the schmidt and boyer reactions revisited: the chemistry of prof. jeffrey aubé alexandre lemire...
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The Schmidt and Boyer Reactions Revisited: The Chemistry of Prof. Jeffrey Aubé
Alexandre Lemire
Litterature MeetingNovember 8th, 2004
Prof. Jeffrey Aubé
•Interim Chair, 2003 - present•Professor, 1996 – present•Associate Professor, 1992 -1996•Assistant Professor, 1986 -1992
•Olin Petefish/Higuchi Award for Achievement in the Basic Sciences, 2001 •Fellow, Japanese Society for the Promotion of Science, 1996 •Phi Beta Kappa, honorary member, 1996 •American Cyanamid Faculty Award in Organic Chemistry, 1993 •Alfred P. Sloan Research Fellow, 1993 -1995 •Eli Lilly Grantee, 1989 -1991
Department of Medicinal ChemistrySchool of PharmacyUniversity of KansasLawrence, Kansas 66045-2506Tel: 1.785.864.4496Fax: 1.785.864.5326e-mail: [email protected]
University of Kansas
Prof. Jeffrey Aubé
85 publications
•NIS Postdoctoral fellow 1984-1986 Yale U. (Prof. Danishefsky)•PhD Duke University 1984 (Durham, NC) •BSc U. of Miami 1980
Department of Medicinal ChemistrySchool of PharmacyUniversity of KansasLawrence, Kansas 66045-2506Tel: 1.785.864.4496Fax: 1.785.864.5326e-mail: [email protected]
The Schmidt Reaction (1)
Name Reaction in Organic Chemistry, p. 190-191Schmidt, R. F. Ber. 1924, 57, 704.
Reviews: (a) Wolff, H. Org. React. 1946, 3, 307-336. (b) Krow, G. R. Tetrahedron 1981, 37, 1283-1307.
General scheme: R
O
OH
R NH2+ HN3H
H2O
Mechanism R
O
OH
+ HN3H R
O
N N N
H
R
O
N N N
H
..- N2 R N
C
O
H
H2O R NH2- CO2
ExamplesPh
OH
OPh NH2 67%
NaN3
PPA
Me O
Me
H
Me
H
NH
O
Me
30%NaN3, H2SO4
benzene
O O
NH
NaN3
TFA59%
- H2O
Mechanism?
R R
OR' N3+
R R
HO N
N2
R'
R R
NN2
R N
O
R'
R
- H2Opossible only if R' = H
- N2, - H
R
NR
N
R
R
H2O, - H
H
R' = H
The Schmidt Reaction (2)
The Merck Index, 12th Edition, p. ONR-82
HN3
H2SO4
HN3
H2SO4
HN3
H2SO4
R
O
OH
R NH2
R
O
R R NH
R
O
OH
R
R
R N
R
R
R
R
RR
RN
R
R
H
R
R
HN3
H2SO4
The Schmidt Reaction (2)
OH
R
R
R N
R
R
RHN3
H2SO4
R
R
RNH
R
R
R
N
N
N
R
R R
H
- N2
- H
HN3
H2SO4
R
RR
RN
R
R
H
R
R
R
RR
R H HNN
N
- N2
RR
R
H
NRH
- H
Analogous Rearrangements
NaOBr;
H2O, - CO2
NaN3;R
O
Cl
R NH2
R
O
NH2
R NH2
H2O, - CO2
Curtius
Hofmann
1. H2NOH
2. HBeckmann R1
O
R2
R1
O
NH
R2
Reactions with Alkyl Azides
O
R N3 N
OR
conditions?
Reactions with Alkyl Azides
CH3
O
H3C N3 azide decompositionno amide observed
O
R N3 N
OR
conditions?
Briggs, Smith (1940s)1
H2SO4
H
O
PhN3
10%NH
O
Ph
H
O
HON3
73-82%O
N
Boyer (1950s)2
( )n
( )n
NO2 NO2
n = 1, 2
1 (a) Briggs, L. H. et al. J. Chem. Soc. 1942, 61-63. (b) Smith, P. A. J. Am. Chem. Soc. 1948, 70, 320-323.2 Boyer, J. H. et al. J. Am. Chem. Soc. 1956, 78, 325-327. Boyer, J. H.; Morgan, L. R., Jr. J. Am. Chem. Soc. 1959, 81, 561-562.
Aubé and Milligan’s Discovery
R
O
N3
TFA
R = H, Me91%
N
O
R
Communication: J. Am. Chem. Soc. 1991, 113, 8965-8966. Full paper: J. Am. Chem. Soc. 1995, 117, 10449-10459.
Aubé and Milligan’s Discovery
R
O
N3
TFA
R = H, Me91%
N
O
R
R
NOH
N
N
H - N2, - H..
Questions to address
R
O
N3
TFA
R = H, Me91%
N
O
R
• Effects of ring size and tether length
• Reaction conditions to effectively promote the process
• Regiochemical rules to predict the product of the intramolecular Schmidt reaction
• Stereochemistry (retention or inversion) at the migrating carbon
Effect of ring size and tether length
R1
O
N3
O
Me N3
N
O
Me
R2
( )n ( )m( )n
( )m
Reactant ProductConditions1 Yield (%)
TFA, 15 min 66
1 TFA used as solvent (0.08M vs reactant). TiCl4 1.0M in CH2Cl2 (0.22M vs reactant)
O N3
TFA, 45 minTiCl4, 16 h N
O
8364
O N3
TFA, 16 hTiCl4, 30 min
N
O
6670
CO2MeCO2Me
O N3
TiCl4, 16 h N
O
68Me
Me
O
TiCl4, 16 h N
O
56
N3
N
O
R1
R2
O
N3
TFA, 24 h N
O
0 (50% SM)
O
N3
TFA, 3.5 h N
O
85
O
N3TFA, 1 h N
O
93
CO2MeMeO2C
Reactant ProductConditions1 Yield (%)
pyrrolizidine
indolizidine
quinolizidine
90% SM recovery after 1 h!(stability of azide in TFA)
Effect of ring size and tether length
R1
O
N3
R2
( )n ( )m( )n
( )m
Reactant ProductConditions1 Yield (%)
1 TFA used as solvent (0.08M vs reactant). TiCl4 1.0M in CH2Cl2 (0.22M vs reactant)
N
O
R1
R2
O TFA, 16 hBF3OEt2, 16 hTiCl4, 16 h
N
O
02991
Reactant ProductConditions1 Yield (%)
N3
O
TiCl4, 16 h N
O
0N3
ON3
TFA, 3 h 80
O
TiCl4, 16 h 0
N3
ON3
(12)
O
N3
(13)
N
N
O
O
TFA, 16 h
TFA, 2 h
96
89N
O
N
O
TiCl4 can help with recalcitrant substrates but not always
Effect of ring size and tether length
Results inconsistent with a mechanism implying a nitrene or nitrenium species: given their high reactivity, their formation would be rate limiting and they would not be affected by
structural change near the carbonyl group 4 carbons away
The most readily accomplished ring-expansion reactions involved substrates containing 4 carbons betweenthe carbonyl group and the azido substitutent. The reaction proceeds through a presumably optimal six-membered
cyclic azidohydrin intermediate previously shown
Formation of the five-membered azidohydrin should be facile, but the reaction fails, presumably due to strain encountered en route to the expected azetidine product
Ring expansion of aromatic ketones are less efficient:
TFA: 17%
TiCl4: SM onlyTfOH: 45%
O
N3N
O
R1
O
N3
R2
( )n ( )m( )n
( )m
N
O
R1
R2
Regiochemistry
Theoritical and experimental insights support a mechanism were the proximal nitrogen atom of the aminodiazonium ion intermediate has appreciable tetrahedral character in the transition state leading to product.
Chairlike azidohydrins are likely achieved when possible and migration of an antiperiplanar substituent duringnitrogen loss leads to four possible intermediates:
HO N3 N
OHN2
ab
bond a
bond b
migration
migration
N
N
O
O
fused lactam
bridged lactam
Regiochemistry
Only intermediate d has a pseudoaxial N2+ moiety, wich leads to bridged product. This intermediate might lead to an
higher energy transition state so the corresponding product is not observed
Another explanation is that the bridged bicyclic amide is not accessible because of the instability of the amide linkage
In the acyclic series, this would not be an issue anymore:
antiperiplanar C-Cbond migration
N2
HO
HO
R
ON3
N
N
NN
N
N
OHN2
R
N2
R
OH
N2R
OHR
N2
R
RN2
OH
O
R
N3
N
O
R
N
R
O
N
O
R
a
b
c
d
Not observed
Regiochemistry: Acyclic Ketones
The population of azidohydrin type c would be expected to increase with smaller R1 substituents, like H
antiperiplanar C-Cbond migration
N2
HO
HO
R2R1
R2
ON3
R2 R1 N
NR2
R1
NR2
R1
OHN2
R2
R2
N2
R2
a
b
c
N
R2
R2
R1
O
N
O
R2 R2
R1
Regiochemistry: Acyclic Substrates
No azetidine formed, pyrrolidinone occurred only from aldehydes
R1
O
R2 R2
N3( )m
R1 N
O
R2
R2
( )m
+NO
R2
R2
R1
( )m
Reactant ProductConditions1 Yield (%)
TFA 0
Product Yield (%)
H
O
Ph Ph
N3 H N
O
PhPh
NO
Ph
Ph
H
29
TFA 0H3C
O
N3 H3C N
O
NOCH3
0
TFA or TiCl4 0 (65% SM)O
N3 N
O
NO0
PhPh
Ph
Regiochemistry: Acyclic Substrates
Again, lactams only observed when aldehydes are reacted Possibly because only H is small enough to permit path c discussed
R1
O
R2 R2
N3( )m
R1 N
O
R2
R2
( )m
+NO
R2
R2
R1
( )m
Reactant ProductConditions1 Yield (%)
TFAAlCl3SnCl4ZnCl2
TMSOTf
8169594861
Product Yield (%)
H
O
Ph Ph
88151722
TFA 75H3C
O
0
TFA 69
O
0H3CO2C
N3
NN
H
O
PhPh
Ph
Ph
O
H
N3
NH3C
O
NO
CH3
N3
N
O
H3CO2CNO
CO2CH3
TFA 77Ph
O
0N3
NPh
O
NO
Ph
Regiochemistry: Acyclic Aldehydes
H migration has been rarely observed, the elimination/tautomerization pathway is though to be favored
TFA
H
O
N3
NH
O
NO
H
N
N2
HO
H
NHO
C migration
H migrationH elimination
Another mechanism could explain the formation of these lactams
Stereochemistry of the Migrating Carbon
Note that we can deprotect the carbonyl group without triggering the intramolecular Schmidt reaction
Ring expansion occurred with retention of configuration, as known for the intermolecular process (HN 3):
O
CH3Ph NH2
CH3
1.
2.CO2Et
OCH3
CO2EtHO
OH
1. TsOH,
2. LAH (87%, 4 steps)
CH3
OO
OH
CH3
N3
O
1. HN3, DEAD, Ph3P2. LiBF4, H2O/MeCN 69% (2 steps)
N
O
CH3
91% ee89% ee
TFA
87%
Stereochemistry of the Migrating Carbon
The classical Schmidt affords also the regioisomer and tetrazole byproduct
The major compound forms the lactam with identical ee
CH3
OO
OH
CH3
N3
O
1. HN3, DEAD, Ph3P2. LiBF4, H2O/MeCN 69% (2 steps)
N
O
CH391% ee89% ee
TFA
87%
1. MsCl, pyr2. LiCl, DMF3. LiBF4, H2O/MeCN
88% (3 steps)CH3
Cl
OTFA, NaN3
HN
OCl
CH315%
+
N
Cl
CH3
NN
N
28%HN
Cl
CH3
ONaH
93%
42%
H2O
+
Stereochemistry of the Migrating Carbon: Enolizable Ketone
Little isomerization occurred with TFA for the trans ketone
Can be avoided using TiCl4/CH2Cl2
NN
LDA, I(CH2)3Cl;
H3O+
92%
Cl
O
2 diasteromers
1. NaN3
2. separateN3
O
32%
+
N3
O
54%
TFA96%
TFA: 79% + 6% dia.TiCl4: 92%
N N
O O
Stereochemistry of the Migrating Carbon
O N3
CH3
TFA
91% N
O
CH3
O
N3
MeO
MeOTFA
85%
N
MeO
MeO
O
Ring Expansion of Alkyl Azides to Ketones
H
O
PhN3
10%
NH
O
Ph
H2SO4
Boyer, J. H. et al. J. Am. Chem. Soc. 1956, 78, 325-327.
Ring Expansion of Alkyl Azides to Ketones
R = Bn, (CH2)5CH3
TiCl4, DCM
O
N
O
RR-N3
Communication: J. Org. Chem. 1992, 57, 1635-1637.Full paper: J. Am. Chem. Soc. 2000, 122, 7226-7232.
Follow up: J. Org. Chem. 2001, 66, 886-889.
Ring Expansion of Alkyl Azides to Ketones
R = Bn, (CH2)5CH3
TiCl4, DCM
O
N
O
Ketone Azide Products Yield (%) Ketone Azide Products Yield (%)
O
Ph
HexN3N
O
hex51
O
HexN3N
O
hex
<5
OHexN3
BnN3 N
O
R8088
O
HexN3 N
O
hex 12
CH3
CH3
+ N
O
hex
CH3
R-N3
1.7:1 ratio
O ON R
R
HexN3
BnN3
10098
OHexN3
BnN3
PhN
O
R4870
Ph
OHexN3
BnN3
t-BuN
O
R6365
t-Bu
N
NOO
hex O
hexH
H
H
H
H
H1:1 ratio
50HexN3
O HexN3
BnN3
O
Nhex
+
+
O
Nhex
5:1 (R = hex) to 2:1 (R = Bn)
4046
Ring Expansion of Alkyl Azides to Ketones
R = Bn, (CH2)5CH3
TiCl4, DCM
O
N
O
RR-N3
Reaction using BF3OEt2 or protic acids failed
Unindered cyclohexanones and cyclobutanone are successful
Unsymmetrical ketones gave mixtures of lactams
Only BnN3 and HexN3 reported
???
???
Use of TfOH: Mechanism
Use of TfOH
TfOH, DCM
O
Bn-N3
O
NH
Ph
O O
NH
Ph79
Ketone Product Yield (%)
O O
NH
Ph98
CH3CH3
O O
NH
Ph66
CO2EtCO2Et
O O
NH
Ph84
Ring Expansion of Hydroxy Azides to Ketones: The Boyer Reaction
H
O
PhN3
10%NH
O
Ph
H
O
HON3
73-82%
O
N
( )n
( )n
NO2 NO2
n = 1, 2
Boyer, J. H. et al. J. Am. Chem. Soc. 1956, 78, 325-327.Boyer, J. H.; Morgan, L. R., Jr. J. Am. Chem. Soc. 1959, 81, 561-562.
The Boyer Reaction Revisited by Aubé
O + N3TiCl4
N
O
< 5%
O + N3 OH H or
N
O
OH
98%
Lewis acid N
O
N2
Communication: J. Am. Chem. Soc. 1995, 117, 8047-8048. Follow up: J. Org. Chem. 1996, 61, 2484-2487.Full paper: Tetrahedron 1997, 53, 16241-16252.
Related paper: J. Org. Chem. 2000, 65, 3771-3774.
Mechanism
R1 R2
O+ HO
N3
R1 R2
HO O
N3
R1 R2
O- H2O
NN
N
O
NR1R2
N2
O
NR1
R2
- N2H2OR1 N
O
OH
R2 - H
H
H
R1 R2
HO N
OHN2
R1 N
O
R2
HOH
- N2
H2O R1 N
O
OH
R2
- HR1 N
O
R2
H
Mechanism originally proposed by Boyer
Mechanism
R1 R2
O+ HO
N3
R1 R2
HO O
N3
R1 R2
O- H2O
NN
N
O
NR1R2
N2
O
NR1
R2
- N2H2OR1 N
O
OH
R2 - H
H
H
R1 R2
HO N
OHN2
R1 N
O
R2
HOH
- N2
H2O R1 N
O
OH
R2
- HR1 N
O
R2
H
Mechanism seems more reasonable in light of relative easyness of intramolecular Schmidt reaction
Bronsted and Lewis Acid Survey
+HO
N3
O
N
OOH
Acid Yield (%)
TFA 64
TfOH 82
BF3OEt2 90
TiCl4 86
SnCl4 85
TMSOTf 64
Azide Tether Length
+ RON3
O
N
OOR
Acid Yield (%)
90
BF3OEt2 98
TMSOTf (O.2 equiv)TMSOTf (1.0 equiv)
2092
019
03414
( )n
( )n
Azide
HON3
N3HO
N3TMSO
N3H3CO
N3
HO
N3HO
N3HO
N3H3C
BF3OEt2
TfOH
BF3OEt2
BF3OEt2
TfOHTiCl4
BF3OEt2
TfOHTiCl4
0337
BF3OEt2 0
BF3OEt2
TfOHTi(OiPr)4
TiCl4
030080
Azide Tether Length
+ RON3
O
N
OOR
Acid Yield (%)
90
BF3OEt2 98
TMSOTf (O.2 equiv)TMSOTf (1.0 equiv)
2092
019
03414
( )n
( )n
Azide
HON3
N3HO
N3TMSO
N3H3CO
N3
HO
N3HO
N3HO
N3H3C
BF3OEt2
TfOH
BF3OEt2
BF3OEt2
TfOHTiCl4
BF3OEt2
TfOHTiCl4
0337
BF3OEt2 0
BF3OEt2
TfOHTi(OiPr)4
TiCl4
030080
2 or 3 C between OH and N3 is optimal
Longer alkyl chain leads to transient formation of a
seven or higher-membered ring system
This leads to the shift in mechanism shown above, to the original proposal of
Boyer
These behave as simple alkyl azides
Mechanism
R1 R2
O+
R3
N3
R1 R2
HO O
N3
R1 R2
O- H2O
NN
N
O
NR1R2
N2
O
NR1
R2
- N2H2OR1 N
O
OH
R2 - H
H
H
R1 R2
HO N
R3N2
R1 N
O
R2
H
- N2 - H( )n
( )n( )n
( )n
( )n( )n
( )n
R3 = OH
n = 1,2
R3
R1 N
O
R2
R3
Symmetrical Ketones
+ HON3
O
N
OOH
Product Yield (%)
( )n
( )n
n (azide)
BF3OEt2
Ketone
Ph
O
N
O OH
Ph
2 73
O
12 N
O
OH( )n
9698
H
H
O 2
H
H
N
O
OH88
NO
O
OH2 80
O
PhN
OOH
882
N
O
H3CN N
OOH
732H3C
Ph
O
N
OOH
792O
O
O
O
Unsymmetrical Ketones
O
N
O
OH
H3C
CH3
N
O
OH
CH3
HON3
BF3OEt2
73% (1:1.3 ratio)
+
O
N
O
OH
H3CO
OCH3
HO
BF3OEt2
51%
N3
Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones:Desymetrization of meso-Ketones
O
R
N
O
R
R*
R*N3N
O
R
H
Deprotection
Communication: Org. Lett. 1999, 1, 495-497.Full paper: J. Am. Chem. Soc. 2003, 125, 7914-7922.
Follow up: J. Am. Chem. Soc. 2003, 125, 13948-13949.Theoritical studies: J. Org. Chem. 2004, 69, 3439-3446.
Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones
O
CH3
N
O
H3C
BF3OEt2
-82 °C to RT
Ph N3
OH Ph
HO
N
O
CH3
Ph
OH
+
98% (93:7 d.r.)
Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones
O
N
O
BF3OEt2
-82 °C to RT
Ph N3
OH Ph
HO
O
R
N
O
R
Ph
HO
Ketone Product d.r. Yield (%)
R= CH3 93:7R = Ph 96:4
R = t-Bu 95:5
9899100
O
H3C CH3
N
OPh
HO
CH3
H3C
98:2 86
O
N
OPh
HO
96:4 90
H3CH3C
O
Ph
N
O Ph
Ph
65:35 82
O
H
H
N
OH
O
Ph
OH
H
H
60:40 57
Ketone Product d.r. Yield (%)
Stereoselectivity
O
CH3
N
H3C
BF3OEt2
-82 °C to RT
Ph N3
OH
H3C N
O
Ph
N2
ON
H3C
N2Ph
O
Ph
H2O
- H
N
O
H3C
Ph
HO
Every substituents in pseudoequatorial position exept N2+
Antiperiplanar bond to N2+ migrates
Deprotection of the Lactam
N
O
H3C
Ph
HO
1. PCC, 82%
2. NaH, 75%
NH
O
H3C
Ph
O+
Destruction of the chiral auxiliairy
Use in Total Synthesis: Dendrobatid Alkaloid 251F
• Isolation reported in 1992 from the skin of the Columbian dendrobatid poison frog Minyobates bombetes1
• Skin extracts caused severe locomotor difficulties, muscle spasms and convulsions upon injection into mice
• Pharmacological profile of the alkaloid is still unknown• First synthesized by Taber and You2
1 Spande, T. F. et al. J. Nat. Prod. 1992, 55, 707-722.2 Taber, D. F.; You, K. K. J. Am. Chem. Soc. 1995, 117, 5757-5762.
N
Me
MeMe
OHH
H
H
Dendrobatid Alkaloid 251F
Cyclopenta[b]quinolizidine7 stereogenic centers, 6 contiguous
Retrosynthetic Analysis to Dendrobatid Alkaloid 251F
Communication: J. Am. Chem. Soc. 2002, 124, 9974-9975.Full paper: J. Am. Chem. Soc. 2004, 126, 5475-5481.
N
Me
MeMe
OHH
H
H
Me
OHH
HO
Me
Me
N3
Me
H
HO
Me
CO2H
Synthesis of the Bicyclic Enone
Diels-Alder: Evans, D. A. et al. J. Am. Chem. Soc. 1988, 110, 1238-1256.Metathesis: Grubbs, R. H. et al. J. Org. Chem. 1990, 55, 843-862.
Me
H
HO
Me
Me
+
Me
O
Me NH2Cl
OMe
MgBr
1. BOP, NEt3;
2.
85% (2 steps)
5 mol%
BOP =
Ru
PCy3
PCy3
Cl
Cl Ph
ethylene, DCM93%
N
O
O
O Me
Ph
OHO
1. Et2AlCl
2. LiOH, H2O2
88%
Me
+
HN
OO
OMe
PhCl
BuLi, 93%
N P N
N
O
N N
N
PF6
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
98:2 d.r60:1 endo-exo
Diastereoselective Diels-Alder
Diels-Alder: Evans, D. A. et al. J. Am. Chem. Soc. 1988, 110, 1238-1256.
Me
Me
+
N
O
O
O Me
Ph
OHO
98:2 d.r60:1 endo-exo
Et2AlCl
Me
N
O
O
O Me
Ph
Al
Me
Me
Et2AlCl2
Synthesis of the Bicyclic Enone
Me
H
HO
Me
O
5 mol% Ru
PCy3
PCy3
Cl
Cl Ph
ethylene, DCM93%
Ru CH2
PCy3
PCy3
Cl
ClMe
O
LnRu
Me
O
LnRu
Me
OLnRu
Ru
PCy3
PCy3
Cl
Cl
Me
O
Synthesis of the Bicyclic Enone
Me
H
HO
Me
O
5 mol% Ru
PCy3
PCy3
Cl
Cl Ph
ethylene, DCM93%
Ru CH2
PCy3
PCy3
Cl
ClMe
O
Ln
RuMe
O
LnRu
Ru
PCy3
PCy3
Cl
Cl
Me
O
LnRu
Me
O O
Synthesis of the 4-C Side Chain Leading to the Third Ring
NHO
Ph Me
O
NO
Ph Me
O O
BuLi
Cl
O
NaHMDS
INO
Ph Me
O O
Me
1. LAH2. NaH, BnBr
Me
BnOOsO4, NMO
NaIO4, H2OMe
OBnO
>95 d.e.
36%, 5 steps
Installation of the 4-C Side Chain Leading to the Third Ring
Me
H
HO Me
H
HLiO
Me
Me2CuLi
THF
Convex faceless shielded
OBnO
Me
H
HO
Me
OBn65%
1. Na, NH3, t-BuOH2. Zn(N3)2- 2 pyr, DEAD, PPh3
50% (2 steps)
Me
H
HO
Me
N3
4:1
Completion of the Synthesis
O3, DCM;
DMS EtOH52% (2 steps)
TfOH, DCM, 0 °C79%
Me
H
HO
Me
N3
4:1
Me
OH
HO
Me
N3
NaBH4
Me
OHH
HO
Me
N3
Reduction sensitive groups
N
Me
MeMe
OHH
H
H
O
LAH, Et2O
93%N
Me
MeMe
OHH
H
H
13 steps overall, 6.5% yield