (m, 1H), 2.99 (s, 1H), 2.14ꢀ1.98 (m, 2H), 1.81 (d, J = 5.8 Hz,
2H), 1.38ꢀ1.21 (m, 13H), 1.14 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.4 (d, J =
5.7 Hz), 152.6 (d, J = 31.7 Hz), 147.3, 119.7, 112.7, 59.98 (d, J = 8.6 Hz), 59.57 (d, J = 8.8 Hz),
45.17 (d, J = 3.0 Hz), 44.62 (d, J = 3.3 Hz), 29.86 (d, J = 9.8 Hz), 29.30 (d, J = 9.4 Hz), 24.5, 24.4,
22.0 (d, J = 3.5 Hz), 21.0 (d, J = 2.8 Hz), 20.8, 20.6; 31P NMR (162 MHz, CDCl3) δ 25.58; HRMS
(ESIꢀTOF) m/z [C17H28N3O2P+Na]+ calcd for 360.1811, found 360.1813.
(3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀ((E)ꢀ(thiophenꢀ2ꢀylmethylene)amino)octahydroꢀ1Hꢀbe
nzo[d][1,3,2]diazaphosphole 2ꢀoxide(1p):
Yellow solid, 157 mg, 44%; [α]D20 = +36.9 (c = 0.51, CHCl3); 1H NMR (400
MHz, CDCl3) δ 9.08 (dd, J = 31.5, 0.6 Hz, 1H), 7.63 (d, J = 4.0 Hz, 2H), 7.17 (t, J
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= 4.3 Hz, 1H), 3.48ꢀ3.31 (m, 2H), 3.12ꢀ3.03 (m, 1H), 2.89 (s, 1H), 2.07 (d, J = 5.7 Hz, 2H), 1.81
(s, 2H), 1.39ꢀ1.24 (m, 13H), 1.13 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.9, 134.9,
133.0, 128.3, 59.9 (d, J = 8.3 Hz), 59.5 (d, J = 8.8 Hz), 45.2 (s), 44.7 (d, J = 3.0 Hz), 29.8 (d, J =
10.0 Hz), 29.5 (d, J = 9.5 Hz), 24.5, 24.4, 22.0 (d, J = 3.0 Hz), 21.1 (d, J = 2.8 Hz), 20.9, 20.6; 31P
NMR (162 MHz, CDCl3) δ 25.20; HRMS (ESIꢀTOF) m/z [C17H28N3OPS+Na]+ calcd for 376.1583,
found 376.1586.
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Synthesis and Characterization of Azlactones 2a-2q
The azlactones 2aꢀ2q were prepared according to the literature method.21 To a suspension of
Nꢀaroyl amino acid (1 equiv) in dry DCM (0.1 M based on substrate) under N2 at 0 oC was added
EDCI (1.1 equiv). The materials were stirred at 0 oC for 1 hour. The reaction mixture was diluted
with an equal volume of DCM, and washed successively with saturated aqueous NaHCO3, water
and brine (each 1/2 the volume of the organic phase), then dried over Na2SO4 and concentrated
under reduced pressure. In all cases products were obtained in a form suitable for use without
further purification. The NMR data agree with the literature report.21 Some newly synthesized
azlactones were characterized as follows.
4ꢀmethylꢀ2ꢀ(thiophenꢀ2ꢀyl)oxazolꢀ5(4H)ꢀone (2i): white solid, 2.33g, 89%; 1H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 3.7 Hz, 1H), 7.60 (d, J = 5.0 Hz, 1H), 7.15 (dd, J = 5.0,
3.8 Hz, 1H), 4.43 (q, J = 7.5 Hz, 1H), 1.58 (d, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
178.4, 157.5, 132.0, 131.8, 128.5, 128.1, 60.9, 17.0; HRMS (ESIꢀTOF) m/z [C8H7NO2S+Na]+
calcd for 204.0090, found 204.0089.
4ꢀ(4ꢀhydroxybenzyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (2o): white solid, 875mg, 65%; 1H NMR (400
MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.1 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.10 (d,
J = 8.1 Hz, 2H), 6.68 (d, J = 8.2 Hz, 2H), 4.67 (t, J = 5.4 Hz, 1H), 3.32 (dd, J = 14.1, 4.4 Hz, 1H),
3.13 (dd, J = 14.1, 6.3 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 177.4, 162.3, 155.0, 133.1, 131.0,
129.0, 128.1, 127.1, 125.6, 115.5, 66.7, 36.6; HRMS (ESIꢀTOF) m/z [C16H13NO3+Na]+ calcd for
290.0788, found 204.0791.
4ꢀ(2ꢀ(methylthio)ethyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (2p): colorless oil, 1.12g,
95%; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 6.9 Hz, 1H), 7.49 (t, J =
7.5 Hz, 2H), 4.60 (t, J = 6.3 Hz, 1H), 2.74 (t, J = 6.9 Hz, 2H), 2.36ꢀ2.25 (m, 1H), 2.21ꢀ2.13 (m,
1H), 2.12 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 178.4, 162.2, 132.9, 128.9, 128.0, 125.9, 63.8,
30.6, 30.2, 15.2; HRMS (ESIꢀTOF) m/z [C12H13NO2S+Na]+ calcd for 258.0559, found 258.0561.
4ꢀ((1Hꢀindolꢀ2ꢀyl)methyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (2q): yellow solid,
1.18g, 81%; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 7.3
Hz, 1H), 7.52 (t, J = 7.1 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 7.18ꢀ7.07 (m,
3H), 4.76 (s, 1H), 3.59ꢀ3.48 (m, 1H), 3.41 (dd, J = 14.7, 5.9 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ 178.0, 162.1, 136.1, 132.8, 128.8, 128.1, 127.5, 125.9, 123.5, 122.2, 119.7, 119.3, 111.1, 109.8,
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66.6, 27.4; HRMS (ESIꢀTOF) m/z [C18H14N2O2+Na]+ calcd for 313.0947, found 313.0948.
Typical Procedure for the Asymmetric Synthesis of Mannich Products 3aa-3pa through GAP
Progress
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In an oven dried and nitrogen charged 50 mL roundꢀbottom vial, a solution of 0.4 mmol
Nꢀphosphonyl imine 1 in 5 mL DCM was stirred at room temperature. Then a solution of 0.48
mmol azlactone 2 in 5mL DCM was added. The reaction mixture was stirred for 8~18 hours until
TLC analysis indicated complete consumption of the imine. After that, the solution was
concentrated before adding hexane to form precipitation. After filtration, the crude solid was
washed once or twice with hexane/DCM (v/v, 10/1) to afford the pure product. In some cases,
further recrystallization was conducted to obtain the single isomer for characterization.
Data for Pure Products 3aa-3pa
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3aa): 2.0 g imine 1 (5.76
mmol) was applied in this reaction, obtaining a white solid, 2.50 g, 83% yield; m.p. 171.4ꢀ174.2
oC; [α]D20 = ꢀ53.5 (c = 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 2H), 7.59
(t, J = 7.3 Hz, 1H), 7.54ꢀ7.46 (m, 4H), 7.32 (t, J = 7.3 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 4.93ꢀ4.85
(m, 1H), 3.63ꢀ3.48 (m, 1H), 2.96ꢀ2.75 (m, 3H), 2.68 (t, J = 8.0 Hz, 1H), 1.95 (m, 2H), 1.67 (d, J =
10.1 Hz, 2H), 1.36 (s, 3H), 1.30ꢀ1.16 (m, 7H), 0.98 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H),
0.65 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.2, 161.2, 140.5, 133.0, 128.9, 128.6,
128.5, 128.2, 128.0, 126.1, 74.1 (d, J = 10.3 Hz), 62.1, 59.4 (d, J = 11.6 Hz), 58.8 (d, J = 9.5 Hz),
44.1 (d, J = 3.9 Hz), 44.0 (d, J = 3.4 Hz), 32.0 (d, J = 12.2 Hz), 31.1 (d, J = 10.1 Hz), 24.4 (d, J =
3.6 Hz), 24.3 (d, J = 9.1 Hz), 23.5 (d, J = 4.3 Hz), 22.4, 19.7, 19.1; 31P NMR (162 MHz, CDCl3) δ
21.84; HRMS (ESIꢀTOF) m/z [C29H39N4O3P+Na]+ calcd for 545.2652, found 545.2650.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀmethyloxazolꢀ5(4H)ꢀone (3ab): white solid,
174 mg, 79% yield; m.p. 96.1ꢀ98.0 oC; [α]D20 = ꢀ44.3 (c = 0.84, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.24 (t, J =
7.3 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 4.84 (dd, J = 11.3, 9.5 Hz, 1H), 3.88 (s, 3H), 3.60ꢀ3.45 (m,
1H), 3.00ꢀ2.78 (m, 3H), 2.75ꢀ2.64 (m, 1H), 1.95 (t, J = 12.1 Hz, 2H), 1.67 (d, J = 11.1 Hz, 2H),
1.33 (s, 3H), 1.29ꢀ1.18 (m, 7H), 0.95 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.66 (d, J = 6.8
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.3, 163.4, 160.9, 140.2, 130.1, 128.7, 128.4, 128.0,
118.3, 114.3, 74.1 (d, J = 7.3 Hz), 61.5, 59.5 (d, J = 11.4 Hz), 59.1 (d, J = 10.6 Hz), 55.7, 44.1 (d,
J = 3.1 Hz), 43.5 (d, J = 4.8 Hz), 31.9 (d, J = 12.0 Hz), 31.3 (d, J = 10.3 Hz), 24.7 (d, J = 8.5 Hz),
24.4, 23.7 (d, J = 5.0 Hz), 22.4, 19.6, 19.2; 31P NMR (162 MHz, CDCl3) δ 22.02; HRMS
(ESIꢀTOF) m/z [C30H41N4O4P+Na]+ calcd for 575.2758, found 575.2759.
(S)ꢀ2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3
,2]diazaphospholꢀ2(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀmethyloxazolꢀ5(4H)ꢀone (3ac): white solid,
178 mg, 80% yield; m.p. 110.5ꢀ111.8 oC; [α]D20 = ꢀ41.4 (c = 0.78, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.3 Hz, 4H), 7.31 (t, J = 7.2 Hz, 2H), 7.25 (t, J =
7.3 Hz, 1H), 4.88 (t, J = 10.5 Hz, 1H), 3.60ꢀ3.48 (m, 1H), 2.94ꢀ2.73 (m, 3H), 2.72ꢀ2.60 (m, 1H),
2.00ꢀ1.89 (m, 2H), 1.68 (d, J = 10.5 Hz, 2H), 1.37 (s, 3H), 1.31ꢀ1.15 (m, 7H), 0.97 (d, J = 6.4 Hz,
3H), 0.86 (d, J = 6.7 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.8,
160.3, 139.9, 139.3, 129.5, 129.3, 128.5, 128.4, 128.1, 124.4, 74.4 (d, J = 7.2 Hz), 61.5, 59.4 (d, J
= 11.1 Hz), 59.1 (d, J = 10.6 Hz), 44.2 (d, J = 4.9 Hz), 43.6 (d, J = 4.7 Hz), 31.8 (d, J = 13.2 Hz),
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31.2 (d, J = 10.0 Hz), 24.7 (d, J = 8.4 Hz), 24.4, 23.6 (d, J = 4.9 Hz), 22.3, 19.6, 19.1; 31P NMR
(162 MHz, CDCl3) δ 21.78; HRMS (ESIꢀTOF) m/z [C29H38ClN4O3P+Na]+ calcd for 579.2262,
found 579.2266.
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀ(4ꢀnitrophenyl)oxazolꢀ5(4H)ꢀone (3ad): After GAP
washing procedure, the single isomer was recrystallized as a pale yellow solid, 160 mg, 71% yield;
m.p. 125.4ꢀ126.6 oC; [α]D20 = ꢀ26.4 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J =
8.6 Hz, 2H), 8.17 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 7.0 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.26ꢀ7.23
(m, 1H), 4.94 (t, J = 10.6 Hz, 1H), 3.64ꢀ3.49 (m, 1H), 3.01ꢀ2.78 (m, 3H), 2.77ꢀ2.61 (m, 1H),
2.03ꢀ1.89 (m, 2H), 1.69 (d, J = 10.4 Hz, 2H), 1.45 (s, 3H), 1.31ꢀ1.15 (m, 7H), 1.00 (d, J = 5.0 Hz,
3H), 0.86 (d, J = 6.7 Hz, 3H), 0.65 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.1,
159.4, 150.3, 139.4, 131.4, 129.1, 128.4, 128.2, 128.1, 123.9, 74.7 (d, J = 6.9 Hz), 61.5, 59.3 (d, J
= 9.5 Hz), 59.0 (d, J = 10.8 Hz), 44.2 (d, J = 8.3 Hz), 43.5 (d, J = 4.6 Hz), 31.7 (d, J = 10.0 Hz),
31.1 (d, J = 10.2 Hz), 24.5 (d, J = 8.1 Hz), 24.3, 23.4 (d, J = 4.5 Hz), 22.1, 19.4, 19.0; 31P NMR
(162 MHz, CDCl3) δ 21.72; HRMS (ESIꢀTOF) m/z [C29H38N5O5P+Na]+ calcd for 590.2503,
found 590.2505.
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ2ꢀ(4ꢀfluorophenyl)ꢀ4ꢀmethyloxazolꢀ5(4H)ꢀone (3ae): white solid,
160 mg, 74% yield; m.p. 151.3ꢀ153.2 oC; [α]D20 = ꢀ37.8 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.02 (dd, J = 8.7, 5.4 Hz, 2H), 7.47 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.25 (t,
J = 7.3 Hz, 1H), 7.17 (t, J = 8.6 Hz, 2H), 4.88 (dd, J = 11.2, 9.7 Hz, 1H), 3.62ꢀ3.48 (m, 1H),
2.96ꢀ2.78 (m, 3H), 2.75ꢀ2.62 (m, 1H), 2.01ꢀ1.89 (m, 2H), 1.68 (d, J = 10.4 Hz, 2H), 1.37 (s, 3H),
1.31ꢀ1.17 (m, 7H), 0.97 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 179.8, 165.5 (d, J = 254.5 Hz), 160.1, 139.8, 130.5 (d, J = 9.1 Hz),
128.4, 128.3, 128.0, 122.1 (d, J = 3.2 Hz), 116.1 (d, J = 22.2 Hz), 74.2 (d, J = 7.1 Hz), 61.4, 59.3
(d, J = 11.4 Hz), 59.0 (d, J = 10.6 Hz), 43.4 (d, J = 4.7 Hz), 31.7 (d, J = 12.1 Hz), 31.1 (d, J = 10.3
Hz), 24.5 (d, J = 8.3 Hz), 24.3, 23.5 (d, J = 4.9 Hz), 22.2, 19.5, 19.0; 31P NMR (162 MHz, CDCl3)
δ 21.76; HRMS (ESIꢀTOF) m/z [C29H38FN4O3P+Na]+ calcd for 563.2558, found 563.2563.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀ(pꢀtolyl)oxazolꢀ5(4H)ꢀone (3af): white solid, 174 mg,
81% yield; m.p. 104.8ꢀ105.0 oC; [α]D20 = ꢀ37.6 (c = 0.92, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.91 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 7.2 Hz, 2H), 7.34ꢀ7.28 (m, 4H), 7.26ꢀ7.22 (m, 1H), 4.87 (dd,
J = 11.4, 9.4 Hz, 1H), 3.59ꢀ3.46 (m, 1H), 2.93ꢀ2.73 (m, 3H), 2.63 (t, J = 9.3 Hz, 1H), 2.44 (s, 3H),
2.00ꢀ1.88 (m, 2H), 1.67 (d, J = 13.3 Hz, 2H), 1.35 (s, 3H), 1.31ꢀ1.17 (m, 7H), 0.96 (d, J = 6.9 Hz,
3H), 0.85 (d, J = 6.8 Hz, 3H), 0.63 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.3,
161.2, 143.7, 140.1, 129.6, 128.6, 128.4, 128.2, 128.0, 123.2, 74.2 (d, J = 7.2 Hz), 61.5, 59.5 (d, J
= 11.4 Hz), 59.1 (d, J = 10.6 Hz), 44.1 (d, J = 3.4 Hz), 43.5 (d, J = 4.8 Hz), 31.9 (d, J = 12.2 Hz),
31.3 (d, J = 10.2 Hz), 24.7 (d, J = 8.5 Hz), 24.4, 23.7 (d, J = 5.0 Hz), 22.3, 21.9, 19.6, 19.2; 31P
NMR (162 MHz, CDCl3) δ 21.88; HRMS (ESIꢀTOF) m/z [C30H41N4O3P+Na]+ calcd for 559.2808,
found 559.2813.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀ(naphthalenꢀ1ꢀyl)oxazolꢀ5(4H)ꢀone (3ag): Pale yellow
solid, 194 mg, 85% yield; m.p. 149.5ꢀ150.7 oC; [α]D20 = ꢀ45.4 (c = 0.92, CHCl3); 1H NMR (400
MHz, CDCl3) δ 8.49 (s, 1H), 8.11 (dd, J = 8.6, 1.6 Hz, 1H), 7.98ꢀ7.88 (m, 3H), 7.65ꢀ7.50 (m, 4H),
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7.33 (t, J = 7.4 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 4.93 (dd, J = 11.5, 9.5 Hz, 1H), 3.64ꢀ3.50 (m,
1H), 2.88 (dt, J = 9.7, 6.8 Hz, 3H), 2.64 (t, J = 8.2 Hz, 1H), 2.02ꢀ1.87 (m, 2H), 1.69ꢀ1.60 (m, 2H),
1.41 (s, 3H), 1.31ꢀ1.18 (m, 7H), 0.97 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.65 (d, J = 6.8
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.1, 161.3, 140.1, 135.5, 132.7, 129.7, 129.3, 128.8,
128.6, 128.5, 128.4, 128.1, 128.0, 127.2, 123.8, 123.2, 74.4 (d, J = 7.3 Hz), 61.6, 59.5 (d, J = 12.0
Hz), 59.1 (d, J = 10.5 Hz), 44.3 (d, J = 7.4 Hz), 43.6 (d, J = 5.0 Hz), 31.3 (d, J = 10.0 Hz), 31.1,
24.6 (d, J = 7.3 Hz), 24.4, 23.70 (d, J = 5.0 Hz), 22.4, 19.6, 19.2; 31P NMR (162 MHz, CDCl3) δ
21.92; HRMS (ESIꢀTOF) m/z [C33H41N4O3P+Na]+ calcd for 595.2808, found 595.2813.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ2ꢀ(furanꢀ2ꢀyl)ꢀ4ꢀmethyloxazolꢀ5(4H)ꢀone (3ah): white solid, 153
mg, 75% yield; m.p. 162.9ꢀ165.0 oC; [α]D20 = ꢀ55.8 (c = 0.90, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.69 (d, J = 0.8 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 7.29ꢀ7.24 (m, 1H),
7.10 (d, J = 3.4 Hz, 1H), 6.59 (dd, J = 3.5, 1.7 Hz, 1H), 4.87 (dd, J = 11.4, 9.5 Hz, 1H), 3.57ꢀ3.44
(m, 1H), 2.93ꢀ2.80 (m, 2H), 2.76 (t, J = 10.3 Hz, 1H), 2.68ꢀ2.60 (m, 1H), 2.02ꢀ1.88 (m, 2H), 1.68
(d, J = 11.4 Hz, 2H), 1.33 (s, 3H), 1.29ꢀ1.16 (m, 7H), 0.96 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.8 Hz,
3H), 0.62 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.8, 153.4, 146.9, 140.8, 139.6,
128.4, 128.0, 117.4, 112.2, 73.8 (d, J = 7.1 Hz), 61.4, 59.4 (d, J = 11.5 Hz), 58.9 (d, J = 10.7 Hz),
43.9 (d, J = 3.0 Hz), 43.4 (d, J = 4.6 Hz), 31.8 (d, J = 12.1 Hz), 31.2 (d, J = 10.3 Hz), 24.5 (d, J =
8.6 Hz), 24.3, 23.6 (d, J = 5.0 Hz), 22.2, 19.5, 18.9; 31P NMR (162 MHz, CDCl3) δ 21.67; HRMS
(ESIꢀTOF) m/z [C27H37N4O4P+Na]+ calcd for 535.2445, found 535.2448.
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀ(thiophenꢀ2ꢀyl)oxazolꢀ5(4H)ꢀone (3ai): white solid,
184 mg, 88% yield; m.p. 158.7ꢀ160.7 oC; [α]D20 = ꢀ28.0 (c = 0.92, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.70 (dd, J = 3.7, 1.1 Hz, 1H), 7.61 (dd, J = 5.0, 1.1 Hz, 1H), 7.46 (d, J = 7.2 Hz, 2H),
7.32 (t, J = 7.3 Hz, 2H), 7.26ꢀ7.22 (m, 1H), 7.16 (dd, J = 4.9, 3.8 Hz, 1H), 4.86 (dd, J = 11.5, 9.5
Hz, 1H), 3.58ꢀ3.44 (m, 1H), 2.94ꢀ2.74 (m, 3H), 2.66 (t, J = 8.5 Hz, 1H), 2.01ꢀ1.88 (m, 2H), 1.68
(d, J = 10.7 Hz, 2H), 1.35 (s, 3H), 1.29ꢀ1.16 (m, 7H), 0.97 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.8 Hz,
3H), 0.64 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.5, 157.1, 139.9, 132.2, 131.9,
128.7, 128.6, 128.5, 128.2, 128.1, 74.3 (d, J = 7.1 Hz), 61.6, 59.5 (d, J = 11.4 Hz), 59.1 (d, J =
10.5 Hz), 44.2 (d, J = 2.6 Hz), 43.6 (d, J = 4.7 Hz), 31.9 (d, J = 12.4 Hz), 31.3 (d, J = 10.3 Hz),
24.6 (d, J = 8.6 Hz), 24.4, 23.7 (d, J = 5.0 Hz), 22.3, 19.6, 19.2; 31P NMR (162 MHz, CDCl3) δ
21.78; HRMS (ESIꢀTOF) m/z [C27H37N4O3PS+Na]+ calcd for 551.2216, found 551.2220.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3aj): white solid, 154 mg, 72%
yield; m.p. 157.0ꢀ159.0 oC; [α]D20 = ꢀ65.9 (c = 0.81, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05
(d, J = 8.0 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 6.7 Hz, 4H), 7.31 (t, J = 7.2 Hz, 2H),
7.26ꢀ7.22 (m, 1H), 4.90 (dd, J = 11.4, 9.4 Hz, 1H), 3.65ꢀ3.48 (m, 1H), 2.98ꢀ2.59 (m, 4H),
2.01ꢀ1.87 (m, 3H), 1.67 (d, J = 9.8 Hz, 2H), 1.61ꢀ1.51 (m, 1H), 1.32ꢀ1.13 (m, 7H), 1.00 (s, 3H),
0.85 (d, J = 6.8 Hz, 3H), 0.74 (t, J = 7.4 Hz, 3H), 0.63 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 179.5, 161.5, 140.5, 132.9, 128.9, 128.7, 128.4, 128.3, 128.0, 125.9, 79.3 (d, J = 7.1 Hz),
61.2, 59.4 (d, J = 11.4 Hz), 59.1 (d, J = 10.5 Hz), 44.1, 43.5 (d, J = 4.7 Hz), 31.9 (d, J = 12.1 Hz),
31.3 (d, J = 10.1 Hz), 28.9, 24.7 (d, J = 8.7 Hz), 24.4, 23.7 (d, J = 5.0 Hz), 19.6, 19.1, 8.3; 31P
NMR (162 MHz, CDCl3) δ 21.84; HRMS (ESIꢀTOF) m/z [C30H41N4O3P+Na]+ calcd for 559.2808,
found 559.2811.
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀisopropylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ak): white solid, 97 mg,
44% yield; m.p. 144.5ꢀ145.6 oC; [α]D20 = ꢀ38.4 (c = 0.84, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.00 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 6.8 Hz, 3H), 7.49 (t, J = 7.5 Hz, 2H), 7.31ꢀ7.27 (m, 2H),
7.25ꢀ7.19 (m, 1H), 5.09 (dd, J = 11.1, 9.4 Hz, 1H), 3.66ꢀ3.51 (m, 1H), 2.89 (t, J = 9.6 Hz, 1H),
2.82ꢀ2.60 (m, 3H), 2.10 (dt, J = 13.6, 6.8 Hz, 1H), 1.98 (d, J = 10.3 Hz, 1H), 1.90 (d, J = 9.7 Hz,
1H), 1.67 (d, J = 9.2 Hz, 2H), 1.32ꢀ1.18 (m, 7H), 1.06 (t, J = 7.5 Hz, 6H), 0.95 (d, J = 6.8 Hz, 3H),
0.84 (d, J = 6.8 Hz, 3H), 0.56 (d, J = 6.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.2, 161.1,
140.6, 132.8, 128.8, 128.3, 128.2, 127.9, 125.9, 81.4 (d, J = 7.1 Hz), 59.3 (d, J = 11.1 Hz), 59.1,
59.0, 44.2 (d, J = 9.8 Hz), 43.4 (d, J = 4.4 Hz), 32.6, 31.9 (d, J = 12.1 Hz), 31.5 (d, J = 10.4 Hz),
24.8 (d, J = 8.9 Hz), 24.4, 24.0 (d, J = 5.4 Hz), 19.6, 19.0, 17.5, 16.1; 31P NMR (162 MHz, CDCl3)
δ 21.96; HRMS (ESIꢀTOF) m/z [C31H43N4O3P+Na]+ calcd for 573.2965, found 573.2968.
(S)ꢀ4ꢀbenzylꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazap
hospholꢀ2(3H)ꢀyl)amino)(phenyl)methyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3al): white solid, 177 mg, 74%
yield; m.p. 128.3ꢀ130.1 oC; [α]D20 = ꢀ123.9 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.80
(d, J = 7.7 Hz, 2H), 7.55 (d, J = 7.4 Hz, 2H), 7.50 (d, J = 7.3 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H),
7.33 (t, J = 7.4 Hz, 2H), 7.28ꢀ7.23 (m, 1H), 7.11ꢀ7.01 (m, 5H), 5.13ꢀ5.05 (m, 1H), 3.66ꢀ3.54 (m,
1H), 3.27 (d, J = 13.3 Hz, 1H), 2.95ꢀ2.77 (m, 4H), 2.66 (t, J = 8.6 Hz, 1H), 1.98 (d, J = 11.4 Hz,
1H), 1.92 (d, J = 10.6 Hz, 1H), 1.68 (d, J = 11.9 Hz, 2H), 1.33ꢀ1.16 (m, 7H), 1.01 (d, J = 6.9 Hz,
3H), 0.86 (d, J = 6.7 Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.9,
161.1, 140.3, 134.4, 132.7, 130.3, 128.7, 128.6, 128.5, 128.2, 128.1, 128.0, 127.1, 125.8, 79.8 (d, J
= 6.9 Hz), 61.5, 59.5 (d, J = 11.4 Hz), 59.1 (d, J = 10.7 Hz), 44.1 (d, J = 3.1 Hz), 43.6 (d, J = 4.7
Hz), 41.9, 32.0 (d, J = 12.1 Hz), 31.3 (d, J = 10.4 Hz), 24.8 (d, J = 8.4 Hz), 24.4, 23.6 (d, J = 5.1
Hz), 19.6, 19.2; 31P NMR (162 MHz, CDCl3) δ 21.86; HRMS (ESIꢀTOF) m/z [C35H43N4O3P+Na]+
calcd for 621.2965, found 621.2970.
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(S)ꢀ4ꢀbutylꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazapho
spholꢀ2(3H)ꢀyl)amino)(phenyl)methyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3am): white solid, 144 mg, 64%
yield; m.p. 85.2ꢀ89.1 oC; [α]D20 = ꢀ40.1 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J
= 7.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.53ꢀ7.44 (m, 4H), 7.30 (t, J = 7.3 Hz, 2H), 7.26ꢀ7.21 (m,
1H), 4.93ꢀ4.86 (m, 1H), 3.64ꢀ3.50 (m, 1H), 2.94ꢀ2.73 (m, 3H), 2.70ꢀ2.61 (m, 1H), 2.01ꢀ1.87 (m,
3H), 1.67 (d, J = 10.4 Hz, 2H), 1.55 (td, J = 12.9, 4.0 Hz, 1H), 1.31ꢀ1.06 (m, 11H), 0.99 (d, J = 6.8
Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.76 (t, J = 7.0 Hz, 3H), 0.63 (d, J = 6.7 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 179.7, 161.2, 140.4, 132.9, 128.9, 128.6, 128.4, 128.2, 127.9, 125.9, 78.6 (d,
J = 7.1 Hz), 61.3, 59.4 (d, J = 11.5 Hz), 59.0 (d, J = 10.6 Hz), 44.1, 43.5 (d, J = 4.8 Hz), 35.4, 31.9
(d, J = 12.1 Hz), 31.3 (d, J = 10.3 Hz), 26.1, 24.8 (d, J = 8.6 Hz), 24.4, 23.8 (d, J = 5.0 Hz), 22.6,
19.6, 19.1, 13.9; 31P NMR (162 MHz, CDCl3) δ 21.87; HRMS (ESIꢀTOF) m/z
[C32H45N4O3P+Na]+ calcd for 587.3121, found 587.3128.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀisobutylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3an): white solid, 153 mg,
68% yield; m.p. 109.0ꢀ111.9 oC; [α]D20 = ꢀ41.6 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.97 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 7.2 Hz, 2H),
7.29ꢀ7.24 (m, 2H), 7.23ꢀ7.17 (m, 1H), 4.92ꢀ4.84 (m, 1H), 3.70ꢀ3.57 (m, 1H), 2.95ꢀ2.72 (m, 3H),
2.66 (s, 1H), 2.03ꢀ1.94 (m, 2H), 1.92 (d, J = 9.7 Hz, 1H), 1.76ꢀ1.63 (m, 3H), 1.52ꢀ1.40 (m, 1H),
1.30ꢀ1.16 (m, 7H), 1.06 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H),
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0.76 (d, J = 6.6 Hz, 3H), 0.62 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.5, 160.7,
140.3, 132.8, 128.9, 128.6, 128.3, 128.2, 127.9, 126.0, 78.0 (d, J = 6.8 Hz), 62.3, 59.3 (d, J = 10.3
Hz), 59.1 (d, J = 10.6 Hz), 44.3, 43.5 (d, J = 4.8 Hz), 31.9 (d, J = 11.4 Hz), 31.3 (d, J = 10.2 Hz),
25.1, 24.8 (d, J = 7.6 Hz), 24.4 (d, J = 3.0 Hz), 24.0, 23.7 (d, J = 5.1 Hz), 23.5, 19.5, 19.1; 31P
NMR (162 MHz, CDCl3) δ 21.98; HRMS (ESIꢀTOF) m/z [C32H45N4O3P+Na]+ calcd for 587.3121,
found 587.3128.
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀ(4ꢀhydroxybenzyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ao): white solid,
219 mg, 89% yield; m.p. 176.5ꢀ179.4 oC; [α]D20 = ꢀ122.6 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.80 (d, J = 7.3 Hz, 2H), 7.52ꢀ7.43 (m, 3H), 7.37 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.2 Hz,
2H), 7.26ꢀ7.21 (m, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 4.99 (dd, J = 11.2, 9.6
Hz, 1H), 3.63ꢀ3.50 (m, 1H), 3.11 (d, J = 13.5 Hz, 1H), 2.97ꢀ2.62 (m, 5H), 1.98ꢀ1.84 (m, 2H), 1.66
(d, J = 10.2 Hz, 2H), 1.31ꢀ1.18 (m, 4H), 1.13 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H), 0.77 (d,
J = 6.8 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.9, 161.0, 156.3,
140.1, 132.5, 131.1, 128.6, 128.5, 128.4, 127.95, 127.92, 125.7, 124.7, 79.8 (d, J = 6.9 Hz), 61.2,
59.3 (d, J = 11.2 Hz), 59.0 (d, J = 10.4 Hz), 44.1, 43.4 (d, J = 4.4 Hz), 41.0, 31.6 (d, J = 11.3 Hz),
31.2 (d, J = 10.8 Hz), 24.5 (d, J = 8.4 Hz), 24.2, 23.4 (d, J = 5.1 Hz), 19.3, 19.0; 31P NMR (162
MHz, CDCl3) δ 22.06; HRMS (ESIꢀTOF) m/z [C35H43N4O4P+Na]+ calcd for 637.2914, found
637.2921.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(phenyl)methyl)ꢀ4ꢀ(2ꢀ(methylthio)ethyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ap): white
solid, 186 mg, 80% yield; m.p. 117.0ꢀ118.7 oC; [α]D20 = ꢀ52.2 (c = 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 8.00 (d, J = 7.5 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.46 (d,
J = 9.1 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 4.94 (dd, J = 11.5, 9.7 Hz, 1H),
3.68ꢀ3.57 (m, 1H), 2.95ꢀ2.63 (m, 4H), 2.44ꢀ2.36 (m, 1H), 2.34ꢀ2.24 (m, 2H), 2.05ꢀ1.98 (m, 2H),
1.97 (s, 3H), 1.91 (d, J = 10.3 Hz, 1H), 1.68 (d, J = 9.1 Hz, 2H), 1.30ꢀ1.19 (m, 7H), 1.07 (d, J =
6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
179.6, 161.8, 139.9, 133.0, 128.9, 128.6, 128.5, 128.3, 128.2, 125.8, 77.4, 61.5, 59.3 (d, J = 11.2
Hz), 59.1 (d, J = 10.6 Hz), 44.4, 43.6 (d, J = 5.0 Hz), 34.6, 31.8 (d, J = 15.0 Hz), 31.3 (d, J = 10.2
Hz), 28.8, 24.8 (d, J = 9.2 Hz), 24.4 (d, J = 5.7 Hz), 23.6 (d, J = 5.1 Hz), 19.5, 19.1, 15.3; 31P
NMR (162 MHz, CDCl3) δ 21.86; HRMS (ESIꢀTOF) m/z [C31H43N4O3PS+Na]+ calcd for
605.2686, found 605.2689.
(S)ꢀ4ꢀ((1Hꢀindolꢀ2ꢀyl)methyl)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo
[d][1,3,2]diazaphospholꢀ2(3H)ꢀyl)amino)(phenyl)methyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3aq): white
solid, 227 mg, 89% yield; m.p. 145.1ꢀ147.8 oC; [α]D20 = ꢀ135.8 (c = 0.82, CHCl3); 1H NMR (400
MHz, CDCl3) δ 8.48ꢀ8.27 (m, 1H), 7.73 (d, J = 7.3 Hz, 2H), 7.59 (d, J = 7.3 Hz, 2H), 7.53 (d, J =
7.5 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.38ꢀ7.27 (m, 5H), 7.18 (d, J = 7.1 Hz, 1H), 7.02ꢀ6.95 (m,
2H), 6.93 (d, J = 2.3 Hz, 1H), 5.13 (dd, J = 11.3, 9.4 Hz, 1H), 3.66ꢀ3.54 (m, 1H), 3.40 (d, J = 14.2
Hz, 1H), 3.02ꢀ2.78 (m, 4H), 2.74ꢀ2.64 (m, 1H), 2.00ꢀ1.89 (m, 2H), 1.67 (d, J = 12.2 Hz, 2H),
1.33ꢀ1.14 (m, 7H), 1.00 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 179.6, 161.3, 140.5, 135.9, 132.4, 128.8, 128.5, 128.1, 128.0, 127.7,
125.9, 123.9, 121.6, 119.7, 119.2, 111.0, 108.5, 80.4 (d, J = 7.0 Hz), 61.2, 59.4 (d, J = 11.1 Hz),
59.1 (d, J = 10.5 Hz), 44.3, 43.6 (d, J = 4.9 Hz), 31.8, 31.7, 31.3 (d, J = 10.2 Hz), 24.6 (d, J = 10.5
Hz), 24.4, 23.6 (d, J = 5.1 Hz), 19.5, 19.2; 31P NMR (162 MHz, CDCl3) δ 22.09; HRMS
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(ESIꢀTOF) m/z [C37H44N5O3P+Na]+ calcd for 660.3074, found 660.3077.
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(4ꢀfluorophenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ba): white solid,
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179 mg, 83% yield; m.p. 108.2ꢀ110.0 C; [α]D = ꢀ61.0 (c = 0.90, CHCl3); H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.53ꢀ7.45 (m, 4H), 7.01 (t, J = 8.6 Hz,
2H), 4.91 (t, J = 10.4 Hz, 1H), 3.60ꢀ3.47 (m, 1H), 2.93ꢀ2.59 (m, 4H), 2.00ꢀ1.88 (m, 2H), 1.67 (d, J
= 11.6 Hz, 2H), 1.35 (s, 3H), 1.29ꢀ1.14 (m, 7H), 0.99 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H),
0.67 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.9, 162.5 (d, J = 246.7 Hz), 161.3,
136.2 (d, J = 3.2 Hz), 133.0, 130.3 (d, J = 8.4 Hz), 128.9, 128.2, 125.9, 115.2 (d, J = 21.3 Hz),
74.2 (d, J = 7.3 Hz), 60.8, 59.4 (d, J = 11.1 Hz), 59.1 (d, J = 10.7 Hz), 44.2, 43.5 (d, J = 4.8 Hz),
31.8 (d, J = 11.9 Hz), 31.3 (d, J = 10.2 Hz), 24.7 (d, J = 8.6 Hz), 24.4, 23.6 (d, J = 4.8 Hz), 22.3,
19.6, 19.2; 31P NMR (162 MHz, CDCl3) δ 21.62; HRMS (ESIꢀTOF) m/z [C29H38FN4O3P+Na]+
calcd for 563.2558, found 563.2561.
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(S)ꢀ4ꢀ((R)ꢀ(4ꢀchlorophenyl)(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2
]diazaphospholꢀ2(3H)ꢀyl)amino)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ca): white solid,
182 mg, 83% yield; m.p. 116.8ꢀ118.2 oC; [α]D20 = ꢀ68.8 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 7.3 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.46 (d, J =
8.2 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.90 (dd, J = 11.3, 9.4 Hz, 1H), 3.59ꢀ3.48 (m, 1H),
2.95ꢀ2.74 (m, 3H), 2.71ꢀ2.64 (m, 1H), 2.00ꢀ1.89 (m, 2H), 1.68 (d, J = 12.7 Hz, 2H), 1.35 (s, 3H),
1.28ꢀ1.16 (m, 7H), 1.00 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.69 (d, J = 6.9 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 179.8, 161.4, 138.7, 133.9, 133.1, 130.1, 129.0, 128.5, 128.3, 125.8,
74.1 (d, J = 7.1 Hz), 60.8, 59.4 (d, J = 11.5 Hz), 59.1 (d, J = 10.5 Hz), 44.2, 43.6 (d, J = 4.7 Hz),
31.8 (d, J = 12.0 Hz), 31.3 (d, J = 10.2 Hz), 24.6 (d, J = 8.6 Hz), 24.4, 23.7 (d, J = 4.9 Hz), 22.4,
19.6, 19.3; 31P NMR (162 MHz, CDCl3) δ 21.64; HRMS (ESIꢀTOF) m/z [C29H38ClN4O3P+Na]+
calcd for 579.2262, found 579.2260.
(S)ꢀ4ꢀ((R)ꢀ(4ꢀbromophenyl)(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2
]diazaphospholꢀ2(3H)ꢀyl)amino)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3da): white solid,
190 mg, 80% yield; m.p. 138.6ꢀ139.8 oC; [α]D20 = ꢀ65.0 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.54ꢀ7.45 (m, 4H), 7.40 (d, J = 8.1 Hz,
2H), 4.93ꢀ4.83 (m, 1H), 3.61ꢀ3.48 (m, 1H), 3.01ꢀ2.67 (m, 4H), 2.00ꢀ1.91 (m, 2H), 1.68 (d, J =
10.5 Hz, 2H), 1.34 (s, 3H), 1.29ꢀ1.19 (m, 7H), 1.01 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H),
0.70 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.8, 161.4, 139.2, 133.1, 131.5, 130.4,
128.9, 128.2, 125.8, 122.0, 74.0 (d, J = 7.0 Hz), 60.8, 59.4 (d, J = 11.4 Hz), 59.0 (d, J = 10.6 Hz),
44.1, 43.5 (d, J = 4.5 Hz), 31.8 (d, J = 12.0 Hz), 31.2 (d, J = 10.1 Hz), 24.6 (d, J = 8.4 Hz), 24.4,
23.7 (d, J = 4.9 Hz), 22.3, 19.6, 19.2; 31P NMR (162 MHz, CDCl3) δ 21.59; HRMS (ESIꢀTOF)
m/z [C29H38BrN4O3P+Na]+ calcd for 623.1757, found 623.1755.
(S)ꢀ4ꢀ((R)ꢀ(4ꢀnitrilephenyl)(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]
diazaphospholꢀ2(3H)ꢀyl)amino)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ea): white solid,
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181 mg, 80% yield; m.p. 141.5ꢀ143.1 C; [α]D = ꢀ61.5 (c = 0.90, CHCl3); H NMR (400 MHz,
CDCl3) δ 8.04ꢀ7.99 (m, 2H), 7.70ꢀ7.64 (m, 4H), 7.64ꢀ7.59 (m, 1H), 7.51 (t, J = 7.6 Hz, 2H), 4.97
(dd, J = 11.2, 9.3 Hz, 1H), 3.56ꢀ3.44 (m, 1H), 3.10ꢀ2.98 (m, 1H), 2.94ꢀ2.77 (m, 2H), 2.70 (t, J =
8.8 Hz, 1H), 2.00ꢀ1.92 (m, 2H), 1.74ꢀ1.65 (m, 2H), 1.35 (s, 3H), 1.29ꢀ1.16 (m, 7H), 0.96 (d, J =
6.9 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
179.5, 161.8, 145.4, 133.3, 132.2, 132.0, 130.5, 129.6, 129.0, 128.3, 125.6, 118.7, 112.0, 73.7 (d, J
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= 7.0 Hz), 61.1, 59.6 (d, J = 11.7 Hz), 59.2 (d, J = 10.5 Hz), 44.3 (d, J = 4.3 Hz), 43.6 (d, J = 4.7
Hz), 31.8 (d, J = 10.6 Hz), 31.3 (d, J = 10.1 Hz), 24.5 (d, J = 8.6 Hz), 24.4, 23.7 (d, J = 4.7 Hz),
22.4, 19.53, 19.47; 31P NMR (162 MHz, CDCl3) δ 21.73; HRMS (ESIꢀTOF) m/z
[C30H38N5O3P+Na]+ calcd for 570.2604, found 570.2601.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(4ꢀmethoxyphenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3fa): After GAP
washing procedure, the single isomer was recrystallized as a white solid, 156 mg, 71% yield; m.p.
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110.1ꢀ112.0 C; [α]D = ꢀ52.3 (c = 0.88, CHCl3); H NMR (400 MHz, CDCl3) δ 8.08ꢀ7.98 (m,
2H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz,
2H), 4.86 (dd, J = 11.4, 9.5 Hz, 1H), 3.79 (s, 3H), 3.61ꢀ3.47 (m, 1H), 2.94ꢀ2.81 (m, 2H), 2.76ꢀ2.59
(m, 2H), 2.01ꢀ1.87 (m, 2H), 1.67 (d, J = 12.6 Hz, 2H), 1.35 (s, 3H), 1.30ꢀ1.15 (m, 7H), 0.98 (d, J
= 6.9 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.67 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
180.1, 161.1, 159.3, 132.9, 132.4, 129.7, 128.8, 128.2, 126.0, 113.7, 74.5 (d, J = 7.3 Hz), 60.9,
59.4 (d, J = 11.4 Hz), 59.0 (d, J = 10.6 Hz), 55.4, 44.1, 43.5 (d, J = 4.6 Hz), 31.8 (d, J = 12.1 Hz),
31.2 (d, J = 10.2 Hz), 24.7 (d, J = 8.5 Hz), 24.4, 23.6 (d, J = 5.1 Hz), 22.3, 19.6, 19.2; 31P NMR
(162 MHz, CDCl3) δ 21.86; HRMS (ESIꢀTOF) m/z [C30H41N4O4P+Na]+ calcd for 575.2758,
found 575.2756.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(4ꢀ(trifluoromethyl)phenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ga):
white solid, 165 mg, 70% yield; m.p. 134.7ꢀ135.5 oC; [α]D20 = ꢀ61.2 (c = 0.92, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.04 (d, J = 7.5 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.6 Hz, 3H),
7.52 (t, J = 7.6 Hz, 2H), 4.98 (dd, J = 11.1, 9.4 Hz, 1H), 3.53 (dd, J = 11.3, 6.7 Hz, 1H), 2.97ꢀ2.63
(m, 4H), 2.00ꢀ1.90 (m, 2H), 1.68 (d, J = 12.1 Hz, 2H), 1.34 (s, 3H), 1.28ꢀ1.20 (m, 7H), 0.98 (d, J
= 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
179.7, 161.7, 144.3, 133.3, 130.4 (q, J = 32.8 Hz), 129.2, 129.0, 128.3, 125.8, 125.4 (q, J = 3.8
Hz), 73.9 (d, J = 7.1 Hz), 61.1, 59.5 (d, J = 11.9 Hz), 59.2 (d, J = 10.6 Hz), 44.2, 43.6 (d, J = 4.8
Hz), 31.8 (d, J = 12.9 Hz), 31.3 (d, J = 10.1 Hz), 24.6 (d, J = 8.4 Hz), 24.4, 23.7 (d, J = 4.8 Hz),
22.3, 19.6, 19.3; 31P NMR (162 MHz, CDCl3) δ 21.58; HRMS (ESIꢀTOF) m/z
[C30H38F3N4O3P+Na]+ calcd for 613.2526, found 613.2524.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(pꢀtolyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ha): white solid, 183 mg,
81% yield; m.p. 160.3ꢀ161.8 oC; [α]D20 = ꢀ66.7 (c = 0.84, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.03 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H),
7.12 (d, J = 7.6 Hz, 2H), 4.85 (t, J = 10.4 Hz, 1H), 3.60ꢀ3.44 (m, 1H), 2.95ꢀ2.79 (m, 2H), 2.72 (t, J
= 10.3 Hz, 1H), 2.63 (t, J = 8.8 Hz, 1H), 2.31 (s, 3H), 2.00ꢀ1.87 (m, 2H), 1.67 (d, J = 11.0 Hz, 2H),
1.34 (s, 3H), 1.28ꢀ1.13 (m, 7H), 0.95 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.65 (d, J = 6.7
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.1, 161.1, 137.6, 137.0, 132.8, 128.9, 128.8, 128.5,
128.2, 126.0, 74.4 (d, J = 7.3 Hz), 61.2, 59.4 (d, J = 11.4 Hz), 59.0 (d, J = 10.6 Hz), 44.1 (d, J =
3.0 Hz), 43.5 (d, J = 4.7 Hz), 31.8 (d, J = 12.2 Hz), 31.3 (d, J = 10.3 Hz), 24.6 (d, J = 8.5 Hz),
24.4, 23.7 (d, J = 5.0 Hz), 22.3, 21.2, 19.6, 19.1; 31P NMR (162 MHz, CDCl3) δ 21.93; HRMS
(ESIꢀTOF) m/z [C30H41N4O3P+Na]+ calcd for 559.2808, found 559.2809.
(S)ꢀ4ꢀ((R)ꢀ(3ꢀbromophenyl)(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]
diazaphospholꢀ2(3H)ꢀyl)amino)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ia): white solid,
178 mg, 74% yield; m.p. 95.2ꢀ96.7 oC; [α]D20 = ꢀ63.2 (c = 0.78, CHCl3); 1H NMR (400 MHz,
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CDCl3) δ 8.04 (d, J = 7.4 Hz, 2H), 7.70 (s, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H),
7.46ꢀ7.39 (m, 2H), 7.20 (t, J = 7.8 Hz, 1H), 4.88 (dd, J = 11.3, 9.3 Hz, 1H), 3.60ꢀ3.45 (m, 1H),
2.95ꢀ2.65 (m, 4H), 2.00ꢀ1.90 (m, 2H), 1.68 (d, J = 11.0 Hz, 2H), 1.36 (s, 3H), 1.31ꢀ1.17 (m, 7H),
0.99 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 179.7, 161.5, 142.5, 133.1, 131.6, 131.2, 129.9, 129.0, 128.3, 127.6, 125.8, 122.5, 74.0
(d, J = 7.2 Hz), 61.0, 59.4 (d, J = 11.6 Hz), 59.1 (d, J = 10.5 Hz), 44.3, 43.6 (d, J = 4.8 Hz), 31.7
(d, J = 12.0 Hz), 31.4 (d, J = 10.2 Hz), 24.6 (d, J = 8.4 Hz), 24.4, 23.4 (d, J = 5.0 Hz), 22.4, 19.6,
19.2; 31P NMR (162 MHz, CDCl3) δ 21.64; HRMS (ESIꢀTOF) m/z [C29H38BrN4O3P+Na]+ calcd
for 623.1757, found 623.1759.
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(mꢀtolyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ja): white solid, 169 mg,
79% yield; m.p. 132.5ꢀ134.1 oC; [α]D20 = ꢀ42.7 (c = 0.90, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.02 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.31ꢀ7.27 (m, 2H), 7.19
(t, J = 7.7 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 4.85 (dd, J = 11.5, 9.4 Hz, 1H), 3.60ꢀ3.48 (m, 1H),
2.92ꢀ2.72 (m, 3H), 2.66 (t, J = 8.5 Hz, 1H), 2.33 (s, 3H), 2.00ꢀ1.89 (m, 2H), 1.67 (d, J = 12.3 Hz,
2H), 1.37 (s, 3H), 1.30ꢀ1.16 (m, 7H), 0.97 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.66 (d, J
= 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.2, 161.1, 139.9, 137.9, 132.9, 129.4, 128.9,
128.7, 128.3, 128.2, 126.1, 125.7, 74.3 (d, J = 7.3 Hz), 61.5, 59.4 (d, J = 11.3 Hz), 59.1 (d, J =
10.5 Hz), 44.2, 43.5 (d, J = 4.8 Hz), 31.8 (d, J = 12.2 Hz), 31.4 (d, J = 10.4 Hz), 24.6 (d, J = 8.4
Hz), 24.4, 23.8 (d, J = 5.0 Hz), 22.4, 21.6, 19.6, 19.1; 31P NMR (162 MHz, CDCl3) δ 21.94;
HRMS (ESIꢀTOF) m/z [C30H41N4O3P+Na]+ calcd for 559.2808, found 559.2809.
(S)ꢀ4ꢀ((R)ꢀ(2ꢀbromophenyl)(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]
diazaphospholꢀ2(3H)ꢀyl)amino)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ka): After GAP
washing procedure, the single isomer was recrystallized as a white solid, 151 mg, 63% yield; m.p.
101.5ꢀ102.5 oC; [α]D20 = ꢀ37.5 (c = 0.88, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.4
Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.55ꢀ7.46 (m, 3H), 7.36 (t, J = 7.5 Hz,
1H), 7.13 (t, J = 7.6 Hz, 1H), 5.32 (dd, J = 11.3, 8.6 Hz, 1H), 3.37ꢀ3.10 (m, 3H), 3.00 (t, J = 8.3
Hz, 1H), 2.89 (t, J = 9.9 Hz, 1H), 2.10 (d, J = 9.5 Hz, 1H), 1.89 (d, J = 11.1 Hz, 1H), 1.74ꢀ1.64 (m,
2H), 1.37 (s, 3H), 1.33ꢀ1.19 (m, 4H), 1.14ꢀ1.05 (m, 9H), 0.42 (d, J = 6.6 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 179.6, 161.7, 139.7, 133.2, 132.6, 129.5, 128.9, 128.4, 128.0, 125.6, 125.3, 74.1
(d, J = 8.9 Hz), 59.8 (d, J = 12.4 Hz), 59.2 (d, J = 10.2 Hz), 58.3, 44.5, 43.8 (d, J = 4.9 Hz), 31.8
(d, J = 8.7 Hz), 31.7 (d, J = 10.6 Hz), 24.6 (d, J = 3.1 Hz), 24.5 (d, J = 7.6 Hz), 23.6 (d, J = 10.2
Hz), 21.5, 20.3 (d, J = 2.8 Hz), 19.3; 31P NMR (162 MHz, CDCl3) δ 22.44; HRMS (ESIꢀTOF) m/z
[C29H38BrN4O3P+Na]+ calcd for 623.1757, found 623.1753.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(oꢀtolyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3la): white solid, 156 mg, 76%
yield; m.p. 123.2ꢀ125.5 oC; [α]D20 = ꢀ31.0 (c = 0.86, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.99
(d, J = 7.5 Hz, 2H), 7.60ꢀ7.52 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.21ꢀ7.14 (m, 1H), 7.13ꢀ7.07 (m,
2H), 5.34ꢀ5.22 (m, 1H), 3.62ꢀ3.49 (m, 1H), 2.96ꢀ2.83 (m, 2H), 2.80ꢀ2.64 (m, 2H), 2.57 (s, 3H),
1.98 (d, J = 11.7 Hz, 1H), 1.92 (d, J = 9.0 Hz, 1H), 1.68 (d, J = 9.8 Hz, 2H), 1.43 (s, 3H),
1.32ꢀ1.17 (m, 7H), 0.99 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 180.7, 160.9, 139.0, 136.8, 132.9, 130.3, 128.9, 128.2, 127.7, 127.2,
126.4, 126.0, 74.7 (d, J = 7.5 Hz), 59.4 (d, J = 11.5 Hz), 59.0 (d, J = 10.5 Hz), 56.2, 44.4, 43.5 (d,
J = 4.8 Hz), 31.8 (d, J = 13.0 Hz), 31.3 (d, J = 9.9 Hz), 24.4 (d, J = 3.6 Hz), 23.6 (d, J = 4.9 Hz),
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22.8, 21.7, 20.4, 19.5, 19.1; 31P NMR (162 MHz, CDCl3) δ 22.44; HRMS (ESIꢀTOF) m/z
[C30H41N4O3P+Na]+ calcd for 559.2808, found 559.2803.
(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(2ꢀ(trifluoromethyl)phenyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3ma):
white solid, 176 mg, 78% yield; m.p. 124.3ꢀ126.6 oC; [α]D20 = ꢀ60.5 (c = 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.02 (d, J = 7.4 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H),
7.63ꢀ7.57 (m, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 5.26 (dd, J = 10.9, 8.6 Hz,
1H), 3.34ꢀ3.04 (m, 3H), 2.93ꢀ2.75 (m, 2H), 2.06ꢀ1.99 (m, 1H), 1.90 (d, J = 11.9 Hz, 1H),
1.72ꢀ1.61 (m, 2H), 1.30 (s, 3H), 1.35ꢀ1.19 (m, 4H), 1.14 (d, J = 6.7 Hz, 3H), 1.05 (d, J = 6.8 Hz,
3H), 0.88 (d, J = 6.8 Hz, 3H), 0.51 (d, J = 5.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.5,
161.5, 139.1, 133.1, 132.1, 129.5, 128.79 (q, J = 29.8 Hz), 128.77, 128.2, 128.0, 125.9 (q, J = 5.9
Hz), 125.5, 124.7(q, J = 251.7 Hz), 73.9 (d, J = 8.0 Hz), 59.0 (d, J = 10.3 Hz), 58.9 (d, J = 10.2
Hz), 55.0, 44.4, 43.4 (d, J = 5.2 Hz), 31.8 (d, J = 9.1 Hz), 31.4 (d, J = 14.0 Hz), 24.5 (d, J = 4.0
Hz), 24.3 (d, J = 10.4 Hz), 23.7 (d, J = 9.8 Hz), 22.1, 19.3 (d, J = 2.3 Hz), 19.0; 31P NMR (162
MHz, CDCl3) δ 22.11; HRMS (ESIꢀTOF) m/z [C30H38F3N4O3P+Na]+ calcd for 613.2526, found
613.2523.
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(S)ꢀ4ꢀ((R)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(naphthalenꢀ1ꢀyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3na): white solid,
194 mg, 85% yield; m.p. 158.1ꢀ159.3 oC; [α]D20 = ꢀ62.6 (c = 0.87, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.53 (d, J = 8.7 Hz, 1H), 7.96ꢀ7.90 (m, 3H), 7.81 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.2 Hz,
1H), 7.62 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.51ꢀ7.43 (m, 4H), 6.00ꢀ5.91 (m, 1H),
3.64ꢀ3.48 (m, 1H), 3.00 (s, 1H), 2.90ꢀ2.81 (m, 1H), 2.63 (dd, J = 13.5, 6.6 Hz, 2H), 1.95ꢀ1.82 (m,
2H), 1.70ꢀ1.58 (m, 2H), 1.37 (s, 3H), 1.30ꢀ1.10 (m, 7H), 0.90 (d, J = 6.9 Hz, 3H), 0.65 (d, J = 6.8
Hz, 3H), 0.42 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.4, 161.1, 137.2, 133.6,
132.9, 132.1, 128.8, 128.6, 128.5, 128.2, 126.7, 125.9, 125.8, 125.32, 125.30, 124.1, 75.1 (d, J =
7.2 Hz), 59.4 (d, J = 11.5 Hz), 59.1 (d, J = 10.5 Hz), 54.7, 44.2 (d, J = 2.9 Hz), 43.3 (d, J = 4.7
Hz), 31.8 (d, J = 12.3 Hz), 31.3 (d, J = 10.2 Hz), 24.6 (d, J = 8.7 Hz), 24.4, 23.6 (d, J = 5.0 Hz),
22.0, 19.6, 18.8; 31P NMR (162 MHz, CDCl3) δ 22.09; HRMS (ESIꢀTOF) m/z
[C33H41N4O3P+Na]+ calcd for 595.2808, found 595.2810.
(S)ꢀ4ꢀ((S)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(furanꢀ2ꢀyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3oa): After GAP washing
procedure, the single isomer was recrystallized as a white solid, 124 mg, 61% yield; m.p.
o
20
147.7ꢀ148.3 C; [α]D = ꢀ47.5 (c = 0.93, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.3
Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 1.0 Hz, 1H), 6.33 (d, J =
3.2 Hz, 1H), 6.25 (dd, J = 3.0, 1.9 Hz, 1H), 5.04 (dd, J = 11.3, 9.8 Hz, 1H), 3.68ꢀ3.55 (m, 1H),
3.07ꢀ2.88 (m, 3H), 2.67 (t, J = 8.5 Hz, 1H), 2.01 (d, J = 11.5 Hz, 1H), 1.95 (d, J = 10.2 Hz, 1H),
1.70 (d, J = 9.9 Hz, 2H), 1.53 (s, 3H), 1.35ꢀ1.19 (m, 7H), 1.10 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.8
Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.8, 161.2, 152.7, 142.0,
132.9, 128.8, 128.2, 125.9, 110.3, 108.7, 72.9 (d, J = 6.7 Hz), 59.4 (d, J = 11.1 Hz), 59.1 (d, J =
10.7 Hz), 55.5, 44.1 (d, J = 3.1 Hz), 43.9 (d, J = 4.4 Hz), 31.9 (d, J = 11.8 Hz), 31.0 (d, J = 10.5
Hz), 24.7 (d, J = 7.8 Hz), 24.4, 23.3 (d, J = 5.4 Hz), 22.0, 19.8, 19.0; 31P NMR (162 MHz, CDCl3)
δ 21.55; HRMS (ESIꢀTOF) m/z [C27H37N4O4P+Na]+ calcd for 535.2445, found 535.2442.
(S)ꢀ4ꢀ((S)ꢀ(((3aR,7aR)ꢀ1,3ꢀdiisopropylꢀ2ꢀoxidohexahydroꢀ1Hꢀbenzo[d][1,3,2]diazaphospholꢀ2
(3H)ꢀyl)amino)(thiophenꢀ2ꢀyl)methyl)ꢀ4ꢀmethylꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone (3pa): white solid, 165
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mg, 77% yield; m.p. 155.0ꢀ157.1 oC; [α]D20 = ꢀ46.3 (c = 0.82, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.09 (d, J = 7.3 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 5.1 Hz,
1H), 7.19 (d, J = 3.3 Hz, 1H), 6.95 (dd, J = 5.0, 3.6 Hz, 1H), 5.28 (dd, J = 11.0, 9.6 Hz, 1H),
3.62ꢀ3.48 (m, 1H), 3.00ꢀ2.84 (m, 2H), 2.63 (t, J = 8.7 Hz, 1H), 2.47 (t, J = 9.9 Hz, 1H), 2.00ꢀ1.87
(m, 2H), 1.66 (d, J = 13.3 Hz, 2H), 1.40 (s, 3H), 1.32ꢀ1.14 (m, 7H), 1.02 (d, J = 6.9 Hz, 3H), 0.92
(d, J = 6.8 Hz, 3H), 0.69 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.3, 161.7, 143.0,
133.1, 128.9, 128.4, 127.7, 126.3, 126.0, 125.9, 74.4 (d, J = 7.0 Hz), 59.3 (d, J = 11.4 Hz), 59.1 (d,
J = 10.8 Hz), 57.3, 44.1 (d, J = 2.7 Hz), 43.8 (d, J = 4.8 Hz), 31.8 (d, J = 12.0 Hz), 31.3 (d, J =
10.3 Hz), 24.8 (d, J = 8.4 Hz), 24.4, 23.8 (d, J = 5.3 Hz), 22.1, 19.6, 18.9; 31P NMR (162 MHz,
CDCl3) δ 21.48; HRMS (ESIꢀTOF) m/z [C27H37N4O3PS+Na]+ calcd for 551.2216, found
551.2218.
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Synthesis of Protected α-Quaternary-syn-α, β-Diamino Ester 4
The Mannich product 3aa (5.0 mmol, 2.61g) was dissolved in 20 mL MeOH, followed by
addition of 3.10 mL 48% aq. HBr (50 mmol, 10 equiv.). The reaction mixture was stirred at room
temperature for 24 hours. After complete conversion of 3aa, volatiles were evaporated under
vacuum at 50 °C and dried for 3 hours under high vacuum to obtain a crude solid. The solid was
dissolved in 20 mL of dichloromethane, and then the suspension was cooled to 0 °C. At this
temperature, triethylamine (2.08 mL, 15.0 mmol) and diꢀtertꢀbutyl dicarbonate (2.30 mL, 10.0
mmol) were added to the resulting mixture, and the reaction mixture was stirred overnight. The
reaction mixture was concentrated, and pure product 4 was obtained in 60% overall yield through
column chromatography on silica gel using PE/EA (v/v, 4/1) as eluent.
(2S,3R)ꢀmethyl 2ꢀbenzamidoꢀ3ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ2ꢀmethylꢀ3ꢀphenylpropanoate (4):
white solid, 988 mg, 60% yield; [α]D20 = ꢀ20.8 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.16 (s, 1H), 7.84 (t, J = 11.8 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.35ꢀ7.29
(m, 3H), 7.22 (d, J = 5.9 Hz, 2H), 5.92 (d, J = 7.1 Hz, 1H), 5.31 (d, J = 7.9 Hz, 1H), 3.58 (s, 3H),
1.71 (s, 3H), 1.48 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.9, 166.9, 157.2, 136.5, 134.1, 131.7,
128.7, 128.6, 128.5, 127.8, 127.4, 81.1, 65.8, 60.8, 52.5, 28.5, 17.5; HRMS (ESIꢀTOF) m/z
[C23H28N2O5+Na]+ calcd for 435.1890, found 435.1889. Chiral HPLC (CHIRALPAK IC column;
hexane/iꢀPrOH, v/v = 80:20; 1.0 mL/min, 254nm), synꢀmajor tr = 24.97 min, synꢀminor tr = 22.95
min, 94% ee.
Synthesis of Fully Deprotected α, β-Diamino Acid 5
Into an ordinary 50 mL roundꢀbottom vial equipped with a magnetic stirring bar, diamino ester
4 (1.0 mmol, 412mg), phenol (3.0 mmol, 282 mg), acetic acid (3.0 mmol, 0.17mL) and 10mL 6M
HCl were added subsequently. The reaction mixture were set to reflux and stirred for 12 hours.
After cooling to room temperature, the orange solution was washed with EA (3×30 mL), and the
aqueous phase was concentrated at 50 °C under vacuum to yield 5 as a crystalline solid.
(2S,3R)ꢀ2,3ꢀdiaminoꢀ2ꢀmethylꢀ3ꢀphenylpropanoic acid hydrochloride (5):
Colorless crystalline solid, 270 mg, quantitative yield, slightly contaminated by impurities.
[α]D20 = ꢀ10.5 (c = 0.44, MeOH); 1H NMR (400 MHz, MeOD) δ 7.56 (s, 5H), 4.86ꢀ4.83 (m, 1H),
1.91 (s, 3H); 13C NMR (101 MHz, MeOD) δ 169.5, 130.7, 130.4, 129.7, 128.2, 60.6, 58.5, 20.5.
These NMR data match those found in the literature.22
Synthesis of dipeptide 6
Trifluoroacetic acid was added to a solution of 4 (0.10 mmol, 31 mg) in DCM (5 mL). The
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reaction solution was stirred for 10 hours at room temperature. The reaction was quenched with
saturated aqueous Na2CO3 (10 mL) and was then extracted with EA (3×10 mL), dried with
anhydrous sodium sulfate and concentrated in vacuo to yield crude white solid. This material was
carried forward without any further purification.
Triethylamine (0.25 mmol, 35 ꢁL), HOBt (0.12 mmol, 16 mg) and EDCI (0.12 mmol, 23 mg)
were added to a solution of the crude material obtained above and BocꢀLꢀValꢀOH (0.12 mmol, 26
mg) in DCM (5 mL). The reaction solution was stirred for 12 hours before washed with saturated
aqueous Na2CO3, water and brine. The organic phase was dried with anhydrous sodium sulfate and
concentrated in vacuo to yield a white solid, which was characterized without further purification.
(2S,3R)ꢀmethylꢀ2ꢀbenzamidoꢀ3ꢀ((S)ꢀ2ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀmethylbutanamido)ꢀ2ꢀme
thylꢀ3ꢀphenylpropanoate (6):
White solid, 51 mg, 94% yield, >20:1 dr. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 6.0 Hz, 1H),
7.82 (d, J = 7.3 Hz, 2H), 7.74 (s, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.31 (d, J = 6.5
Hz, 3H), 7.26 – 7.21 (m, 2H), 5.56 (d, J = 7.9 Hz, 1H), 5.06 (s, 1H), 3.99 – 3.89 (m, 1H), 3.62 (s, 3H),
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2.25 (td, J = 13.4, 6.7 Hz, 1H), 1.66 (s, 3H), 1.37 (s, 9H), 0.92 (t, J = 7.8 Hz, 6H);
13C NMR (101
MHz, CDCl3) δ 173.0, 171.7, 167.5, 136.4, 133.9, 131.9, 128.7, 128.6, 128.0, 127.4, 65.4, 60.8,
59.5, 52.7, 29.8, 28.3, 19.6, 19.3, 18.0. HRMS (ESIꢀTOF) m/z [C28H37N3O6+Na]+ calcd for
534.2575, found 534.2568.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Xꢀray crystal data for 3ah.
31P NMR analysis of the crude reaction mixtures.
1H and 13C NMR spectra for all pure products.
HPLC data of compound 4
ACKNOWLEDGEMENTS
We would like to acknowledge the financial support from the National Natural Science
Foundation of China (No. 21332005, 21672100) and Robert A. Welch Foundation (Dꢀ1361, USA).
REFERENCES
$Summer High School Participant: Shanghai High School International Division No. 989, Baise
Road, Shanghai, China 200231.
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Org. Chem. 2012, 8, 2124. (f) Callebaut，G.; Meiresonne ，T.; De Kimpe, N.; Mangelinckx, S.
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(6) Selected examples of catalytic Mannich reactions: (a) HernandezꢀToribio, J.; Go´mez Arraya´s,
R.; Carretero, J. C. J. Am. Chem. Soc. 2008, 130, 16150. (b) HernandezꢀToribio, J.; Gomez
Arrayas, R.; Carretero, J. C. Chem. Eur. J. 2010, 16, 1153. (c) Shang, D.; Liu, Y.; Zhou, X.;
Liu, X.; Feng, X. Chem. Eur. J. 2009, 15, 3678. (d) Cutting, G. A.; Stainforth, N. E.; John, M.
P.; KociokꢀKohn, G.; Willis, M. C. J. Am. Chem. Soc. 2007, 129, 10632. (e) Okada, A.;
Shibuguchi, T.; Ohshima, T.; Masu, H.;Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed.
2005, 44, 4564. (f) Li, L.; Ganesh, M.; Seidel,D. J. Am. Chem. Soc. 2009, 131, 11648. (g)
Zhang,H.; Syed, S.; Barbas III, C. F. Org. Lett. 2010, 12, 708.
(7) Selected review articles of azlactones: (a) Castro, P. P.; Carpanez A. G.; Amarante, G. W.
Chem. Eur. J. 2016, 22, 10294. (b) Alba, A. R.; Rios, R. Chem. Asian J. 2011, 6, 720 (c) Fisk,
J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36, 1432–1440.
(8) Selected examples of enantioselective Mannichꢀtype reaction between imines and azlactones:
(a) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 14088. (b) Liu, X.; Deng, L.;
Jiang, X.; Yan, W.; Liu, C.; Wang, R. Org. Lett. 2010, 12, 876. (c) Melhado, A. D.; Amarante,
G. W.; Wang, Z. J.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 3517. (d) Zhang,
W.ꢀQ.; Cheng, L.ꢀF.; Yu, J.; Gong, L.ꢀZ. Angew. Chem. Int. Ed. 2012, 51, 4085. (e) Shi, S.ꢀH.;
Huang, F.ꢀP.; Zhu, P.; Dong, Z.ꢀW.; Hui, X.ꢀP. Org. Lett. 2012, 14, 2010. (f) Ávila, E. P.;
Justo, R. M. S.; Gonçalves, V. P.; Pereira, A. A.; Diniz, R.; Amarante, G. W. J. Org. Chem.
2015, 80, 590.
(9) Uraguchi, D.; Yoshioka, K.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc. 2012, 134, 19370.
(10) Zabka, M.; Malastova, A.; Sebesta, R. RSC Adv. 2015, 5, 12890.
(11) A review article of Nꢀphosphonyl imines and GAP chemistry: An, G.; Seifert C.; Li, G. Org.
Biomol. Chem. 2015, 13, 1600.
(12) (a) Yang, B.; Shen, M.; Ji, X.; Sun, H.; Jiang, B.; Li, G. J. Org. Chem. 2016, 81, 2488.
(13) (a) Xie, J.; Luo, J.; Winn, T. R.; Cordes, D. B.; Li, G. Beilstein J. Org. Chem. 2014, 10, 746.
(14) Kattamuri, P. V.; Ai, T.; Pindi, S.; Sun, Y.; Gu, P.; Shi, M.; Li, G. J. Org. Chem. 2011, 76,
2792.
(15) Seifert, C. W.; Pindi, S.; Li, G. J. Org. Chem. 2015, 80, 447.
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(16) Seifert, C. W.; Paniagua, A.; White, G. A.; Cai, L.; Li, G. Eur. J. Org. Chem. 2016, 9, 1714.
(17) In recent work, we have reported the asymmetric addition between Ni(II)ꢀcomplexed alanine
Schiff base and Nꢀphosphonyl imines which provided the asymmetric synthesis of
αꢀmethylꢀα,βꢀdiamino acid derivatives with good to high yields (61%ꢀ93%) and complete
diastereoselectivity (>99:1 dr). However, aside from glycine and alanine, the Ni(II)
complexes derived from other αꢀamino acids were not suitable for the Mannich reactions
with Nꢀphosphonyl imines.
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(18) The Mannichꢀtype reaction between Ni(II)ꢀcomplexed alanine Schiff base and Nꢀphosphonyl
imines led to (2R, 3S) configuration using the same auxiliary. See: Zhang, H.; Yang, B.;
Yang, Z.; Lu, H.; Li, G. J. Org. Chem., 2016, 81, 7654.
(19) (a) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem. 2006, 118, 2312. (b) Fisk, J. S.;
Tepe, J. J. J. Am. Chem. Soc. 2007, 129, 3058. (c) Terada, M.; Moriya, K.; Kanomata, K.;
Sorimachi, K. Angew. Chem. Int. Ed. 2011, 50, 12586
(20) Kattuboina, A.; Kaur, P.; Ai, T.; Li, G. Chem. Biol. Drug Des. 2008, 71, 216.
(21) Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12638.
(22) Guerrini, A.; Varchi, G.; Samori, C.; Battaglia, A. Eur. J. Org. Chem. 2008, 3834.
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