[ CAS No. 84000-07-7 ] {[proInfo.proName]}

Name: 84000-07-7|Fmoc-N-Me-Ala-OH|97%
Brand: Ambeed
SKU: A158676
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2D 3D

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Quality Control of [ 84000-07-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 84000-07-7 ]

SDS Specification

Alternatived Products of [ 84000-07-7 ]

Product Details of [ 84000-07-7 ]

CAS No. :	84000-07-7	MDL No. :	MFCD00153384
Formula :	C₁₉H₁₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JOFHWKQIQLPZTC-LBPRGKRZSA-N
M.W :	325.36	Pubchem ID :	688634
Synonyms :

Calculated chemistry of [ 84000-07-7 ]

Physicochemical Properties

Num. heavy atoms :	24
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.26
Num. rotatable bonds :	6
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	90.07
TPSA :	66.84 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.04
Log Po/w (XLOGP3) :	3.24
Log Po/w (WLOGP) :	3.34
Log Po/w (MLOGP) :	2.55
Log Po/w (SILICOS-IT) :	2.48
Consensus Log Po/w :	2.73

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.87
Solubility :	0.0436 mg/ml ; 0.000134 mol/l
Class :	Soluble
Log S (Ali) :	-4.32
Solubility :	0.0157 mg/ml ; 0.0000482 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.56
Solubility :	0.00898 mg/ml ; 0.0000276 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.72

Safety of [ 84000-07-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 84000-07-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 84000-07-7 ]
Downstream synthetic route of [ 84000-07-7 ]

[ 84000-07-7 ] Synthesis Path-Upstream 1~8

1
[ 83999-95-5 ]
[ 84000-07-7 ]

Yield	Reaction Conditions	Operation in experiment
6.1 g	With triethylsilane; trifluoroacetic acid In chloroform at 20℃; for 10 h; Inert atmosphere	To a suspension of Fmoc-L-Ala (6.2 g, 19.9mmol) in toluene (400 mL)was added paraformaldehyde (4.0 g, 133 mmol) andp-toluenesulfonic acid (0.5 g, 13.3 mmol). The mixture was refluxedfor 30 min to remove azeotropic water. The solution was cooleddown, washed with 1 M aqueous NaHCO3 (2 × 100 mL) and dried over Na2SO4.Concentration in vacuo gave a white solid.To the above oxazolidinone in CHC13 (75 mL) was added trifluoroacetic acid (75mL) and triethylsilane (7.2 mL, 44.8 mmol). The reaction was stirred at roomtemperature for 10 h, and then concentrated in vacuo. The resulting oil wasre-dissolved in CH2C12 and concentrated for three times. The obtained oil crystallizedon standing. The crystals were re-dissolved in ether and concentrated. The collectedwhite solid 5 was washed with 5percent ether in hexane and dried (6.1 g, 94percent). .
2.51 g	With triethylsilane; trifluoroacetic acid In chloroform at 20℃;	General procedure: Paraformaldehyde (1.92 g, 64.0 mmol) and p-toluenesulfonic acid (0.1920 g, 0.12 mmol) were added to a solution of Fmoc-Ala-OH (3.00 g, 9.6 mmol) in toluene (150 mL). The mixture was refluxed for 3 h with Dean–Stark apparatus. After cooled to room temperature, the resultant mixture was washed with saturated NaHCO₃, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. After recrystallization with ethylacetate and petroleum ether, the intermediate was obtained without further purification. Trifluoroacetic acid (48.0 mL) and triethylsilane (4.60 mL,28.8 mmol) were added to a solution of above intermediate in CHCl₃ (25 mL). The resultant mixture was stirred at room temperature overnight. After concentration, the residue was dissolved in CH₂Cl₂ and concentrated again; after repeated for three times, the oil liquid was turned to white solid. Then the white solid was dissolved in diethyl ether, concentrated, washed three times with petroleum ether. The residue was purified by flash-column chromatography on silica gel, to yield the white solid product (2.51 g,80percent yield). ¹H NMR (400 MHz, CDCl₃): (isomer I) d = 7.77–7.29(8H, m), 4.91 (1H, dd, J = 14.2, 6.8 Hz), 4.51–4.37 (2H, m), 4.27(1H, t, J = 6.7 Hz), 2.91 (3H, s), 1.46 (3H, d, 7.4 Hz); (isomer II)d = 7.77–7.29 (8H, m), 4.62 (1H, dd, J = 14.1, 6.9 Hz), 4.51–4.37(2H, m), 4.22 (1H, t, J = 6.4 Hz), 2.90 (3H, s), 1.37 (3H, d, J = 6.9 Hz).

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 30, p. 3872 - 3875
[2] European Journal of Organic Chemistry, 2013, # 21, p. 4509 - 4513
[3] Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6918 - 6920
[4] Tetrahedron Letters, 2006, vol. 47, # 11, p. 1691 - 1694
[5] Tetrahedron Letters, 2014, vol. 55, # 44, p. 6109 - 6112
[6] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 6, p. 1163 - 1170

2
[ 50-00-0 ]
[ 35661-39-3 ]
[ 84000-07-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 6, p. 1232 - 1238

3
[ 1220527-64-9 ]
[ 84000-07-7 ]

Reference： [1] Amino Acids, 2010, vol. 38, # 1, p. 133 - 143

4
[ 693-13-0 ]
[ 84000-07-7 ]

Reference： [1] Patent: US2014/178414, 2014, A1, . Location in patent: Page/Page column

5
[ 1208119-53-2 ]
[ 28920-43-6 ]
[ 84000-07-7 ]

Reference： [1] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1386 - 1392

6
[ 35661-39-3 ]
[ 84000-07-7 ]

Reference： [1] European Journal of Organic Chemistry, 2013, # 21, p. 4509 - 4513
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 6, p. 1163 - 1170

7
[ 186581-53-3 ]
[ 28920-43-6 ]
[ 59724-75-3 ]
[ 84000-07-7 ]

Reference： [1] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3723 - 3728

8
[ 67-56-1 ]
[ 56-41-7 ]
[ 28920-43-6 ]
[ 84000-07-7 ]

Reference： [1] Tetrahedron Letters, 1997, vol. 38, # 42, p. 7307 - 7310

[ 84000-07-7 ] Synthesis Path-Downstream 1~88

1
[ 83999-95-5 ]
[ 84000-07-7 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 77 - 81

2
[ 35661-60-0 ]
[ 84000-07-7 ]
[ 71989-14-5 ]
[ 84624-17-9 ]
Fmoc-D-Trp [ No CAS ]
(R)-3-[(R)-2-Amino-3-(1H-indol-3-yl)-propionylamino]-N-{(S)-1-[(R)-1-((S)-1-hydrazinocarbonyl-3-methyl-butylcarbamoyl)-2-methyl-propylcarbamoyl]-ethyl}-N-methyl-succinamic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2139 - 2142

3
[ 112883-29-1 ]
[ 84000-07-7 ]
[ 105047-45-8 ]
[ 35737-15-6 ]
ValPhe [ No CAS ]
[ 81377-02-8 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 8197 - 8200

4
[ 84000-07-7 ]
[ 103478-58-6 ]
[ 84000-14-6 ]
all-N-Me-(Ser(OBz)-Val-Ala-Ser(OBz)-Val-Ala) [ No CAS ]

Reference： [1]Chemical Communications,2006,p. 497 - 499

5
[ 863671-50-5 ]
[ 84000-07-7 ]
[ 863671-51-6 ]

Yield	Reaction Conditions	Operation in experiment
89%		To a solution of Fmoc-N(Me) L-Ala (6 g, 18.5 mmol) and HOBt (2.5 g, 18.5 mmol) in CH2Cl2 (60 ml) was added EDCI (3.5 g, 18.5 mmol) at 0 C. stirred for 1 hr and an additional hour at room temperature. To the reaction mixture was added Pd (PPh3)4 (3.6 g, 3.0 mmol), a solution of 4 (3 g, 6.2 mmol) in CH2Cl2 (30 ml) and DABCO (3.7 g, 31 mmol) at room temperature followed by stirred for 15 min. The reaction mixture was concentrated in vacuo and purified by silica gel column with (hexane:EtOAc=1:1) to furnish 5 (3.8 g, 89%) as pale yellow foam. [alpha]D -31.9 (c 1.56, CHCl3). 1H NMR (400 MHz, CDCl3): delta 1.20 (d, J=3.6 Hz, 3H), 1.41 (d, J=4.2 Hz, 3H), 1.75-1.98 (bm, 4H), 2.50 (bs, 1H), 2.95 (s, 3H), 3.60 (bm, 1H), 3.70 (bm, 1H), 4.01 (bm, 1H), 4.10 (dq J=5.6 Hz, 18.1 Hz, 2H), 4.20 (bm, 1H), 4.25 (bm,1H), 4.28 (bm, 2H) 4.32 (bm,1H), 4.40 (bm, 2H), 4.59 (dd, J=4.2, 8.0 Hz,1H), 6.81 (bd,1H), 7.28 (bm, 2H), 7.34 (bm, 5H), 7.52 (br m, 4H), 7.72 (d, J=7.6 Hz, m, 2H); 13C NMR (75 MHz, CDCl3): delta 16.1, 24.3, 27.5, 47.4, 48.5, 55.3, 56.4, 68.2, 74.0, 75.0, 79.8, 120.1, 125.2, 125.3, 127.2, 127.6, 127.9, 128.6, 129.9, 130.1, 132.2, 132.4, 133.3, 141.5, 153.5, 169.3, 171.4; IR (film): 3297, 2978, 1693, 1650, 1442, 1400, 1312, 1157, 10948, 758, 742 cm-1; MS:(ESI) [M+1]+ 708.2

Reference： [1]Patent: US2005/197403,2005,A1 .Location in patent: Page/Page column 27; 29; 30

6
[ 863671-56-1 ]
[ 84000-07-7 ]
[ 863671-57-2 ]

Yield	Reaction Conditions	Operation in experiment
73%		8b was synthesized according to scheme 2. 1H NMR (400 MHz, CDCl3): delta 1.20 (d, J=6.4 Hz, 6H), 1.29 (d, J=6.8 Hz, 6H), 1.65-2.15 (m, 8H), 2.50 (s, 6H), 3.05 (q, J=6.8 Hz, 2H), 3.59 (m, 2H), 3.75 (m, 2H), 4.03 (m, 2H), 4.20 (ABq, J=11.6, 16.4 Hz, 4H), 4.39 (m, 2H), 4.60 (m 4H), 4.67 (dd, J=4.4 Hz, 8.4 Hz, 2H), 7.20 (m, 2H), 7.40 (m, 8H), 7.82 (d, J=8.4 Hz, 2H); MS:(ESI) [M+1]+ 937.5

Reference： [1]Patent: US2005/197403,2005,A1 .Location in patent: Page/Page column 30

7
[ 863671-62-9 ]
[ 84000-07-7 ]
[ 863671-63-0 ]

Reference： [1]Patent: US2005/197403,2005,A1 .Location in patent: Page/Page column 31; 32

8
[ 863671-68-5 ]
[ 84000-07-7 ]
[ 863671-69-6 ]

Reference： [1]Patent: US2005/197403,2005,A1 .Location in patent: Page/Page column 33

9
[ 863671-74-3 ]
[ 84000-07-7 ]
[ 863671-75-4 ]

Reference： [1]Patent: US2005/197403,2005,A1 .Location in patent: Page/Page column 34

10
[ 863671-84-5 ]
[ 84000-07-7 ]
C₄₂H₄₅ClN₄O₈ [ No CAS ]

Reference： [1]Patent: US2005/197403,2005,A1 .Location in patent: Page/Page column 36

11
[ 863671-92-5 ]
[ 84000-07-7 ]
[ 863671-93-6 ]

Reference： [1]Patent: US2005/197403,2005,A1 .Location in patent: Page/Page column 40

12
C₅₀H₈₆Cl₃N₅O₁₂S [ No CAS ]
[ 84000-07-7 ]
C₆₉H₁₀₃Cl₃N₆O₁₅S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3902 - 3905

13
C₅₀H₈₆Cl₃N₅O₁₂S [ No CAS ]
[ 84000-07-7 ]
C₆₉H₁₀₃Cl₃N₆O₁₅S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3902 - 3905

14
[ 1058711-61-7 ]
[ 84000-07-7 ]
[ 1058711-70-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3902 - 3905

15
[ 1208119-53-2 ]
[ 28920-43-6 ]
[ 84000-07-7 ]

Reference： [1]Journal of Organic Chemistry,2010,vol. 75,p. 1386 - 1392

16
[ 29022-11-5 ]
[ 108-24-7 ]
[ 84000-07-7 ]
[ 84624-17-9 ]
[ 173963-93-4 ]
[ 1233962-32-7 ]

Reference： [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 3473 - 3476

17
[ 29022-11-5 ]
[ 108-24-7 ]
[ 84000-07-7 ]
[ 173963-93-4 ]
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3-thienyl)propanoic acid [ No CAS ]
[ 1233962-35-0 ]

Reference： [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 3473 - 3476

18
[ 1220527-64-9 ]
[ 84000-07-7 ]

Reference： [1]Amino Acids,2010,vol. 38,p. 133 - 143

19
C₂₂H₂₀NO₂Pol [ No CAS ]
[ 84000-07-7 ]
C₄₁H₃₇N₂O₅Pol [ No CAS ]

Reference： [1]Organic Letters,2010,vol. 12,p. 3792 - 3795

20
[ 84000-07-7 ]
[ 77128-73-5 ]
[ 77128-70-2 ]
[ 1219925-93-5 ]

Reference： [1]Journal of Peptide Science,2010,vol. 16,p. 136 - 140

21
[ 84000-07-7 ]
[ 77128-73-5 ]
[ 77128-70-2 ]
[ 1219925-94-6 ]

Reference： [1]Journal of Peptide Science,2010,vol. 16,p. 136 - 140

22
[ 84000-07-7 ]
[ 103478-58-6 ]
[ 77128-70-2 ]
[ 1219925-98-0 ]

Reference： [1]Journal of Peptide Science,2010,vol. 16,p. 136 - 140

23
[ 84000-07-7 ]
[ 77128-70-2 ]
[ 138775-22-1 ]
[ 1219925-99-1 ]

Reference： [1]Journal of Peptide Science,2010,vol. 16,p. 136 - 140

24
[ 84000-07-7 ]
[ 138775-22-1 ]
[ 152548-66-8 ]
[ 1219925-97-9 ]

Reference： [1]Journal of Peptide Science,2010,vol. 16,p. 136 - 140

25
C₃H₉N₂Pol [ No CAS ]
[ 68858-20-8 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 84000-07-7 ]
[ 1269628-05-8 ]

Reference： [1]Chemical Communications,2011,vol. 47,p. 1309 - 1311

26
[ 1177263-67-0 ]
C₄₀H₃₅NO₄S [ No CAS ]
[ 71989-23-6 ]
[ 84000-07-7 ]
[ 77128-72-4 ]
C₆₇H₈₈Cl₃N₅O₁₂S [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2011,vol. 6,p. 180 - 188

27
[ 1263721-14-7 ]
C₃₉H₅₀N₂O₇S [ No CAS ]
[ 84000-07-7 ]
[ 77128-72-4 ]
C₄₅H₇₀N₈O₉S [ No CAS ]
C₄₅H₇₀N₈O₉S [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2011,vol. 6,p. 180 - 188

28
C₃₉H₅₀N₂O₇S [ No CAS ]
[ 71989-23-6 ]
[ 84000-07-7 ]
[ 77128-72-4 ]
C₄₅H₇₁N₅O₉S [ No CAS ]
C₄₅H₇₁N₅O₉S [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2011,vol. 6,p. 180 - 188

29
[ 1263721-02-3 ]
C₄₀H₃₅NO₄S [ No CAS ]
[ 71989-23-6 ]
[ 84000-07-7 ]
[ 77128-72-4 ]
C₅₈H₇₅N₅O₉S [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2011,vol. 6,p. 180 - 188

30
C₄₀H₃₅NO₄S [ No CAS ]
[ 71989-23-6 ]
[ 84000-07-7 ]
[ 77128-72-4 ]
C₆₁H₆₆N₄O₈S [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2011,vol. 6,p. 180 - 188

31
[ 84000-07-7 ]
[ 77128-72-4 ]
C₂₉H₂₈N₂O₅ [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2011,vol. 6,p. 180 - 188

32
[ 84000-07-7 ]
Fmoc-D-(N-Me)Ala-Cl [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 4700 - 4703
[2]Organic and Biomolecular Chemistry,2016,vol. 14,p. 9093 - 9104
[3]Organic Letters,2018,vol. 20,p. 2033 - 2036
[4]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 365 - 369

33
[ 84000-07-7 ]
N-allyl-(S)-phenylalanine [ No CAS ]
tert-butyl (S)-2-{(S)-N-allyl-2-[(9H-fluoren-9-ylmethoxycarbonyl)methylamino]propanamido}-3-phenylpropanoate [ No CAS ]

Reference： [1]Synthesis,2012,vol. 44,p. 2682 - 2694

34
[ 1219953-58-8 ]
C₁₁H₁₅N₂O₃PolS [ No CAS ]
[ 84000-07-7 ]
[ 132684-60-7 ]
C₃₂H₄₄N₅O₇PolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Peptides were synthesized on a CEM Liberty automated microwave peptide synthesizer (CEM Microwave Technology Ltd, Buckingham, England, UK). In essence, each peptide was synthesised, on a 0.1-0.5mmol scale, using either Rink Amide MBHA resin (substitution 0.65 mmol/g, 100-200mesh) for peptides (18-20) or a pre-loaded 4-Sulfamylbutyryl AM resin (substitution 0.6-0.8 mmol/g, loaded as described under Section 2.1.2) for peptides (10a) and (11a-f). Fmoc removal was performed using 2 repeat cycles employing 20% (V/V) piperidine as solution in DMF. A first deprotection cycle of 30 s at 50W was employed, followed by a second deprotection cycle of 3min at 50W. Both cycles were carried out at 75C. Coupling steps were carried out by introducing each Fmoc-amino acid (0.2M solution in DMF) at a fivefold excess over resin loading, together with HBTU activation reagent and DIEA activation base used in the molar ratios HBTU/DIEA/AA (1/2/1). Each coupling reaction was performed for 10min, at 22W, at 75C. Finally, cleavage of peptides (18-20) from Rink Amide MBHA was performed manually, at room temperature, using TFA/H2O/triisopropylsilane (95/2.5/2.5, v/v/v), for two 1h cycles, with washing with dichloromethane after every cycle. The collected cleavage reaction mixtures and washes were evaporated under vacuum, at 30C, cooled, and the products precipitated by the addition of cold diethylether. The precipitates were collected by centrifugation (3-5 min at 2000-3000 g) and the pellet washed thoroughly with diethylether. This process was repeated 2-3 times, each time the solid was collected by centrifugation. On the other hand, cleavage of peptides 10a and 11a-f from 4-Sulfamylbutyryl AM resin was performed as described under Section 2.1.3. After a brief drying in vacuum to remove all traces of solvents, the peptide products were dissolved in 10% TFA aqueous solution and freeze dried. Peptide purity was checked through RP-HPLC, using Waters HPLC system fitted with Waters 1525 binary HPLC pump and Waters 2489 UV/visible detector (lambda216 nm) (Waters, Milford, Massachusetts, USA) and employing a Phenomenex Jupiter C12 column (250 ×4.66mm; particle size, 10mum). The runs were carried out on an analytical scale with a flow rate of 1ml/min. An elution gradient was utilized to resolve the crude product components that went from 90% solvent A (0.05% TFA in H2O)/10% Solvent B (0.05% TFA in CH3OH) to 10% solvent A/90% solvent B in 60min. Peptides with crude purity less than 95% were purified with semi-preparative RP-HPLC, using Phenomenex Jupiter C12 column (250 ×21.20mm; particle size, 10mum) and using the same above stated elution gradient with a flow rate of 10ml/min. 2.1.2 General procedure for 4-sulfamylbutyryl AM ?Safety-Catch? resin loading. 4-Sulfamylbutyryl AM Resin (625mg, 0.5mmol) suspended in 17ml CHCl3, DIEA (476.6mul, 2.5mmol) and an Fmoc-amino acid [(2S,4R)-Fmoc-4-phenyl-pyrrolidine-2-carboxylic acid (620mg, 1.5mmol); (2S,4S)-Fmoc-4-phenoxy-pyrrolidine-2-carboxylic acid (643mg, 1.5mmol); Fmoc-Tic-OH (600mg, 1.5mmol)] were added to a 100ml round bottom flask. The reaction mixture was stirred for 10min, cooled to -20C and after 20min PyBop (780mg, 1.5mmol) was added as solid. The reaction mixture was stirred for 8h at -20C after which the resin was filtered and washed with CHCl3 (3 ×5ml). The resin was dried in a desiccator under vacuum. The resin loading was checked spectrophotometrically by performing Fmoc-group removal on accurately weighed samples (?4mg) of resin derivatized by these three Fmoc-derivatives, and measuring the formation of the dibenzofulvene-piperidine adduct (molar absorptivity epsilon=5253M-1cm-1 at lambda290nm), using a UV spectrophotometer (50 Scan UV-Visible Spectrophotometer, VARIAN, Australia).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5004 - 5011

35
C₁₁H₁₅N₂O₃PolS [ No CAS ]
[ 84000-07-7 ]
[ 132684-60-7 ]
[ 171859-74-8 ]
C₃₁H₄₂N₅O₆PolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Peptides were synthesized on a CEM Liberty automated microwave peptide synthesizer (CEM Microwave Technology Ltd, Buckingham, England, UK). In essence, each peptide was synthesised, on a 0.1-0.5mmol scale, using either Rink Amide MBHA resin (substitution 0.65 mmol/g, 100-200mesh) for peptides (18-20) or a pre-loaded 4-Sulfamylbutyryl AM resin (substitution 0.6-0.8 mmol/g, loaded as described under Section 2.1.2) for peptides (10a) and (11a-f). Fmoc removal was performed using 2 repeat cycles employing 20% (V/V) piperidine as solution in DMF. A first deprotection cycle of 30 s at 50W was employed, followed by a second deprotection cycle of 3min at 50W. Both cycles were carried out at 75C. Coupling steps were carried out by introducing each Fmoc-amino acid (0.2M solution in DMF) at a fivefold excess over resin loading, together with HBTU activation reagent and DIEA activation base used in the molar ratios HBTU/DIEA/AA (1/2/1). Each coupling reaction was performed for 10min, at 22W, at 75C. Finally, cleavage of peptides (18-20) from Rink Amide MBHA was performed manually, at room temperature, using TFA/H2O/triisopropylsilane (95/2.5/2.5, v/v/v), for two 1h cycles, with washing with dichloromethane after every cycle. The collected cleavage reaction mixtures and washes were evaporated under vacuum, at 30C, cooled, and the products precipitated by the addition of cold diethylether. The precipitates were collected by centrifugation (3-5 min at 2000-3000 g) and the pellet washed thoroughly with diethylether. This process was repeated 2-3 times, each time the solid was collected by centrifugation. On the other hand, cleavage of peptides 10a and 11a-f from 4-Sulfamylbutyryl AM resin was performed as described under Section 2.1.3. After a brief drying in vacuum to remove all traces of solvents, the peptide products were dissolved in 10% TFA aqueous solution and freeze dried. Peptide purity was checked through RP-HPLC, using Waters HPLC system fitted with Waters 1525 binary HPLC pump and Waters 2489 UV/visible detector (lambda216 nm) (Waters, Milford, Massachusetts, USA) and employing a Phenomenex Jupiter C12 column (250 ×4.66mm; particle size, 10mum). The runs were carried out on an analytical scale with a flow rate of 1ml/min. An elution gradient was utilized to resolve the crude product components that went from 90% solvent A (0.05% TFA in H2O)/10% Solvent B (0.05% TFA in CH3OH) to 10% solvent A/90% solvent B in 60min. Peptides with crude purity less than 95% were purified with semi-preparative RP-HPLC, using Phenomenex Jupiter C12 column (250 ×21.20mm; particle size, 10mum) and using the same above stated elution gradient with a flow rate of 10ml/min. 2.1.2 General procedure for 4-sulfamylbutyryl AM ?Safety-Catch? resin loading. 4-Sulfamylbutyryl AM Resin (625mg, 0.5mmol) suspended in 17ml CHCl3, DIEA (476.6mul, 2.5mmol) and an Fmoc-amino acid [(2S,4R)-Fmoc-4-phenyl-pyrrolidine-2-carboxylic acid (620mg, 1.5mmol); (2S,4S)-Fmoc-4-phenoxy-pyrrolidine-2-carboxylic acid (643mg, 1.5mmol); Fmoc-Tic-OH (600mg, 1.5mmol)] were added to a 100ml round bottom flask. The reaction mixture was stirred for 10min, cooled to -20C and after 20min PyBop (780mg, 1.5mmol) was added as solid. The reaction mixture was stirred for 8h at -20C after which the resin was filtered and washed with CHCl3 (3 ×5ml). The resin was dried in a desiccator under vacuum. The resin loading was checked spectrophotometrically by performing Fmoc-group removal on accurately weighed samples (?4mg) of resin derivatized by these three Fmoc-derivatives, and measuring the formation of the dibenzofulvene-piperidine adduct (molar absorptivity epsilon=5253M-1cm-1 at lambda290nm), using a UV spectrophotometer (50 Scan UV-Visible Spectrophotometer, VARIAN, Australia).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5004 - 5011

36
C₁₁H₁₅N₂O₃PolS [ No CAS ]
[ 316833-44-0 ]
[ 84000-07-7 ]
[ 132684-60-7 ]
C₃₂H₄₄N₅O₆PolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Peptides were synthesized on a CEM Liberty automated microwave peptide synthesizer (CEM Microwave Technology Ltd, Buckingham, England, UK). In essence, each peptide was synthesised, on a 0.1-0.5mmol scale, using either Rink Amide MBHA resin (substitution 0.65 mmol/g, 100-200mesh) for peptides (18-20) or a pre-loaded 4-Sulfamylbutyryl AM resin (substitution 0.6-0.8 mmol/g, loaded as described under Section 2.1.2) for peptides (10a) and (11a-f). Fmoc removal was performed using 2 repeat cycles employing 20% (V/V) piperidine as solution in DMF. A first deprotection cycle of 30 s at 50W was employed, followed by a second deprotection cycle of 3min at 50W. Both cycles were carried out at 75C. Coupling steps were carried out by introducing each Fmoc-amino acid (0.2M solution in DMF) at a fivefold excess over resin loading, together with HBTU activation reagent and DIEA activation base used in the molar ratios HBTU/DIEA/AA (1/2/1). Each coupling reaction was performed for 10min, at 22W, at 75C. Finally, cleavage of peptides (18-20) from Rink Amide MBHA was performed manually, at room temperature, using TFA/H2O/triisopropylsilane (95/2.5/2.5, v/v/v), for two 1h cycles, with washing with dichloromethane after every cycle. The collected cleavage reaction mixtures and washes were evaporated under vacuum, at 30C, cooled, and the products precipitated by the addition of cold diethylether. The precipitates were collected by centrifugation (3-5 min at 2000-3000 g) and the pellet washed thoroughly with diethylether. This process was repeated 2-3 times, each time the solid was collected by centrifugation. On the other hand, cleavage of peptides 10a and 11a-f from 4-Sulfamylbutyryl AM resin was performed as described under Section 2.1.3. After a brief drying in vacuum to remove all traces of solvents, the peptide products were dissolved in 10% TFA aqueous solution and freeze dried. Peptide purity was checked through RP-HPLC, using Waters HPLC system fitted with Waters 1525 binary HPLC pump and Waters 2489 UV/visible detector (lambda216 nm) (Waters, Milford, Massachusetts, USA) and employing a Phenomenex Jupiter C12 column (250 ×4.66mm; particle size, 10mum). The runs were carried out on an analytical scale with a flow rate of 1ml/min. An elution gradient was utilized to resolve the crude product components that went from 90% solvent A (0.05% TFA in H2O)/10% Solvent B (0.05% TFA in CH3OH) to 10% solvent A/90% solvent B in 60min. Peptides with crude purity less than 95% were purified with semi-preparative RP-HPLC, using Phenomenex Jupiter C12 column (250 ×21.20mm; particle size, 10mum) and using the same above stated elution gradient with a flow rate of 10ml/min. 2.1.2 General procedure for 4-sulfamylbutyryl AM ?Safety-Catch? resin loading. 4-Sulfamylbutyryl AM Resin (625mg, 0.5mmol) suspended in 17ml CHCl3, DIEA (476.6mul, 2.5mmol) and an Fmoc-amino acid [(2S,4R)-Fmoc-4-phenyl-pyrrolidine-2-carboxylic acid (620mg, 1.5mmol); (2S,4S)-Fmoc-4-phenoxy-pyrrolidine-2-carboxylic acid (643mg, 1.5mmol); Fmoc-Tic-OH (600mg, 1.5mmol)] were added to a 100ml round bottom flask. The reaction mixture was stirred for 10min, cooled to -20C and after 20min PyBop (780mg, 1.5mmol) was added as solid. The reaction mixture was stirred for 8h at -20C after which the resin was filtered and washed with CHCl3 (3 ×5ml). The resin was dried in a desiccator under vacuum. The resin loading was checked spectrophotometrically by performing Fmoc-group removal on accurately weighed samples (?4mg) of resin derivatized by these three Fmoc-derivatives, and measuring the formation of the dibenzofulvene-piperidine adduct (molar absorptivity epsilon=5253M-1cm-1 at lambda290nm), using a UV spectrophotometer (50 Scan UV-Visible Spectrophotometer, VARIAN, Australia).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5004 - 5011

37
[ 68858-20-8 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-38-3 ]
[ 84000-07-7 ]
[ 1449693-93-9 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Peptides were synthesized on a CEM Liberty automated microwave peptide synthesizer (CEM Microwave Technology Ltd, Buckingham, England, UK). In essence, each peptide was synthesised, on a 0.1-0.5mmol scale, using either Rink Amide MBHA resin (substitution 0.65 mmol/g, 100-200mesh) for peptides (18-20) or a pre-loaded 4-Sulfamylbutyryl AM resin (substitution 0.6-0.8 mmol/g, loaded as described under Section 2.1.2) for peptides (10a) and (11a-f). Fmoc removal was performed using 2 repeat cycles employing 20% (V/V) piperidine as solution in DMF. A first deprotection cycle of 30 s at 50W was employed, followed by a second deprotection cycle of 3min at 50W. Both cycles were carried out at 75C. Coupling steps were carried out by introducing each Fmoc-amino acid (0.2M solution in DMF) at a fivefold excess over resin loading, together with HBTU activation reagent and DIEA activation base used in the molar ratios HBTU/DIEA/AA (1/2/1). Each coupling reaction was performed for 10min, at 22W, at 75C. Finally, cleavage of peptides (18-20) from Rink Amide MBHA was performed manually, at room temperature, using TFA/H2O/triisopropylsilane (95/2.5/2.5, v/v/v), for two 1h cycles, with washing with dichloromethane after every cycle. The collected cleavage reaction mixtures and washes were evaporated under vacuum, at 30C, cooled, and the products precipitated by the addition of cold diethylether. The precipitates were collected by centrifugation (3-5 min at 2000-3000 g) and the pellet washed thoroughly with diethylether. This process was repeated 2-3 times, each time the solid was collected by centrifugation. On the other hand, cleavage of peptides 10a and 11a-f from 4-Sulfamylbutyryl AM resin was performed as described under Section 2.1.3. After a brief drying in vacuum to remove all traces of solvents, the peptide products were dissolved in 10% TFA aqueous solution and freeze dried. Peptide purity was checked through RP-HPLC, using Waters HPLC system fitted with Waters 1525 binary HPLC pump and Waters 2489 UV/visible detector (lambda216 nm) (Waters, Milford, Massachusetts, USA) and employing a Phenomenex Jupiter C12 column (250 ×4.66mm; particle size, 10mum). The runs were carried out on an analytical scale with a flow rate of 1ml/min. An elution gradient was utilized to resolve the crude product components that went from 90% solvent A (0.05% TFA in H2O)/10% Solvent B (0.05% TFA in CH3OH) to 10% solvent A/90% solvent B in 60min. Peptides with crude purity less than 95% were purified with semi-preparative RP-HPLC, using Phenomenex Jupiter C12 column (250 ×21.20mm; particle size, 10mum) and using the same above stated elution gradient with a flow rate of 10ml/min

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5004 - 5011

38
[ 1263430-79-0 ]
[ 84000-07-7 ]
[ 1422975-04-9 ]

Yield	Reaction Conditions	Operation in experiment
203 mg		Example 17:Synthesis of linker building blocks 15aAmine 14 (503 mg, 0.635 mmol, assuming a MW of 791.1 g/mol of crude 1 ) was dissolved in 4 mL DMF (anhydrous, mol. sieve). Fmoc-N-Me-Ala-OH (310 mg, 0.953 mmol), COMU (408 mg, 0.953 mmol) and DIPEA (332 mu, 1.906 mmol) were added and the reaction was allowed to stir for 3 h at RT. 150 mu piperidine and 150 mu DBU were added to the mixture and stirring was continued for further 60 min. 400 mu acetic acid were added and product was purified by HPLC. HPLC fractions containing product 15a were neutralized with a saturated NaHC03 solution and extracted twice with DCM. Combined organic phases were dried over Na2S04 and volatiles were removed under reduced pressure. Yield: 203 mg (0.336 mmol). MS: m/z 604.1 = [M+H]+ (MW calculated = 603.9 g/mol).
		Example 17: Synthesis of linker building blocks 15a, 15b, and 15c Linker building block 15a was synthesized according to the following scheme: 14 Amine 14 (503 mg, 0.635 mmol, assuming a MW of 791.1 g/mol of crude 1 ) was dissolved in 4 mL DMF (anhydrous, mol. sieve). Fmoc-N-Me-Ala-OH (310 mg, 0.953 mmol), COMU (408 mg, 0.953 mmol) and DIPEA (332 mu, 1.906 mmol) were added and the reaction was allowed to stir for 3 h at RT. 150 mu piperidine and 150 mu DBU were added to the mixture and stirring was continued for further 60 min. 400 mu acetic acid were added and product was purified by HPLC. HPLC fractions containing product 15a were neutralized with a saturated NaHC03 solution and extracted twice with DCM. Combined organic phases were dried over Na2S04 and volatiles were removed under reduced pressure. Yield: 203 mg (0.336 mmol). MS: m/z 604.1 = [M+H]+ (MW calculated = 603.9 g/mol).
203 mg		Amine 1 (503 mg, 0.635 mmol, assuming a MW of 791.1 g/mol of crude 1 ) was dissolved in 4 mL DMF (anhydrous, mol. sieve). Fmoc-N-Me-Ala-OH (310 mg, 0.953 mmol), COMU (408 mg, 0.953 mmol) and DIPEA (332 mu, 1.906 mmol) were added and the reaction was allowed to stir for 3 h at RT. 150 mu piperidine and 150 mu DBU were added to the mixture and stirring was continued for further 60 min. 400 mu acetic acid were added and product was purified by HPLC. HPLC fractions containing product 2a were neutralized with a saturated aqueous NaHC03 solution and extracted twice with DCM. Combined organic phases were dried over Na2S04 and volatiles were removed under reduced pressure. Yield: 203 mg (0.336 mmol). MS: m/z 604.1 = [M+H]+ (MW calculated = 603.9 g/mol).

203 mg		Amine 14 (503 mg, 0.635 mmol, assuming a MW of791.1 g/mol of crude 1) was dissolved in 4 mL DMF(anhydrous, mol. sieve). Fmoc-N-Me-Ala-OH (310 mg,0.953 mmol), COMU (408 mg, 0.953 mmol) and DIPEA(332 jil, 1.906 mmol) were added and the reaction was allowed to stir for 3 h at RT. 150 jil piperidine and 150 jil DBU were added to the mixture and stirring was continued for further 60 mm. 400 j±1 acetic acid were added and product was purified by HPLC. HPLC fractions containing product1 5a were neutralized with a saturated NaHCO3 solution and extracted twice with DCM. Combined organic phases were dried over Na2504 and volatiles were removed under reduced pressure.Yield: 203 mg (0.336 mmol). MS: mlz 604.1=[M+H] (MW calculated=603.9 gmol).
203 mg		Amine 14 (503 mg, 0.635 mmol, assuming a MW of791.1 g/mol of crude 1) was dissolved in 4 mL DMF (anhydrous, mol. sieve). Fmoc-N-Me-Ala-OH (310 mg, 0.953 mmol), COMU (408 mg, 0.953 mmol) and DIPEA (332 jtl, 1.906 mmol) were added and the reaction wasallowed to stir for 3 h at RT. 150 jtl piperidine and 150 jtl DBU were added to the mixture and stirring was continued for further 60 mm. 400 tl acetic acid were added and product was purified by HPLC. HPLC fractions containing product 1 5a were neutralized with a saturated NaHCO3 solution andextracted twice with DCM. Combined organic phases were dried over Na2SO4 and volatiles were removed under reduced pressure.Yield: 203 mg (0.336 mmol).MS: m/z 604.1=[M+H] (MW calculated=603.9 gmol).

Reference： [1]Patent: WO2013/24051,2013,A1 .Location in patent: Page/Page column 106; 107
[2]Patent: WO2013/24052,2013,A1 .Location in patent: Page/Page column 138; 139
[3]Patent: WO2013/160340,2013,A1 .Location in patent: Page/Page column 35; 36
[4]Patent: US9561287,2017,B2 .Location in patent: Page/Page column 117; 118
[5]Patent: US9872864,2018,B2 .Location in patent: Page/Page column 84; 85

39
[ 84000-07-7 ]
[ 1596118-27-2 ]

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 3765 - 3775

40
(-)-maytansinol [ No CAS ]
[ 693-13-0 ]
[ 84000-07-7 ]

Yield	Reaction Conditions	Operation in experiment
	With scandium tris(trifluoromethanesulfonate); In dichloromethane;	Example 1 Esterification of Maytansinol with Fmoc-N-methyl-L-alanine (Fmoc-N-Me-D/L-Ala-MDC) A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2Cl2 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2Cl2. The combined organic phase was washed with NaHCO3 aq, brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D/L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2/MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-MDC), while the lower Rf fraction was the desired L-aminoacyl ester (Fmoc-N-Me-L-Ala-MDC). Fmoc-N-Me-L-Ala-MDC: white solid (0.4262 g, 46.0% yield), 1H NMR (400 MHz, CDCl3): delta0.77 (3H, s), 1.22-1.32 (6H, m), 1.40-1.48 (1H, m), 1.63 (3H, s), 2.13 (1H, dd, J=14.4, 2.8 Hz), 2.53 (1H, dd, J=14.4, 10.8 Hz), 2.64 (3H, s), 2.88 (3H, s), 3.00 (1H, d, J=9.6 Hz), 3.07 (1H, d, J=12.4 Hz), 3.35 (3H, s), 3.48 (1H, d, J=8.8 Hz), 3.59 (1H, d, J=11.2 Hz), 3.97 (3H, s), 4.13-4.19 (1H, m), 4.15 (1H, s), 4.24 (1H, t, J=10.8 Hz), 4.72-4.77 (2H, m), 5.03 (1H, q, J=6.8 Hz), 5.65 (1H, dd, J=15.2, 9.2 Hz), 6.29 (1H, br), 6.41 (1H, dd, J=15.2, 11.2 Hz), 6.52 (1H, d, J=1.2 Hz), 6.70 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=1.2 Hz), 7.33 (1H, t, J=7.6 Hz), 7.36 (1H, t, J=7.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=7.6 Hz), 7.70 (1H, d, J=7.6 Hz), 7.72 (1H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3. Fmoc-N-Me-D-Ala-MDC: white solid (0.3993 g, 43.1% yield), 1H NMR (400 MHz, CDCl3): delta0.84 (3H, s), 1.22-1.27 (3H, m), 1.40-1.48 (1H, m), 1.51 (3H, d, J=7.6 Hz), 1.67 (3H, s), 2.20 (1H, dd, J=14.4, 2.8 Hz), 2.63 (1H, dd, J=14.4, 12.4 Hz), 2.85 (1H, d, J=9.6 Hz), 2.96 (3H, s), 3.17 (3H, s), 3.20 (1H, s), 3.24 (3H, s), 3.40 (1H, d, J=9.2 Hz), 3.51 (1H, d, J=12.8 Hz), 3.99 (3H, s), 4.20-4.28 (2H, m), 4.38-4.43 (2H, m), 4.80-4.98 (2H, m), 5.80 (1H, dd, J=15.2, 11.2 Hz), 6.18 (1H, s), 6.25 (1H, d, J=10.8 Hz), 6.40 (1H, dd, J=15.2, 11.2 Hz), 6.79 (1H, d, J=1.6 Hz), 6.84 (1H, d, J=1.6 Hz), 7.32 (2H, t, J=7.6 Hz), 7.41 (2H, t, J=7.6 Hz), 7.61 (2H, d, J=7.6 Hz), 7.77 (2H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3.

Reference： [1]Patent: US2014/178414,2014,A1 .Location in patent: Page/Page column

41
[ 84000-07-7 ]
[ 57103-68-1 ]
Fmoc-N-Me-D/L-Ala-maytansinol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.5%		Example 1 Esterification of Maytansinol with Fmoc-N-methyl-L-alanine (Fmoc-N-Me-D/L-Ala-MDC) A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2Cl2 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2Cl2. The combined organic phase was washed with NaHCO3 aq, brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D/L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2/MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-MDC), while the lower Rf fraction was the desired L-aminoacyl ester (Fmoc-N-Me-L-Ala-MDC). Fmoc-N-Me-L-Ala-MDC: white solid (0.4262 g, 46.0% yield), 1H NMR (400 MHz, CDCl3): delta0.77 (3H, s), 1.22-1.32 (6H, m), 1.40-1.48 (1H, m), 1.63 (3H, s), 2.13 (1H, dd, J=14.4, 2.8 Hz), 2.53 (1H, dd, J=14.4, 10.8 Hz), 2.64 (3H, s), 2.88 (3H, s), 3.00 (1H, d, J=9.6 Hz), 3.07 (1H, d, J=12.4 Hz), 3.35 (3H, s), 3.48 (1H, d, J=8.8 Hz), 3.59 (1H, d, J=11.2 Hz), 3.97 (3H, s), 4.13-4.19 (1H, m), 4.15 (1H, s), 4.24 (1H, t, J=10.8 Hz), 4.72-4.77 (2H, m), 5.03 (1H, q, J=6.8 Hz), 5.65 (1H, dd, J=15.2, 9.2 Hz), 6.29 (1H, br), 6.41 (1H, dd, J=15.2, 11.2 Hz), 6.52 (1H, d, J=1.2 Hz), 6.70 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=1.2 Hz), 7.33 (1H, t, J=7.6 Hz), 7.36 (1H, t, J=7.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=7.6 Hz), 7.70 (1H, d, J=7.6 Hz), 7.72 (1H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3. Fmoc-N-Me-D-Ala-MDC: white solid (0.3993 g, 43.1% yield), 1H NMR (400 MHz, CDCl3): delta0.84 (3H, s), 1.22-1.27 (3H, m), 1.40-1.48 (1H, m), 1.51 (3H, d, J=7.6 Hz), 1.67 (3H, s), 2.20 (1H, dd, J=14.4, 2.8 Hz), 2.63 (1H, dd, J=14.4, 12.4 Hz), 2.85 (1H, d, J=9.6 Hz), 2.96 (3H, s), 3.17 (3H, s), 3.20 (1H, s), 3.24 (3H, s), 3.40 (1H, d, J=9.2 Hz), 3.51 (1H, d, J=12.8 Hz), 3.99 (3H, s), 4.20-4.28 (2H, m), 4.38-4.43 (2H, m), 4.80-4.98 (2H, m), 5.80 (1H, dd, J=15.2, 11.2 Hz), 6.18 (1H, s), 6.25 (1H, d, J=10.8 Hz), 6.40 (1H, dd, J=15.2, 11.2 Hz), 6.79 (1H, d, J=1.6 Hz), 6.84 (1H, d, J=1.6 Hz), 7.32 (2H, t, J=7.6 Hz), 7.41 (2H, t, J=7.6 Hz), 7.61 (2H, d, J=7.6 Hz), 7.77 (2H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3.
90.5%		Example 1 Esterification of Maytansinol with Fmoc-N-methyl-L-alanine (Fmoc-N-Me-D/L-Ala-MDC) A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2Cl2 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2Cl2. The combined organic phase was washed with NaHCO3 aq, brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D/L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2/MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-MDC), while the lower Rf fraction was the desired L-aminoacyl ester (Fmoc-N-Me-L-Ala-MDC). Fmoc-N-Me-L-Ala-MDC: white solid (0.4262 g, 46.0% yield), 1H NMR (400 MHz, CDCl3): delta0.77 (3H, s), 1.22-1.32 (6H, m), 1.40-1.48 (1H, m), 1.63 (3H, s), 2.13 (1H, dd, J=14.4, 2.8 Hz), 2.53 (1H, dd, J=14.4, 10.8 Hz), 2.64 (3H, s), 2.88 (3H, s), 3.00 (1H, d, J=9.6 Hz), 3.07 (1H, d, J=12.4 Hz), 3.35 (3H, s), 3.48 (1H, d, J=8.8 Hz), 3.59 (1H, d, J=11.2 Hz), 3.97 (3H, s), 4.13-4.19 (1H, m), 4.15 (1H, s), 4.24 (1H, t, J=10.8 Hz), 4.72-4.77 (2H, m), 5.03 (1H, q, J=6.8 Hz), 5.65 (1H, dd, J=15.2, 9.2 Hz), 6.29 (1H, br), 6.41 (1H, dd, J=15.2, 11.2 Hz), 6.52 (1H, d, J=1.2 Hz), 6.70 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=1.2 Hz), 7.33 (1H, t, J=7.6 Hz), 7.36 (1H, t, J=7.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=7.6 Hz), 7.70 (1H, d, J=7.6 Hz), 7.72 (1H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3. Fmoc-N-Me-D-Ala-MDC: white solid (0.3993 g, 43.1% yield), 1H NMR (400 MHz, CDCl3): delta0.84 (3H, s), 1.22-1.27 (3H, m), 1.40-1.48 (1H, m), 1.51 (3H, d, J=7.6 Hz), 1.67 (3H, s), 2.20 (1H, dd, J=14.4, 2.8 Hz), 2.63 (1H, dd, J=14.4, 12.4 Hz), 2.85 (1H, d, J=9.6 Hz), 2.96 (3H, s), 3.17 (3H, s), 3.20 (1H, s), 3.24 (3H, s), 3.40 (1H, d, J=9.2 Hz), 3.51 (1H, d, J=12.8 Hz), 3.99 (3H, s), 4.20-4.28 (2H, m), 4.38-4.43 (2H, m), 4.80-4.98 (2H, m), 5.80 (1H, dd, J=15.2, 11.2 Hz), 6.18 (1H, s), 6.25 (1H, d, J=10.8 Hz), 6.40 (1H, dd, J=15.2, 11.2 Hz), 6.79 (1H, d, J=1.6 Hz), 6.84 (1H, d, J=1.6 Hz), 7.32 (2H, t, J=7.6 Hz), 7.41 (2H, t, J=7.6 Hz), 7.61 (2H, d, J=7.6 Hz), 7.77 (2H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3.
90.5%		Example 3 Esterification of Maytansinol with Fmoc-N-methyl-L-alanine (Fmoc-N-Me-D/L-Ala-MDC) A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2Cl2 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2Cl2. The combined organic phase was washed with NaHCO3 aq, brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D/L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2/MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-MDC), while the lower Rf fraction was the desired L-aminoacyl ester (Fmoc-N-Me-L-Ala-MDC). Fmoc-N-Me-L-Ala-MDC: white solid (0.4262 g, 46.0% yield), 1H NMR (400 MHz, CDCl3): delta0.77 (3H, s), 1.22-1.32 (6H, m), 1.40-1.48 (1H, m), 1.63 (3H, s), 2.13 (1H, dd, J=14.4, 2.8 Hz), 2.53 (1H, dd, J=14.4, 10.8 Hz), 2.64 (3H, s), 2.88 (3H, s), 3.00 (1H, d, J=9.6 Hz), 3.07 (1H, d, J=12.4 Hz), 3.35 (3H, s), 3.48 (1H, d, J=8.8 Hz), 3.59 (1H, d, J=11.2 Hz), 3.97 (3H, s), 4.13-4.19 (1H, m), 4.15 (1H, s), 4.24 (1H, t, J=10.8 Hz), 4.72-4.77 (2H, m), 5.03 (1H, q, J=6.8 Hz), 5.65 (1H, dd, J=15.2, 9.2 Hz), 6.29 (1H, br), 6.41 (1H, dd, J=15.2, 11.2 Hz), 6.52 (1H, d, J=1.2 Hz), 6.70 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=1.2 Hz), 7.33 (1H, t, J=7.6 Hz), 7.36 (1H, t, J=7.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=7.6 Hz), 7.70 (1H, d, J=7.6 Hz), 7.72 (1H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3. Fmoc-N-Me-D-Ala-MDC: white solid (0.3993 g, 43.1% yield), 1H NMR (400 MHz, CDCl3): delta0.84 (3H, s), 1.22-1.27 (3H, m), 1.40-1.48 (1H, m), 1.51 (3H, d, J=7.6 Hz), 1.67 (3H, s), 2.20 (1H, dd, J=14.4, 2.8 Hz), 2.63 (1H, dd, J=14.4, 12.4 Hz), 2.85 (1H, d, J=9.6 Hz), 2.96 (3H, s), 3.17 (3H, s), 3.20 (1H, s), 3.24 (3H, s), 3.40 (1H, d, J=9.2 Hz), 3.51 (1H, d, J=12.8 Hz), 3.99 (3H, s), 4.20-4.28 (2H, m), 4.38-4.43 (2H, m), 4.80-4.98 (2H, m), 5.80 (1H, dd, J=15.2, 11.2 Hz), 6.18 (1H, s), 6.25 (1H, d, J=10.8 Hz), 6.40 (1H, dd, J=15.2, 11.2 Hz), 6.79 (1H, d, J=1.6 Hz), 6.84 (1H, d, J=1.6 Hz), 7.32 (2H, t, J=7.6 Hz), 7.41 (2H, t, J=7.6 Hz), 7.61 (2H, d, J=7.6 Hz), 7.77 (2H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3.

Reference： [1]Patent: US2014/178413,2014,A1 .Location in patent: Paragraph 144; 145
[2]Patent: US2014/178412,2014,A1 .Location in patent: Paragraph 175; 176
[3]Patent: US2014/178411,2014,A1 .Location in patent: Paragraph 161; 162

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[ 84000-07-7 ]
[ 57103-68-1 ]
[ 1452404-53-3 ]
[ 1452404-52-2 ]

Yield	Reaction Conditions	Operation in experiment
43.1%; 46%		A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2Cl2 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2Cl2. The combined organic phase was washed with NaHCO3 aq, brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D/L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2/MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-MDC), while the lower Rf fraction was the desired L-aminoacyl ester (Fmoc-N-Me-L-Ala-MDC). Fmoc-N-Me-L-Ala-MDC: white solid (0.4262 g, 46.0% yield), 1H NMR (400 MHz, CDCl3): delta0.77 (3H, s), 1.22-1.32 (6H, m), 1.40-1.48 (1H, m), 1.63 (3H, s), 2.13 (1H, dd, J=14.4, 2.8 Hz), 2.53 (1H, dd, J=14.4, 10.8 Hz), 2.64 (3H, s), 2.88 (3H, s), 3.00 (1H, d, J=9.6 Hz), 3.07 (1H, d, J=12.4 Hz), 3.35 (3H, s), 3.48 (1H, d, J=8.8 Hz), 3.59 (1H, d, J=11.2 Hz), 3.97 (3H, s), 4.13-4.19 (1H, m), 4.15 (1H, s), 4.24 (1H, t, J=10.8 Hz), 4.72-4.77 (2H, m), 5.03 (1H, q, J=6.8 Hz), 5.65 (1H, dd, J=15.2, 9.2 Hz), 6.29 (1H, br), 6.41 (1H, dd, J=15.2, 11.2 Hz), 6.52 (1H, d, J=1.2 Hz), 6.70 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=1.2 Hz), 7.33 (1H, t, J=7.6 Hz), 7.36 (1H, t, J=7.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=7.6 Hz), 7.70 (1H, d, J=7.6 Hz), 7.72 (1H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3. Fmoc-N-Me-D-Ala-MDC: white solid (0.3993 g, 43.1% yield), 1H NMR (400 MHz, CDCl3): delta0.84 (3H, s), 1.22-1.27 (3H, m), 1.40-1.48 (1H, m), 1.51 (3H, d, J=7.6 Hz), 1.67 (3H, s), 2.20 (1H, dd, J=14.4, 2.8 Hz), 2.63 (1H, dd, J=14.4, 12.4 Hz), 2.85 (1H, d, J=9.6 Hz), 2.96 (3H, s), 3.17 (3H, s), 3.20 (1H, s), 3.24 (3H, s), 3.40 (1H, d, J=9.2 Hz), 3.51 (1H, d, J=12.8 Hz), 3.99 (3H, s), 4.20-4.28 (2H, m), 4.38-4.43 (2H, m), 4.80-4.98 (2H, m), 5.80 (1H, dd, J=15.2, 11.2 Hz), 6.18 (1H, s), 6.25 (1H, d, J=10.8 Hz), 6.40 (1H, dd, J=15.2, 11.2 Hz), 6.79 (1H, d, J=1.6 Hz), 6.84 (1H, d, J=1.6 Hz), 7.32 (2H, t, J=7.6 Hz), 7.41 (2H, t, J=7.6 Hz), 7.61 (2H, d, J=7.6 Hz), 7.77 (2H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3.
43.1%; 46%		A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2C12 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2C12. The combined organic phase was washed with NaHCC aq, brine, dried over anhydrous Na2S04. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2 MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2/MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-MDC), while the lower Rf fraction was the desired L-aminoacyl ester (Fmoc-N-Me-L-Ala-MDC). Fmoc-N-Me-L-Ala-MDC: white solid (0.4262 g, 46.0% yield), 1H NMR (400 MHz, CDC13): 50.77 (3H, s), 1.22-1.32 (6H, m),1.40-1.48 (lH, m), 1.63 (3H, s), 2.13 (1H, dd, J= 14.4, 2.8 Hz), 2.53 (1H, dd, J= 14.4, 10.8 Hz), 2.64 (3H, s), 2.88 (3H, s), 3.00 (1H, d, J = 9.6 Hz), 3.07 (1H, d, J = 12.4 Hz), 3.35 (3H, s), 3.48 (1H, d, J = 8.8 Hz), 3.59 (1H, d, J = 11.2 Hz), 3.97 (3H, s), 4.13-4.19 (1H, m), 4.15 (1H, s), 4.24 (1H, t, J= 10.8 Hz), 4.72-4.77 (2H, m), 5.03 (1H, q, J= 6.8 Hz), 5.65 ( 1H, dd, J= 15.2, 9.2 Hz), 6.29 (1H, br), 6.41 (1H, dd, J = 15.2 , 11.2 Hz), 6.52 (1H, d, J= 1.2Hz), 6.70 (1H, d, J= 10.8 Hz), 6.79 (1H, d, J = 1.2 Hz), 7.33 (1H, t, J = 7.6 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.70 (1H, d, J= 7.6 Hz), 7.72 (1H, d, J= 7.6 Hz). LC-MS (M+Na+) calc : 894.3, found: 894.3. Fmoc-N-Me-D- Ala-MDC : white solid (0.3993 g, 43.1% yield), XH NMR (400 MHz, CDC13): 50.84 (3H, s), 1.22-1.27 (3H, m), 1.40-1.48 (1H, m), 1.51 (3H, d, J= 7.6 Hz), 1.67 (3H, s), 2.20 (1H, dd, J=14.4, 2.8 Hz ), 2.63 (1H, dd, J= 14.4, 12.4 Hz), 2.85 (1H, d, J = 9.6 Hz), 2.96 (3H, s), 3.17 (3H, s), 3.20 (1H, s), 3.24 (3H, s), 3.40 (1H, d, J= 9.2 Hz), 3.51 (1H, d, J = 12.8 Hz), 3.99 (3H, s), 4.20-4.28 (2H, m), 4.38-4.43 (2H, m), 4.80-4.98 (2H, m), 5.80 ( 1H, dd, J= 15.2, 11.2 Hz), 6.18 (1H, s), 6.25 (1H, d, J= 10.8 Hz), 6.40 (1H, dd, J= 15.2 , 11.2 Hz), 6.79 (1H, d, J = 1.6 Hz), 6.84 (1H, d, J = 1.6 Hz ), 7.32 (2H, t, J =7.6 Hz), 7.41 (2H, t, J =7.6 Hz), 7.61 (2H, d, J =7.6 Hz), 7.77 (2H, d, J=7.6 Hz). LC-MS (M+Na+) calc: 894.3, found: 894.3.
43.1%; 46%		A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2Cl2 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2Cl2. The combined organic phase was washed with NaHCO3 aq, brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D/L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2/MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-MDC), while the lower Rf fraction was the desired L-aminoacyl ester (Fmoc-N-Me-L-Ala-MDC). Fmoc-N-Me-L-Ala-MDC: white solid (0.4262 g, 46.0% yield), 1H NMR (400 MHz, CDCl3): delta0.77 (3H, s), 1.22-1.32 (6H, m), 1.40-1.48 (1H, m), 1.63 (3H, s), 2.13 (1H, dd, J=14.4, 2.8 Hz), 2.53 (1H, dd, J=14.4, 10.8 Hz), 2.64 (3H, s), 2.88 (3H, s), 3.00 (1H, d, J=9.6 Hz), 3.07 (1H, d, J=12.4 Hz), 3.35 (3H, s), 3.48 (1H, d, J=8.8 Hz), 3.59 (1H, d, J=11.2 Hz), 3.97 (3H, s), 4.13-4.19 (1H, m), 4.15 (1H, s), 4.24 (1H, t, J=10.8 Hz), 4.72-4.77 (2H, m), 5.03 (1H, q, J=6.8 Hz), 5.65 (1H, dd, J=15.2, 9.2 Hz), 6.29 (1H, br), 6.41 (1H, dd, J=15.2, 11.2 Hz), 6.52 (1H, d, J=1.2 Hz), 6.70 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=1.2 Hz), 7.33 (1H, t, J=7.6 Hz), 7.36 (1H, t, J=7.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=7.6 Hz), 7.70 (1H, d, J=7.6 Hz), 7.72 (1H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3. Fmoc-N-Me-D-Ala-MDC: white solid (0.3993 g, 43.1% yield), 1H NMR (400 MHz, CDCl3): delta0.84 (3H, s), 1.22-1.27 (3H, m), 1.40-1.48 (1H, m), 1.51 (3H, d, J=7.6 Hz), 1.67 (3H, s), 2.20 (1H, dd, J=14.4, 2.8 Hz), 2.63 (1H, dd, J=14.4, 12.4 Hz), 2.85 (1H, d, J=9.6 Hz), 2.96 (3H, s), 3.17 (3H, s), 3.20 (1H, s), 3.24 (3H, s), 3.40 (1H, d, J=9.2 Hz), 3.51 (1H, d, J=12.8 Hz), 3.99 (3H, s), 4.20-4.28 (2H, m), 4.38-4.43 (2H, m), 4.80-4.98 (2H, m), 5.80 (1H, dd, J=15.2, 11.2 Hz), 6.18 (1H, s), 6.25 (1H, d, J=10.8 Hz), 6.40 (1H, dd, J=15.2, 11.2 Hz), 6.79 (1H, d, J=1.6 Hz), 6.84 (1H, d, J=1.6 Hz), 7.32 (2H, t, J=7.6 Hz), 7.41 (2H, t, J=7.6 Hz), 7.61 (2H, d, J=7.6 Hz), 7.77 (2H, d, J=7.6 Hz). LC-MS (M+Na+) calc.: 894.3. found: 894.3.

43.1%; 46%

Maytansinol (0. 600 g, 1.062 mmol), Fmoc-N-methyl-L-alanine (6.911 g, 21 · 24 mmol), Scandium trifluoromethanesulfonate (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) were placed in a 250 ml Schlenck flask and dichloromethane (100 mL) was added under nitrogen and stirred at -8C for 0.5 h. DIC (2.949 g, 23.37 mmol) was added dropwise and the reaction was stirred at -8 C for 0.5 h. The temperature was slowly raised to room temperature, and the catalyst was recovered by filtration. The filtrate was quenched with dilute hydrochloric acid, extracted with methylene chloride, washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and solvent was removed by rotary evaporation. Column chromatography (silica gel, CH2C12/Me0H 30:1) gave the diastereoisomer mixture Fmoc-N-Me-D/L-Ala-MDC as a white solid (0.8385 g, 90.5% yield). Further column chromatography (silica gel, CH2C12/MeOH 100:1 to 20:1) gave two pure diastereomeric components. The larger Rf component was determined to be the D-aminoacyl ester diastereoisomer (Fmoc-N-Me-D-Ala-MDC), and the smaller Rf component was determined to be the L-aminoacyl ester iastereoisomer (Fmoc-N-Me-L-Ala-MDC).

Reference： [1]Patent: US2014/179917,2014,A1 .Location in patent: Paragraph 0460; 0461
[2]Patent: WO2014/94527,2014,A1 .Location in patent: Page/Page column 28-29
[3]Patent: US2014/178415,2014,A1 .Location in patent: Paragraph 0440; 0441
[4]Patent: CN107899020,2018,A .Location in patent: Paragraph 0181-0184
[5]Patent: US2014/178413,2014,A1

43
maytansinol [ No CAS ]
[ 84000-07-7 ]
C₄₇H₅₄ClN₃O₁₁ [ No CAS ]
C₄₇H₅₄ClN₃O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%; 43.1%		A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2C12 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2C12. The combined organic phase was washed with NaHCC aq, brine, dried over anhydrous Na2S04. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2 MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2/MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-MDC), while the lower Rf fraction was the desired L-aminoacyl ester (Fmoc-N-Me-L-Ala-MDC). Fmoc-N-Me-L-Ala-MDC: white solid (0.4262 g, 46.0% yield), 1H NMR (400 MHz, CDC13): 50.77 (3H, s), 1.22-1.32 (6H, m),1.40-1.48 (lH, m), 1.63 (3H, s), 2.13 (1H, dd, J= 14.4, 2.8 Hz), 2.53 (1H, dd, J= 14.4, 10.8 Hz), 2.64 (3H, s), 2.88 (3H, s), 3.00 (1H, d, J = 9.6 Hz), 3.07 (1H, d, J = 12.4 Hz), 3.35 (3H, s), 3.48 (1H, d, J = 8.8 Hz), 3.59 (1H, d, J =11.2 Hz), 3.97 (3H, s), 4.13-4.19 (1H, m), 4.15 (1H, s), 4.24 (1H, t, J= 10.8 Hz), 4.72-4.77 (2H, m), 5.03 (1H, q, J= 6.8 Hz), 5.65 ( 1H, dd, J= 15.2, 9.2 Hz), 6.29 (1H, br), 6.41 (1H, dd, J = 15.2 , 11.2 Hz), 6.52 (1H, d, J= 1.2Hz), 6.70 (1H, d, J= 10.8 Hz), 6.79 (1H, d, J = 1.2 Hz), 7.33 (1H, t, J = 7.6 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.70 (1H, d, J= 7.6 Hz), 7.72 (1H, d, J= 7.6 Hz). LC-MS (M+Na+) calc : 894.3, found: 894.3. Fmoc-N-Me-D- Ala-MDC : white solid (0.3993 g, 43.1% yield), XH NMR (400 MHz, CDC13): 50.84 (3H, s), 1.22-1.27 (3H, m), 1.40-1.48 (1H, m), 1.51 (3H, d, J= 7.6 Hz), 1.67 (3H, s), 2.20 (1H, dd, J=14.4, 2.8 Hz ), 2.63 (1H, dd, J= 14.4, 12.4 Hz), 2.85 (1H, d, J = 9.6 Hz), 2.96 (3H, s), 3.17 (3H, s), 3.20 (1H, s), 3.24 (3H, s), 3.40 (1H, d, J= 9.2 Hz), 3.51 (1H, d, J = 12.8 Hz), 3.99 (3H, s), 4.20-4.28 (2H, m), 4.38-4.43 (2H, m), 4.80-4.98 (2H, m), 5.80 ( 1H, dd, J= 15.2, 11.2 Hz), 6.18 (1H, s), 6.25 (1H, d, J= 10.8 Hz), 6.40 (1H, dd, J= 15.2 , 11.2 Hz), 6.79 (1H, d, J = 1.6 Hz), 6.84 (1H, d, J = 1.6 Hz ), 7.32 (2H, t, J =7.6 Hz), 7.41 (2H, t, J =7.6 Hz), 7.61 (2H, d, J =7.6 Hz), 7.77 (2H, d, J=7.6 Hz). LC-MS (M+Na+) calc: 894.3, found: 894.3.

Reference： [1]Patent: WO2014/94353,2014,A1 .Location in patent: Page/Page column 89-90

44
maytansinol [ No CAS ]
[ 84000-07-7 ]
C₄₇H₅₄ClN₃O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.5%		A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2C12 (100 mL) was stirred for 0.5 h at -8 C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2C12. The combined organic phase was washed with NaHC03 aq, brine, dried over anhydrous Na2S04. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30: 1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D/L-Ala-MDC: white solid (0.8385 g, 90.5%).

Reference： [1]Patent: WO2014/94354,2014,A1 .Location in patent: Page/Page column 73-74

45
[ 940301-35-9 ]
2-chlorotrityl chloride polystyrene resin [ No CAS ]
(S)-2-((R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanamido)propanoic acid [ No CAS ]
(R)-2-(((2S,3R)-2-acetamido-3-hydroxybutanoyl)oxy)-3-phenylpropanoic acid [ No CAS ]
[ 84000-07-7 ]
[ 136092-75-6 ]
C₆₆H₈₈ClN₆O₁₅PolS₂ [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 492 - 495

46
[ 10352-88-2 ]
[ 205526-24-5 ]
[ 35661-39-3 ]
C₄₀H₃₃ClNO₄Pol [ No CAS ]
[ 71989-31-6 ]
[ 84000-07-7 ]
[ 111061-56-4 ]
C₃₇H₅₂F₂N₆O₉ [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 2182 - 2185

47
[ 10352-88-2 ]
Pro-2-Cl-Trt resin [ No CAS ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 84000-07-7 ]
[ 111061-56-4 ]
C₃₆H₅₂N₆O₉ [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 2182 - 2185

48
[ 35661-39-3 ]
Me<SUB>2</SUB>Val-HIV-OH [ No CAS ]
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-methoxypropanoic acid [ No CAS ]
[ 53267-93-9 ]
[ 103478-62-2 ]
[ 84000-07-7 ]
[ 117106-20-4 ]
[ 138775-22-1 ]
C₈₀H₁₂₂N₁₀O₁₉ [ No CAS ]