Total synthesis of (-)-maytansinol

Article abstract of DOI:10.1021/jo960363a

A total synthesis of maytansinol (1) was achieved, in a convergent way, using (3S,6S,7S)-aldehyde 4 and (S)-p-tolyl sulfoxide 3 as fragments. When the anion of 3 was condensed with aldehyde 4, some induction at C(10) was observed (60% de), giving the C(1)-N(19)-open-chain compound 7, after thermal elimination of sulfinate. Pure E/E stereochemistry of the 11,13-diene was obtained. Selective modifications of the functionalities permitted macrocyclization and further elaboration to maytansinol.

Full text of DOI:10.1021/jo960363a

J . Org. Chem. 1996, 61, 7133-7138
7133
Tota l Syn th esis of (-)-Ma yta n sin ol
Michel Be´ne´chie and Franc¸oise Khuong-Huu*
CNRS, Institut de Chimie des Substances Naturelles, 91198 Gif-sur-Yvette, France
Received February 21, 1996X
A total synthesis of maytansinol (1) was achieved, in a convergent way, using (3S,6S,7S)-aldehyde
4 and (S)-p-tolyl sulfoxide 3 as fragments. When the anion of 3 was condensed with aldehyde 4,
some induction at C(10) was observed (60% de), giving the C(1)-N(19)-open-chain compound 7,
after thermal elimination of sulfinate. Pure E/ E stereochemistry of the 11,13-diene was obtained.
Selective modifications of the functionalities permitted macrocyclization and further elaboration
to maytansinol.
Sch em e 1
Maytansine is a naturally occurring ansamacrolide,
isolated originally by Kupchan in 19721 from Maytenus
serrata, which exhibits potent antitumor and antileu-
kemic activity and has been the subject of extensive
chemical2 and biological3 studies. Two independent total
syntheses of maytansine4 and two total syntheses of
maytansinol5 have been reported to date.
In a previous paper, we had proposed a new synthetic
approach that could lead to modified skeleton maytansi-
noids,6 which could replace maytansine in order to
overcome its toxicity7 in clinical use.8 The synthesis of
a C(1)-N(19) open-chain derivative in the 4,6-didemethyl
series was carried out to improve our methodology and
to test its feasability. Accesses to the 4-demethyl and
6-demethyl C(1)-C(9)-fragments were also described.6
In the present paper, we report the synthesis of (-)-
maytansinol (1), by condensation of two fragments,
phenyl sulfoxide 2 or (S -(-)-p-tolyl sulfoxide 3 and
(3S,6S,7S)-aldehyde 4 (Scheme 1).
The synthesis of phenyl sulfoxide 2 was realized from
vanillin in 12 steps as previously described.6 We pre-
pared aldehyde 4 by formylation9 of the anion R to the
dithiane group of the (3S,6S,7S)-C(1)-C(9) fragment 5
(Scheme 2). It was observed that deprotonation of the
dithianyl group needed TMEDA when the C(7)-hydroxyl
was protected as MEM ether. It was not necesary when
a TBDMS protecting group was used for this position.6
Regioselective opening of 2(S),3(S)-epoxy-1-(tosyloxy)-
butane by diethylpropynylalane was the first step of the
Sch em e 2
chiral synthesis of 5, which was performed in seven steps,
with a 26% yield, as reported previously (Scheme 3).10
The best conditions to realize the coupling of aldehyde
4 with the anion R to the sulfoxide group of 2 (R ) Ph)
were to add 1 equiv of LDA to an equimolar solution of
2 and 4, in DME/pentane at -78 °C. After 1 h at -78
°C, the reaction was quenched at this temperature by
acetic acid. Workup gave sulfoxide-alcohol intermedi-
ates (73% yield) plus some starting materials. This
reaction seems to be reversible, and if the temperature
was permitted to raise to ambient before quenching, both
starting materials were recovered with few condensation
products. When THF or ether were used the yield
decreased (Scheme 4).
Crude sulfoxide-alcohols were transformed to diols 7
and 8 as a 1/1 mixture of epimers at C(10) by warming
at 80 °C in toluene solution (Scheme 4). Pure E/ E
stereochemistry of the 11,13-dienic system was obtained.
These alcohols could be separarated by chromatography.
The absolute configuration at C(10) of each alcohol was
determined by Horeau's method.11
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) Kupchan, S. M.; Komoda, Y.; Court, W. A.; Thomas, G. J .; Smith,
R. M.; Karim, A.; Gilmore, C. J .; Haltiwanger, R. C.; Bryan, R. F. J .
Am. Chem. Soc. 1972, 94, 1354-1456.
(2) For reviews: (a) Reider, P. J .; Roland, D. M. The Alkaloids;
Academic Press: New York, 1984; Vol. XXIII, pp 71-155. (b) Isobe,
M. In Recent progress in the chemical synthesis of Antiobiotics; Lukacs,
G., Ohno, M., Eds.; Springer-Verlag: Berlin, Heidelberg. 1990; pp 103-
134.
(3) (a) Rao, P. N.; Freireich, E. J .; Smith, M. L.; Loo, T. L. Cancer
Res.( 1979, 39, 3152-3153. (b) Issell, B. F.; Crooke, S. T. Cancer Treat.
Rev. 1978, 5(4), 199-207.
(4) (a) Corey, E. J .; Weigel, L. O.; Chamberlin, A. R.; Cho, H.; Hua,
D. H. J . Am. Chem. Soc. 1980, 102, 6613-6615. (b) Gu, X.; Pan, B.;
Zhou, Q.; Bai, D.; Gao, Y. Sci. Sin. Ser. B (Engl. Ed.) 1988, 31, 1342-
1351.
(5) (a) Meyers, A. I.; Reider, P. J .; Campbell, A. L. J . Am. Chem.
Soc. 1980, 102, 6597-6598. (b) Kitamura, M.; Isobe, M.; Ichikawa, Y.;
Goto, T. J . Am. Chem. Soc. 1984, 106, 3252-3257.
(6) Be´ne´chie, M.; Delpech, B.; Khuong-Huu, Q.; Khuong-Huu, F.
Tetrahedron 1992, 48, 1895-1910.
(7) Ko, S. S.; Confalone, P. N. Tetrahedron 1985, 41, 3511-3518.
(8) (a) Eagan, R. T.; Creagan, E. T.; Ingle, J . N.; Frytak, S.; Rubin
J . Cancer Treat. Rep. 1978, 62, 1577-1579. (b) J affrey, I. S.; Denefrio,
J . M.; Chahinian, A. P. Cancer Treat. Rep. 1980, 64, 193-194.
(9) (a) Evans, E. A., J . Chem. Soc. 1956, 4691-4692. (b) Seebach,
D.; Corey, E. J . J . Org. Chem. 1975, 40, 231-237.
(10) Be´ne´chie, M.; Khuong-Huu, F. Synlett 1992, 266-268.
(11) Horeau, A. Tetrahedron Lett. 1961, 506-512.
S0022-3263(96)00363-5 CCC: $12.00 © 1996 American Chemical Society

7134 J . Org. Chem., Vol. 61, No. 20, 1996
Be´ne´chie and Khuong-Huu
Sch em e 5
Sch em e 3
the previously described6 allylic bromide 6. The conden-
sation reaction between 3 and 4, followed by thermal
elimination of sulfinate using the conditions previously
described, gave a mixture of 7 and 8 in a 4/1 ratio (60%
de) (Scheme 4). This result confirms the importance of
the steric bulk of the reactants in improving the
stereoselectivity.12c Attempts to increase this diastereo-
meric excess using various transmetalations were un-
successful.14
After chromatographic separation of 7 and 8, 10(R)-
alcohol 7 was methylated with excess methyl iodide in
the presence of Ag2O, giving the C(1)-N(19)-open-chain
compound 9 in 98% yield. The C(9)-dithianyl group was
unaffected by these conditions.
The next steps before ring closure involved hydrolysis
of the C(1)-diethyl acetal protective group, oxidation of
the resulting aldehyde into the acid, and hydrolysis of
the carbamate moiety to give the free N(19)-methylamino
function.
Sch em e 4
In our first experiments, we tried the selective cleavage
of the C(1)-diethyl acetal group. With LiBF4,15 three
compounds were obtained, the desired aldehyde 10 in
70% yield and the cyclized compounds 11 and 12 (Scheme
5). Unfortunately, the unstable aldehyde 10 was not
useful, as elimination of the TBDMS-oxy group occurred
during the next oxidation step.
The successful hydrolysis of the diethyl acetal group,
after n-Bu4NF cleavage of the tert-butyldimethylsilyl
group, was achieved with 0.1 M HCl in THF/H2O at room
temperature. The very sensitive aldehyde intermediate
was not isolated but oxidized into acid 14 with Ag2O
(modified Meyers' procedure).5a Selective protection of
the C(3)-hydroxyl as its tert-butyldimethylsilyl ether was
carried out; and the hydrolysis of the carbamate protec-
tive moiety of 15 was then studied. The use of bases or
strong nucleophiles, such as 4-mercaptopyridine,16 gave
unsatisfactory results. Clean cleavage could be obtained
by DIBAH-controlled reduction of this carbamate when
this reaction was performed at -78 °C < θ < -60 °C in
toluene. The secondary amine 16 was obtained in 72%
yield. There is some formation of the corresponding
dimethylamino-derivative (8%). Ring closure of the
amino acid 16 was effected using Mukayama’s
procedure,4b,17 under high dilution conditions, to give 17
in 66% yield (Scheme 6). In solution, macrolactam 17
exists as a mixture of conformers as shown by the
Various attempts to obtain neighboring asymmetric
induction by modification of the conditions of the reaction
were unsuccessful. Addition of ZnCl2 to fix the geometry
of the MEM group in the transition state by chelation
gave (R)-alcohol 7 as the only product, but the chemical
yield was only 9%. Addition of other divalent salts was
inefficient.
Therefore, in spite of the poor stereoselectivity that was
obtained with most previous examples, we tried to induce
asymmetric condensation by the use of a chiral sulf-
oxide.12 Preliminary approaches with (R)-(+)- and (S)-
(-)-phenyl sulfoxide 2 showed that (S)-(-)-sulfoxide was
required to obtain 10(R)-induction. We prepared chiral
(S)-(-)-p-tolyl sulfoxide 3 by alkylation of the lithio
derivative of (S)-(-)-methyl p-tolylmethyl sulfoxide13 with
1
complexity of its H NMR spectrum.
(13) Zhao, S. H.; Samuel, O.; Kagan, H. B. Org. Synth. 1989, 68,
49-55.
(14) Pyne, S. G.; Boche, G. J . Org. Chem. 1989, 54, 2663-2667.
(15) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267-
277.
(16) Keinan, E.; Eren, D. J . Org. Chem. 1986, 51, 3165-3169.
(17) (a) Bald, E.; Saigo, K.; Mukayama, T. Chem. Lett. 1975, 1163-
1166. (b) Bai, D. L.; Bo, Y.; Zhou, Q. Tetrahedron Lett. 1990, 31, 2161-
2164.
(12) (a) Solladie, A. Synthesis 1981, 185-196. (b) Walker, A. J .
Tetrahedron Asymmetry 1992, 3, 961-998. (c) Casey, M.; Mukherjee,
I.; Trabsa, H. Tetrahedron Lett. 1992, 33, 127-130.

Total Synthesis of (-)-Maytansinol
J . Org. Chem., Vol. 61, No. 20, 1996 7135
Sch em e 6
Sch em e 7
-78 °C, giving 4,5-deoxymaytansinol that was identical
to that previously described.4b,20 Epoxidation of the C(4)-
C(5)-double bond of 22 was performed with tert-butyl
hydroperoxide and VO(acac)2. Following the experimen-
tal conditions described by Pan and al.,4b we obtained (-)-
maytansinol (1) in a yield of 45%. Comparison with an
authentic sample, prepared from maytansine,21 led to the
identification of our synthetic material. In this total
synthesis, the chirality was introduced by L-tartaric acid,
which was used in catalytic amounts in the Sharpless
epoxidation of (E)-crotyl alcohol and in the preparation
of (S)-p-tolyl sulfoxide.
Exp er im en ta l Section
Melting points (mp) were determined in capillary tubes and
are uncorrected. Optical rotations, [R]D, were measured in
CHCl3 with 0.5% EtOH, at 20 °C. Tetrahydrofuran was
distilled from sodium benzophenone ketyl, diethyl ether from
lithium aluminum hydride, dichloromethane from phosphorus
pentoxide, and toluene from sodium. Other solvents and
reagents were purified by standard procedures as necessary.
Numbering for compounds follows the numbering for may-
tansinol (1). Column chromatography was performed on
Merck Kieselgel 60, flash chromatography on Merck Kieselgel
60H. Standard workup means addition of water to the
reaction mixture, extraction with an organic solvent (CH2Cl2,
ether, or AcOEt), washing of the organic phases successively
with brine and water, and evaporation of the solvent in vacuo.
2D 1H-1H, 1H-13C, and HMBC experiments led to the
interpretation of the 1H and 13C NMR spectra. Chemical
shifts, δ, are expressed in ppm and coupling constants, J , in
Hz.
The synthesis of (-)-maytansinol (1) was achieved from
17 by elaboration of the cyclic carbamate between C(7)
and C(9) and epoxidation of the 4,5 double bond. For
these transformations, we adapted the reactions used for
the previously achieved total syntheses of maytansine
and maytansinol4,5 (Scheme 7).
17-[14-Met h yl-11-(p -t olylsu lfoxy)p en t en -13-en yl]-18-
(N-m et h yl-N-ca r b om et h oxya m in o)-19-ch lor o-20-m et h -
oxyben zen e (3). (S)-(-)-Methyl p-tolyl sulfoxide was pre-
pared according to Kagan’s procedure.13 After recrystallization
in heptane, it had mp 74 °C, [R]D -144 (c ) 1, acetone) (99%
ee). A solution of LDA (4 mmol) in THF (10 mL) was prepared
at -5 °C by addition of n-BuLi (3.2 mL of a 1.28 M solution in
hexane) to a solution of DIPA (0.56 mL, 4 mmol). After the
solution was cooled at -78 °C, (S)-(-)-methyl p-tolyl sulfoxide
(569 mg, 3.7 mmol) in THF (3 mL) and HMPA (3.5 mL, 20
mmol) were added.The mixture was stirred at this tempera-
ture for 10 min, and then 6 (1.24 g, 3.3 mmol) in THF (8 mL)
was added. The solution was warmed to -20 °C over ca. 90
min. After being quenched with aqueous ammonium chloride,
the mixture was extracted three times with ether. The organic
phases were washed with brine, dried over MgSO4, and
Selective cleavage of the MEM group was carried out
by 2-chloro-1,3,2-dithioborolane according to William’s
procedure.18 Alcohol 18 was obtained in 53% yield but
had to be separated from thiol 19 formed as byproduct
in 29% yield. The formation of 19, which had not been
pointed out before, could be explained by competitive
attack of the oxonium intermediate by ethanedithiol.19
The free hydroxyl of 18 was transformed into carbam-
ate 20 by reaction with 4-nitrophenyl chloroformate in
pyridine followed by treatment with methanolic NH3.
Hydrolysis of the dithiane by HgCl2/CaCO3 in aqueous
acetonitrile gave cyclic carbamate 21. Cleavage of the
C(3)-silyl ether was carried out with HF in CH3CN at
(18) Williams, D. R.; Sakdarat, S. Tetrahedron Lett. 1983, 24, 3965-
3968.
(19) Quindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett. 1983,
24, 3969-3972.
(20) Song, G.; Gu, X.; Pan, B. Acta Chim. Sin. 1988, 46, 557-560.
(21) Sneden, A. T. Synlett 1993, 313-322.

7136 J . Org. Chem., Vol. 61, No. 20, 1996
Be´ne´chie and Khuong-Huu
evaporated in vacuo without heating. Flash chromatography
of the residue gave 3 (980 mg, 66%) as an oil. [R]D: -86 (CHCl3,
c ) 1.1). Anal. Calcd for C23H28ClNO4S: C, 61.39; H, 6.27.
Found: C, 61.20; H, 6.37. EIMS: M+ 451 and 449, m/ z 435
and 433. 1H NMR (250 MHz, CDCl3) δ ppm: 1.56 (3H, s,
C(14)-CH3), 2.34 and 2.55 (2H, 2 m, C(12)-H2), 2,42 (3H, s, Ar-
CH3), 2.8 (2H, m, C(11)-H2), 3.18 (3H, s, NCH3), 3.25 (2H, bs,
C(15)-H2), 3.62 (major rotamer) and 3.78 (minor rotamer), (3H,
2 s, CO2CH3), 3.88 (3H, s, C(20)-OCH3), 5.26 (1H, t, J ) 7.5
Hz, C(13)-H), 6.61 and 6.68 (2H, 2s, C(17)-H and C(21)-H), 7.32
and 7.51 (4H, J ) 8 Hz, A2B2, C6H4). 13C NMR, (CDCl3) δ:
15.8 (C(14)-CH3), 20.9 (C-12), 21.1 (Ar-CH3), 36.8 (NCH3), 45.5
(C-15), 52.7 (CO2CH3), 56.2 (C(20)-OCH3), 56.8 (C-11), 111.2
(C-21), 118.8 (C-19), 121.1 (C-17), 123.2 (C-13), 123.8 and 129.7
(4 CH, tolyl), 136.5 (C-14), 139.6, 140.5, 141.2, 141.2, (4 C Ar),
155.5, 155.8 (C-20 and CdO).
3S,6S,7S-1,1-Dieth oxy-3-[(ter t-bu tyld im eth ylsilyl)oxy]-
7-[(m e t h oxye t h oxy)m e t h oxy]-9-(1,3)-d it h ia n -2′-yl-4,6-
d im eth yln on -4-en -10-a ld eh yd e (4). n-BuLi (1 mL of a 1.5
M solution in hexane, 1.5 equiv) was added at -30 °C to 5
(600 mg, 1.03 mmol) and TMEDA (2 mL) in THF (40 mL).
After 3 h at -20 °C, the mixture was cooled to -78 °C, and
freshly distilled DMF (720 mg, 10 mmol) was added. The
solution was warmed to 0 °C and stirred for 30 min. The
reaction was quenched with aqueous ammonium chloride. The
mixture was extracted with CH2Cl2. The organic phases
washed with brine and evaporated in vacuo gave a residue
that, when purified by flash chromatography, led to 4 (612 mg,
97%) as a colorless oil. [R]D: +72 (c ) 1.4, CHCl3). Anal. Calcd
for C29H56O7S2Si: C, 57.23; H, 9.21. Found: C, 57.40; H, 9.23.
MS (EI): M+ 608, m/ z 579, 551. 1H NMR (250 MHz, CDCl3)
δ: -0.06 (3H, s, SiCH3), -0.02 (3H, s, SiCH3), 0.85 (9H, s,
t-Bu), 0.87 (3H, d, J ) 7 Hz, C(6)-CH3), 1.16 (3H, t, J ) 7 Hz,
CH2CH3), 1.19 (3H, t, J ) 7 Hz, CH2CH3), 1.53 (3H, d, J ) 1
Hz, C(4)-CH3), 1.57-1.87 (3H, m, C(2)-H2, SCH2CH), 1.89 (1H,
dd, J ) 14, 2.5 Hz, C(8)-Ha), 2.07 (1H, m, SCH2CH), 2.07 (1H,
dd, J ) 14, 9.5 Hz, C(8)-Hb), 2.42-2.67 (3H, m, SCH, SCH2),
2.77 (1H, m, C(6)-H), 3.33 (3H, s, OCH3), 3.33-3.69 (9H, m, 4
OCH2, SCH), 3.77 (1H, m, C(7)-H), 4.07 (1H, dd, J ) 8, 4 Hz,
C(3)-H), 4.49 (1H, dd, J ) 7, 4 Hz, C(1)-H), 4.61 (2H, s,
OCH2O), 5.18 (1H, d, J ) 10 Hz, C(5)-H), 8.78 (1H, s, CHO).
13C NMR, (CDCl3) δ: -5.1 (SiCH3), -4.3 (SiCH3), 11.3 (C(4)-
CH3), 15.4 (2 CH2CH3), 17.1 (C(6)-CH3), 18.1 (CMe3), 24.7
(CH2), 25.85 (CMe3), 26.53 (SCH2), 26.62 (SCH2), 35.16 (C-6),
39.18 (CH2), 40.83 (C-2), 55.67 (C-9), 58.9 (OCH3), 60.8 (OCH2-
CH3), 61.1 (OCH2CH3), 68.1 (OCH2), 71.7 (OCH2), 75.1 (C-3),
77.1 (C-7), 95.5 (OCH2O), 100.6 (C-1), 126 (C-5), 138.9 (C-4),
187.1 (CHO).
(3S,6S,7S,10R)-17-[1,1-Dieth oxy-3-[(ter t-bu tyld im eth yl-
silyloxy]-7-[(m eth oxyeth oxy)m eth oxy]-4,6,14-tr im eth yl-
10-h ydr oxy-9-(1,3)-dith ian -2′-ylpen tadeca-4,11,13-tr ien yl]-
18-(N -m e t h y l-N -c a r b o m e t h o x y a m id o )-19-c h lo r o -20-
m eth oxyben zen e (7). (a) LDA (0.35 mL of a 0.7 M solution
in DME, 0.25 mmol) was added at -78 °C to 2 (100 mg, 0.23
mmol) in DME/heptane 3/1 (5 mL). After 30 min, a preformed
chelate (-78 °C, 1 h) from aldehyde 4 (90 mg, 0.15 mmol) and
ZnCl2 (0.2 mL of a 1 M solution in ether, 0.2 mmol) in DME (3
mL) was added. The mixture was stirred at -78 °C for 1 h.
After the mixture was quenched at -78 °C with acetic acid in
toluene, standard workup led to a residue which was dissolved
in benzene (2 mL) and refluxed in the presence of solid sodium
bicarbonate (70 mg). Thermolysis was monitored by TLC.
Upon completion of the reaction, the solution was poured on
silica gel column and flash chromatography (Hept/AcOEt)
afforded 4 (48 mg, 53%) and 7 (12 mg, 9%).
(b) LDA (5 mL of a 0.7 M solution in DME, 3.5 mmol) was
added at -78 °C to 3 (1.30 g, 2.90 mmol) and 4 (1.5 g, 2.46
mmol) in DME / heptane 3/1(40 mL). This mixture was stirred
at -78 °C for 3 h. After the mixture was quenched at -78 °C
with acetic acid in toluene, standard workup led to a residue
that was dissolved in benzene (30 mL) and refluxed in the
presence of solid sodium bicarbonate (1 g). Thermolysis was
monitored by TLC. Upon completion of the reaction, the
solution was poured onto a silica gel column, and flash
chromatography (Hept/AcOEt) afforded 4 (0.25 g, 17%) and
the mixture of 7 and 8 (81/19, 1.64 g, 73%), which was resolved
by preparative HPLC. Pure 7 was obtained (1.25 g, 55%) as
a colorless oil, but we also obtained 8 contaminated with 5%
of 7.
Absolute configuration, Horeau’s method: 7 (10R), recovered
R-phenylbutyric acid had [R]D +4.5; 8 (10S), recovered R-phen-
ylbutyric acid had [R]D -3.1.
7. [R]D: +16 (CHCl3, c ) 2.4). Anal. Calcd for C45H76
-
ClNO10S2Si: C, 58.88; H, 8.28. Found: C, 58.86; H, 8.26.
EIMS: M+ 919 and 917, m/ z 899 (M - 18)+, 860 (M - 57)+,
579, 452. UV, λmax (nm, EtOH): 240.4 (ꢀ )28 300), 285 (ꢀ )
4400). 1H NMR (400 MHz, CDCl3) δ: 0.0 (3H, s, SiCH3), 0.04
(3H,s, SiCH3), 0.88 (9H, s, C(CH3)3), 0.92 (3H,d, J ) 7 Hz, C(6)-
CH3), 1.20 (3H, t, J ) 7 Hz, CH3CH2O), 1.22 (3H, t, J ) 7 Hz,
CH3CH2O), 1.6 (3H, s, C(4)-CH3), 1.71 (3H, s, C(14)-CH3),
1.76-1.88 (4H, m, C(2)-H2, C(8)-Ha, SCH2CH), 2.05 (1H, m,
SCH2CH), 2.13 (1H, dd, J ) 15, 2.5 Hz, C(8)-Hb), 2.65 (2H, m,
CH2S), 2.77 (1H, m, C(6)-H), 2.98 (2H, m, CH2S), 3.19 (3H, s,
N-CH3), 3.33 (2H, s, C(15)-H2), 3.39 (3H, s, OCH3), 3.4-3.8
(8H, m, 4 OCH2), 3.63 (3H, s, CO2CH3), 3.89 (3H, s, C(20)-
OCH3), 3.95 (1H, m, C(7)-H), 4.10 (1H, dd, J ) 4, 9 Hz, C(3)-
H), 4.56 (1H, dd, J ) 4, 6 Hz, C(1)-H), 4.68 (1H, d, J ) 5.5 Hz,
C(10)-H), 4.82 and 4.89 (2H, AB, J ) 7 Hz, OCH2O), 5.35 (1H,
d, J ) 9 Hz, C(5)-H), 5.97 (1H, dd, J ) 14, 5.5 Hz, C(11)-H),
5.98 (1H, d, J ) 11 Hz, C(13)-H), 6.66 (1H, dd, J ) 14, 11 Hz,
C(12)-H), 6.70 (2H, s, C(17)-H and C(21)-H); 13C NMR (CDCl3)
δ: -5.28 (SiCH3), - 4.47 (SiCH3), 11.40 (C(4)-CH3), 15.28 (2
OCH2-CH3), 16.02 (C(6)-CH3), 16.4 (C(14)-CH3), 17.9 (C-Me3),
24.3 (CH2), 25.7 (C-(CH3)3 and 2 SCH2), 36.5 (C-6), 36.9
(NCH3), 37.6 (CH2), 40.8 (CH2), 45.9 (C-15), 52.8 (OCH3), 56.2
(C(20)-OCH3), 57.7 (C-9), 58.8 (OCH3), 60.6 and 60.9 (2 OCH2-
CH3), 67.7 and 71.7 (OCH2-CH2O), 72.5 (C-10), 74.8 (C-3), 79.2
(C-7), 95.7 (OCH2O), 100.6 (C-1), 111.4 (C-21), 119.1 (C-19),
121.3 (C-17), 126.7 and 128.5 (C-11 and C-13), 127.2 (C-5),
128.8 (C-12), 136.6, 137.7, 139.5, 141.1 (4 C), 155.6 and 155.9
(C-20 and CdO).
8. 1H NMR (400 MHz, CDCl3) δ: 0.0 (3H, s), 0.04 (3H, s),
0.88 (9H, s), 0.93 (3H, d, J ) 7 Hz), 1.20 (3H, t, J ) 7 Hz),
1.22 (3H, t, J ) 7 Hz), 1.60 (3H, s), 1.71 (3H, s), 1.70 (1H, m),
1.80 (1H, ddd, J ) 13, 9, 4 Hz), 1.96 (2H, m), 2.19 (2H, m),
2.66-3.02 (5H, m), 3.19 (3H, s), 3.33 (2H, s), 3.38 (3H, s), 3.4-
3.8 (8H, m), 3.63 (3H, s), 3.89 (3H, s), 3.96 (1H, m), 4.12 (1H,
dd, J ) 4, 9 Hz), 4.54 (2H, m, C(1)-H and C(10)-H), 4.79 and
4.84 (2H, AB, J ) 7 Hz), 5.37 (1H, d, J ) 9 Hz), 5.97 (1H, dd,
J ) 14, 5.5 Hz), 5.98 (1H, d, J ) 11 Hz,), 6.63 (1H, dd, J ) 15,
11 Hz), 6.70 (2H, s).
(3S,6S,7S,10R)-17-[1,1-Dieth oxy-3-[(ter t-bu tyld im eth yl-
silyl)oxy]-7-[(m eth oxyeth oxy)m eth oxy]-4,6,14-tr im eth yl-
10-m eth oxy-9-(1,3)-dith ian -2′-ylpen tadeca-4,11,13-tr ien yl]-
18-(N -m e t h y l-N -c a r b o m e t h o x y a m id o )-19-c h lo r o -20-
m eth oxyben zen e (9). A suspension of 7 (1 g, 1.09 mmol),
MeI (1 mL), and freshly prepared Ag2O (1 g) in ethyl acetate
(20 mL) was stirred at 60 °C for 90 min. The suspension was
filtered off through a silica gel column to afford 9 (1 g, 98%).
Anal. Calcd for C46H78ClNO10S2Si: C, 59.26; H, 8.44. Found:
C, 59.22; H, 8.25. [R]D: +14 (CHCl3, c ) 2). EIMS: M+ 931,
m/ z 900, 886, 874, 856, 814, 602, 579, 473, 352. UV, λmax (nm
(EtOH)): 242.7 (ꢀ ) 25 600), 285 (ꢀ ) 3700). 1H NMR (250
MHz, CDCl3) δ: 0.0 (3H, s, SiCH3), 0.04 (3H, s, SiCH3), 0.87
(9H, s, t-Bu), 0.91 (3H, d, J ) 7 Hz, C(6)-CH3), 1.17 (3H, t, J
) 7 Hz, CH2CH3), 1.20 (3H, t, J ) 7 Hz, CH2CH3), 1.58 (3H,
d, J ) 1 Hz, C(4)-CH3), 1.71 (3H, d, J ) 1 Hz, C(14)-CH3),
1.56-2.3 (6H, m, 3CH2), 2.78 (3H, m, SCH2 and C(6)-H), 2.94
(2H, m, SCH2), 3.17 (3H, s, NCH3), 3.29 (3H, s, OCH3), 3.32
(2H, s, C(15)-H2), 3.37 (3H, s, OCH3), 3.42-3.81 (8H, m, 4
OCH2), 3.61 (3H, broad s, CO2CH3), 3.87 (1H, m, C(7)-H), 3.89
(3H, s, C(20)-OCH3), 3.93 (1H, d, J ) 8 Hz, C(10)-H), 4.11 (1H,
dd, J ) 8, 4 Hz, C(3)-H), 4.53 (1H, dd, J ) 5, 7 Hz, C(1)-H),
4.76 and 4.86 (2H, AB, J ) 7 Hz, OCH2O), 5.38 (1H, d, J ) 9
Hz, C(5)-H), 5.71 (1H, dd, J ) 15, 8 Hz, C(11)-H), 5.97 (1H, d,
J ) 10 Hz, C(13)-H), 6.47 (1H, dd, J ) 15, 10 Hz, C(12)-H),
6.70 (2H, s); 13C NMR (CDCl3) δ: -5.3 (SiCH3), -4.5 (SiCH3),
11.2 (C(4)-CH3), 15.2 (2 CH2CH3), 15.6 (C(6)-CH3), 16.4 (C(14)-
CH3), 17.9 (CMe3), 24.6 (CH2), 25.6 (CMe3), 26.5 (SCH2), 26.5
(SCH2), 36.5 (C(6)-H or NCH3), 36.8 (NCH3 or C(6)-H), 38.6
(C-8), 40.6 (CH2), 45.8 (C-15), 52.7 (OCH3), 55.7 (C-9), 56.1
(C(20)-OCH3), 56.9 (OCH3), 58.7 (OCH3), 60.6 (OCH2CH3, 60.8

Total Synthesis of (-)-Maytansinol
J . Org. Chem., Vol. 61, No. 20, 1996 7137
(OCH2CH3), 67.5 and 71.6 (OCH2CH2O), 74.9 (C-3), 79.5 (C-
7), 88.5 (C-10), 95.8 (OCH2O), 100.5 (C-1), 111.5 (C-21), 119.0
(C-19), 121.3 (C-17), 126.1 (C-13), 127.6 (C-5), 127.9 (C-11),
130.7 (C-12), 137.3 (2C), 139.2 (C), 141.1 (C), 155.6 and 155.7
(C-20) and CdO).
Rea ction of 9 w ith LiBF 4. Com p ou n d s 10-12. LiBF4
(17 mg, 0.18 mmol) was added to a solution of 9 (152 mg, 0.163
mmol) in wet CH3CN (2% H2O) at rt. After 2 h, TLC indicated
the complete disappearance of the starting material. Addition
of ether was followed by careful neutralization (aqueous
NaHCO3). Standard workup and flash chromatography (hep-
tane/ether 2/1) led to compounds 10 (98 mg, 70%), 11 (8 mg,
6%), and 12 (5 mg, 4%).
Acid s 14 a n d 15. Aqueous HCl (0.1 N, 2 mL) was added
to 13 (120 mg, 0.147 mmol) in THF (8 mL) at rt. The
hydrolysis was monitored by TLC. After 2 h, the solution was
made alkaline (pH ) 8) with 0.5 N aqueous NaOH, and freshly
prepared Ag2O (340 mg, 10 equiv) was added. The black
suspension was vigorously stirred until completion of the
oxidation (45 min). After acidification with methanolic oxalic
acid and filtration through a Celite pad to remove silver
residue, extraction with CHCl3 and flash chromatography
(CHCl3/CH3OH, 85/15) afforded 14 (61 mg, 54%). This polar
compound will be described as its O-silylated derivative 15.
14. 1H NMR (250 MHz,CDCl3) δ: 0.92 (3H, d, J ) 7 Hz),
1.66 (3H, s), 1.72 (3H, d, J ) 1 Hz), 1.83-3.06 (11H, m), 3.19
(3H, s, NCH3), 3.30 (3H, s), 3.34 (2H, broad s), 3.36 (3H, s),
3.57 and 3.80 (5H, m,), 3.62 (3H, broad s, CO2CH3), 3.90 (3H,
s), 3.91 (1H), 4.44 (1H, broad d, J ) 8 Hz), 4.73 and 4.87 (2H,
AB, J ) 7 Hz), 5.47 (1H, d, J ) 9 Hz), 5.73 (1H, dd, J ) 14.5,
8 Hz), 5.97 (1H, d, J ) 11 Hz), 6.47 (1H, dd, J ) 14.5, 11 Hz),
6.70 (2H, s).
15. DBU (225 mg, 4 equiv), and TBDMSCl (100 mg, 1.4
equiv) were added to a solution of 14 (348 mg, 0.46 mmol) in
dry CH2Cl2 (10 mL). This mixture was stirred at rt for 18 h.
After addition of water, standard workup led to a residue that
was treated with 1 N methanolic K2CO3 (10 mL) at rt, for 10
min. After careful acidification and addition of ether, the
organic phase was washed with water, dried, and concentrated.
The residue was purified by flash chromatography (SiO2,
eluting with CH2Cl2/CH3OH, 9/1, to give 15 (313 mg, 78%) as
a colorless oil. [R]D: +16 (CHCl3, c ) 2); HRMS (FAB, thio +
NaCl), for C42H68ClNO10S2SiNa: found 896.3612, calcd 896.3640
(M + Na)+. IR ν cm-1: 3412 and 3225 (OH), 1715, (CdO),
1587 (CdC), 1462, 1080 (CO). 1H NMR (250 MHz, CDCl3) δ:
0.02 (3H, s), 0.04 (3H, s), 0.86 (9H, s), 0.92 (3H, d, J ) 7 Hz),
1.62 (3H, s), 1.72 (3H, d, J ) 1 Hz), 1.80-3.0 (11H, m), 3.20
(3H, s), 3.31 (3H, s), 3.34 (2H, bs), 3.38 (3H, s), 3.52-3.90 (5H,
m), 3.63 (3H, bs), 3.89 (3H, s), 3.92 (1H, d, J ) 7.5 Hz), 4.47
(1H, dd, J ) 3, 8 Hz), 4.76 and 4.88 (2H, AB, J ) 7 Hz), 5.49
(1H, d, J ) 9 Hz), 5.76 (1H, dd, J ) 15, 7.5 Hz), 5.98 (1H, d,
J ) 11 Hz), 6.47 (1H, dd, J ) 15, 11 Hz), 6.70 (2H, s). 13C
NMR (CDCl3) δ: -5.3, -4.4, 11.8, 15.8, 16.7, 18.2, 24.8, 25.8,
26.7, 26.9, 36.9, 37.0, 38.8, 42.4, 46.1, 53.2, 55.8, 56.5, 57.2,
59.1, 67.6 and 71.9, 75.2, 80.0, 88.6, 96.3, 111.8, 119.0, 121.5,
126.4, 128.1, 128.9, 131.1, 136.2 and 137.7, 139.5, 141.3, 155.8
and 156.2, 175.9.
DIBAH Redu ction of th e Car bam ate P r otective Gr ou p,
Am in o Acid 16. DIBAH (1.5 N in toluene, 0.45 mL, 4 equiv)
was added to 15 (153 mg, 0.17 mmol) in toluene (5 mL) at
-78 °C. This mixture was warmed to -60 °C, and upon
completion of the reaction monitored by TLC, oxalic acid in
methanol was added. After addition of CHCl3, standard
workup afforded a residue that was purified on a silica gel
column (eluent: toluene/AcOEt: 3/1), giving 16 (103 mg, 72%)
and the dimethylamino acid (8%). 16. [R]D: +20 (CHCl3, c )
0.7). HRMS (FAB) for C40H67ClNO8S2Si (MH)+: found 816.3760,
calcd 816.3766. IR (CHCl3), ν cm-1: 3420, 2958, 2929, 1729
(w), 1590, 1480, 1250. 1H NMR (250 MHz, CDCl3) δ: 0.05 (3H,
s), 0.08 (3H, s), 0.87 (9H, s), 0.93 (3H, d, J ) 6 Hz), 1.64 (3H,
s), 1.76 (3H, d, J ) 1 Hz), 1.95 (2H, m), 2.04 (1H, dd, J ) 16,
2.5 Hz), 2.19 (1H, dd, J ) 16, 6 Hz), 2.46 (1H, dd, J ) 15, 8
Hz), 2.59 (1H, dd, J ) 15, 5 Hz), 2.70-3.10 (5H, m), 2.90 (3H,
s), 3.32 (5H, bs), 3.39 (3H, s), 3.52-3.90 (5H, m), 3.87 (3H, s),
3.92 (1H, d, J ) 8 Hz), 4.47 (1H, dd, J ) 5, 8 Hz), 4.78 and
4.89 (2H, AB, J ) 7 Hz), 5.52 (1H, d, J ) 8 Hz), 5.76 (1H, dd,
J ) 15, 8 Hz), 5.99 (1H, d, J ) 11 Hz), 6.16 (1H, s), 6.17 (1H,
s), 6.49 (1H, dd, J ) 15, 11 Hz). 13C NMR (CDCl3) δ: -5.2,
-4.4, 11.9, 15.6, 16.7, 18.1, 24.9, 25.84 26.8, 26.87, 30.7, 37.1,
39.2, 42.2, 46.9, 55.8, 56.2, 57.1, 59.0, 67. and 71.9, 75.1, 79.9,
89.1, 96.3, 101.7 and 107.2, 125.7, 127.5, 129.2, 131.5, 135.9,
138.9, 139.4, 145.9, 155.3, 175.3.
10, C42H68ClNO9S2Si. EIMS: M+ 857, m/ z 800 (M-57)+,
725 (M-132)+. 1H NMR (250 MHz, CDCl3) δ: 0.03 (3H, s),
0.06 (3H, s), 0.84 (9H, s), 0.91 (3H, d, J ) 7 Hz), 1.62 (3H, s),
1.72 (3H, d, J ) 1 Hz), 1.90-3.10 (8H, m), 2.20 (1H, dd, J )
15, 7 Hz), 2.39 (1H, ddd, J ) 15, 5 Hz, 2 Hz), 2.63 (1H, ddd, J
) 15, 8, 2 Hz), 3.18 (3H, s), 3.29 (3H, s), 3.33 (2H, s), 3.36 (3H,
s), 3.42-3.95 (6H, m), 3.63 (3H, s), 3.89 (3H, s), 4.50 (1H, dd,
J ) 8, 5 Hz), 4.76 and 4.86 (2H, AB, J ) 7.5 Hz), 5.51 (1H, d,
J ) 9.5 Hz), 5.80 (1H, dd, J ) 15, 9 Hz), 5.98 (1H, d, J ) 11
Hz), 6.42 (1H, dd, J ) 15, 11 Hz), 6.68 (2H, s), 9.72 (1H, t, J
) 2 Hz).
11, C41H66ClNO7S2Si. EIMS: M+ 811. 1H NMR (250 MHz,
CDCl3) δ: 0.02 (3H, s), 0.06 (3H, s), 0.89 (9H, s), 1.06 (3H, d,
J ) 6 Hz), 1.20 (3H, t, J ) 7 Hz), 1.22 (3H, t, J ) 7 Hz), 1.65
(3H, s), 1.72 (3H, s), 1.75-2.90 (11H, m), 3.20 (3H, s), 3.3 (2H,
s), 3.42-3.90 (5H, m), 3.64 (3H, s), 3.89 (3H, s), 4.12 (1H, dd,
J ) 8, 5 Hz), 4.43 (1H, d, J ) 7.5 Hz), 4.53 (1H, dd, J ) 5, 7
Hz), 5.12 (1H, d, J ) 10 Hz), 5.78 (1H, dd, J ) 15, 7.5 Hz),
5.99 (1H, d, J ) 11 Hz), 6.62 (1H, dd, J ) 15, 11 Hz), 6.69
(2H, s).
12, C37H56ClNO6S2Si. EIMS: M+ 737, m/ z 680, 605. 1H
NMR (250 MHz, CDCl3) δ: 0.05 (3H, s), 0.07 (3H, s), 0.86 (9H,
s), 1.06 (3H, d, J ) 7 Hz), 1.67 (3H, s), 1.72 (3H, d, J ) 1 Hz),
1.90-2.95 (9H, m), 2.44 (1H, ddd, J ) 15, 5, 2.5 Hz), 2.64 (1H,
ddd, J ) 15, 7.5, 2.5 Hz), 3.19 (3H, s), 3.34 (2H, s), 3.64 (3H,
s), 3.87 (3H, s), 4.42 (1H, d, J ) 8 Hz), 4.50 (1H, dd, J ) 7.5,
5 Hz), 5.26 (1H, d, J ) 10 Hz), 5.76 (1H, dd, J ) 15, 8 Hz),
5.99 (1H, d, J ) 11 Hz), 6.60 (1H, dd, J ) 15, 11 Hz), 6.69
(2H, s), 9.77 (1H, t, J ) 2.5 Hz).
(3S,6S,7S,10R)-17-[1,1-Diet h oxy-3-h yd r oxy-7-[(m et h -
oxyeth oxy)m eth oxy]-4,6,14-tr im eth yl-10-m eth oxy-9-(1,3)-
d ith ia n -2′-ylp en ta d eca -4,11,13-tr ien yl]-18-(N-m eth yl-N-
car bom eth oxyam ido)]-19-ch lor o-20-m eth oxyben zen e (13).
Tetrabutyl ammonium fluoride (142 mg 0.54 mmol) was added
to a solution of 9 (432 mg, 0.46 mmol) in THF (20 mL). This
mixture was warmed to 50 °C for 48 h. After addition of water,
standard workup led to a residue that afforded, after flash
chromatography, 13 (326 mg, 86%) as a colorless oil. [R]D: +32
(CHCl3, c ) 2.8). Anal. Calcd for C40H64ClNO10S2. EIMS: M+
817, m/ z 800, 772. 1H NMR (250 MHz, CDCl3) δ: 0.96 (3H,
d, J ) 7 Hz, C(6)-CH3), 1.21 (6H, t, J ) 7 Hz, 2 OCH2CH3),
1.65 (3H, s, C(4)-CH3), 1.73 (3H, d, J ) 1 Hz, C(14)-CH3), 1.83-
2.05 (4H, m, C(2)-H2, SCH2CH2), 2.01 (1H, dd J ) 15 Hz, 6
Hz, C(8)-Ha), 2.21 (1H, dd, J ) 15 Hz, 2 Hz, C(8)-Hb), 2.78
(3H, m, SCH2, C(6)-H), 2.96 (2H, m, SCH2), 3.19 (3H, s, NCH3),
3.31 (3H, s, OCH3), 3.33 (2H, broad s, C(15)-H2), 3.37 (3H, s,
OCH3), 3.40 -3.90 (9H, m, 4 OCH2 and C(7)-H), 3.63 (3H, bs,
CO2CH3), 3.90 (3H, s, C(20)-OCH3), 3.93 (1H, d, J ) 8 Hz,
C(10)-H), 4.16 (1H, dd, J ) 3, 8 Hz, C(3)-H), 4.63 (1H, t, J )
5 Hz, C(1)-H), 4.76 and 4.91 (2H, AB, J ) 7 Hz, OCH2O), 5.46
(1H, d, J ) 9 Hz, C(5)-H), 5.75 (1H, dd, J ) 15, 8 Hz, C(11)-
H), 5.98 (1H, d, J ) 11 Hz, C(13)-H), 6.48 (1H, dd, J ) 15, 11
Hz, C(12)-H), 6.70 (2H, s, C(17)-H and C(21)-H). 13C NMR,
(CDCl3) δ: 12.0 (C(4)-CH3), 15.3 and 15.4 (2 CH2CH3), 15.8
(C(6)-CH3), 16.6 (C(14)-CH3), 24.7 (SCH2CH2), 26.6 and 26.7
(2 SCH2), 37.0 (C-6 and NCH3), 38.8 and 38.9 (C-8 and C-2),
46.0 (C-15), 53.0 (OCH3), 55.7 (C-9), 56.4 (C(20)-OCH3), 57.2
(OCH3), 58.9 (OCH3), 61.3 and 62.0 (2 OCH2CH3), 67.8 and
71.8 (OCH2CH2O), 74.1 (C-3), 79.7 (C-7), 88.6 (C-10), 96.0
(OCH2O), 101.8 (C-1), 111.6 (C-21), 119.1 (C-19), 121.5 (C-17),
126.2 (C(13), 128.0 (C-11), 128.6 (C-5), 131.0 (C-12), 136.9 and
137.6 (2 C), 139.4 (C16), 141.2 (C18), 156.8 and 157.1 (C-20
and CdO).
Ma cr ocycliza tion . La cta m 17. 16 (115 mg, 0.14 mmol)
and tri-n-butylamine (83 mg, 3.2 equiv) in dry CH2Cl2 (100
mL) were added over ca. 10 h to a well-stirred suspension of
2-chloro-1-methylpyridinium iodide (107 mg, 3 equiv) in
CH2Cl2 (30 mL) at 32 °C. After complete addition, the mixture
was stirred, at this temperature, for 16 h, and then cooled to
rt and diluted with ether. The organic phase was washed with

7138 J . Org. Chem., Vol. 61, No. 20, 1996
Be´ne´chie and Khuong-Huu
brine, dried, and concentrated in vacuo. The residue was
chromatographed over silica gel (toluene/AcOEt: 9/1) to afford
17 (74 mg, 66%) in addition to 16 (8 mg).
successively with brine and water, dried, and concentrated.
The residue was chromatographed by passing on a silica gel
column, eluting with ether/AcOEt, 3/1, giving 4,5-deoxymay-
tansinol (22) (3 mg, 29% for two steps). HR CIMS, for
C28H37ClN2O7: (MH)+ found 549.2328, calcd 549.2367.
CIMS: MH+ 549, m/ z 488, 455. IR (CHCl3), ν (cm-1): 3370-
3260 (NH), 1710 and 1655 (CdO), 1575. 1H NMR (400 MHz,
CDCl3) δ: 1.05 (1H, t, J ) 13 Hz, C(8)-Ha), 1.16 (3H, d, J ) 6
Hz, C(6)-CH3), 1.32 (3H, s, C(4)-CH3), 1.69 (1H, d, J ) 14 Hz),
1.81 (3H, d, J ) 1 Hz, C(14)-CH3), 2.21 (1H, dd, J ) 16, 2 Hz,
C(2)-Ha), 2.45 (1H, m, C(6)-H), 3.20 (3H, s, NCH3), 3.33 (3H,
s, C(10)-OCH3), 3.39 (1H, d, J ) 13 Hz, C(15)-Hb), 3.46 (1H, d,
J ) 8.5 Hz, C(10)-H), 3.97 (3H, s, C(20)-OCH3), 4.23 (2H, m),
5.21 (1H, broad s), 5.42 (2H, m, C(5)-H) and C(11)-H), 5.92
(1H, d, J ) 11 Hz, C(13)-H), 6.14 (1H, broad s, NH), 6.37 (1H,
dd, J ) 15, 11 Hz, C(12)-H), 6.71(1H, d, J ) 1.5 Hz, C(17)-H),
6.82 (1H, d, J ) 1.5 Hz, C(21)-H). 13C NMR (CDCl3) δ: 14.3
(CH3), 16.7 (C(14)-(CH3), 17.3 (CH3), 34.8 (CH2), 35.8 (NCH3),
37.6 (C-6), 38.8 (CH2), 46.5 (C-15), 56.5 (OCH3), 56.6 (OCH3),
70.8 (C-3), 77 6 (C-7), 81.5 (C-9), 89.1 (C-10), 112.6 (C-21), 118.8
(C-19), 121.6 (C-17), 124.2 (C-5), 124.3 (C-13), 126.3 (CH), 132.7
(CH), 136. 0 (C-4), 139.6 (C-16), 140.4 (C-14), 141.7 (C-18),
152.8 (CdO), 156.1 (C-20), 175.3 (C-1).
Ma yta n sin ol (1). A solution of 2,6-lutidine (100 µL, 2 ×
10-2 mmol) in dry toluen was added, at 0 °C, to 22 (1.7 mg, 3
× 10-3 mmol) in toluene (3 mL). Then, anhydrous t-Bu-OOH
(3 × 10-3 mmol) in toluene (100 µL) and VO(acac)2 (20 µL of
a 0.1% solution in toluene) were added. This well-stirred
mixture was allowed to warm to rt. Then ten 10 µL portions
of the VO(acac)2 solution were successively every 1 h, while
five portions of t-BuOOH (10-3 mmol) were added every 2 h.
After 24 h, analysis of the crude mixture using MS (FAB)
showed starting material in addition to maytansinol. Lutidine
(10-2 mmol), t-BuOOH (5 × 10-3 mmol), and the VO(acac)2
solution were added again as previously described. After 24
h, MS analysis showed almost no starting material left, and
the crude solution was poured on a silica gel column. Elution
(AcOEt/Heptane) led to the maytansinol (1) (0.8 mg, 45%)
identical to reference sample. [R]D: -185 (CHCl3, c ) 0.09).
C28H37ClN2O8. MS (FAB, thio + NaCl), m/ z 589, 587 (M +
Na)+. UV, λmax (nm (EtOH)): 250.4 (ꢀ ) 27 000), 279 and 285
(ꢀ ) 6500). IR (CHCl3), ν (cm-1): 3375 (NH), 1709 and 1656
(CdO), 1581. 1H NMR (400 MHz, CDCl3) δ: 0.84 (3H, s, CH3),
1.29 (3H, s, CH3), 1.54 (3H, s, CH3), 1.68 (3H, s, CH3), 2.14
(2H, broad s), 2.28 (1H, dd, J ) 11 Hz, 13 Hz), 2.56 (1H, d, J
) 10 Hz), 3.13 (1H, d, J ) 12 Hz), 3.21 (3H, s, NCH3), 3.36
(3H, s, OCH3), 3.46 (1H, d, J ) 12 Hz), 3.50 (1H, d, J ) 9 Hz),
3.55 (1H, m), 3.99 (3H, s), 4.34 (1H, broad t), 5.52 (1H, dd),
6.15 (1H, d, J ) 11 Hz), 6.29 (1H, broad s), 6.46 (1H, dd, J )
15, 11 Hz), 6.11 (1H, d, J ) 1 Hz), 6.97 (1H, d, J ) 1 Hz). 13C
NMR (CDCl3) δ: 11.5, 14.65, 15.95, 35.25, 35.85, 35.95, 37.95,
47.05, 56.65, 62.8, 66.2, 75.2, 75.7, 81.2, 88.6, 112.7, 123.3,
124.9, 127.1, 133.3, 139.55, 140.2, 142.2, 152.5, 171.2. C(19)
is missing.
17. HR EIMS for C40H64ClNO7SiS2: M+ calcd 797.3582,
found 797.3556. EIMS: M+ 797, m/ z 782, 740, 559. IR, ν
cm-1: 1662 and 1575 (CdO). 1H NMR (300 MHz,CDCl3) δ
for the major conformer: -0.07(3H, s), -0.04 (3H, s), 0.86 (9H,
s), 0.94 (3H, d, J ) 6 Hz,), 1.52 (3H, s), 1.86 (3H, d, J ) 1 Hz),
3.14 (3H, s), 3.33 (3H, s), 3.37 (3H, s), 3.92 (3H, s), 4.04 (1H,
d, J ) 7.5 Hz), 4.35 (1H, m), 4.81 and 4.91 (2H, AB, J ) 7 Hz),
5.3 (1H, m), 5.6 (2H, m), 6.46 (1H, dd, J ) 15, 11 Hz), 6.72
(1H, s), 6.76 (1H, s).
Clea va ge of th e MEM gr ou p . Com p ou n d 18. Freshly
prepared 2-chloro-1,3,2-dithioborolane22 (23 mg, 2.5 equiv) in
dry CH2Cl2 (1 mL) was added to a well-stirred solution of 17
(60 mg, 0.075 mmol) in dry CH2Cl2 (5 mL) at -78 °C. The
mixture was kept at -60 °C for 2 h. Then saturated aqueous
solutions of NH4Cl (1 mL) and (NH4)2CO3 (2 mL) were added
successively. The mixture reached rt over ca. 1 h. After
addition of ether, standard workup gave a residue that was
chromatographed on silica gel (heptane/ether: 2/1) to afford
two compounds (46 mg), 18 (53%) and 19 (29%). 18, C36H56
-
ClNO5SiS2. EIMS: M+ 709, m/ z 691, 677, 652, 620, 559. 1H
NMR (250 MHz,CDCl3) δ for the major conformer: -0.05 (3H,
s), 0.01 (3H, s), 0.86 (9H, s), 0.99 (3H, d, J ) 6 Hz), 1.56 (3H,
s), 1.94 (3H, d, J ) 1 Hz), 3.17 (3H, s), 3.36 (3H, s), 3.93 (3H,
s), 5.22 (1H, m), 5.48 (2H, m), 6.54 (1H, dd, J ) 15, 11 Hz),
6.69 (1H, s), 6.77 (1H, s).
19, C39H62ClNO5SiS4. EIMS: M+ 815, m/ z 800 (M - 15)+,
758 (M - 57)+, 691, 559. 1H NMR (250 MHz, CDCl3) δ for the
major conformer: 0.0 (3H, s), 0.02 (3H, s), 0.84 (9H, s), 0.93
(3H, d, J ) 6 Hz), 1.50 (3H, s), 1.88 (3H, d, J ) 1 Hz), 3.16
(3H, s), 3.31 (3H, s), 3.93 (3H, s), 4.0 (1H, d, J ) 6 Hz), 4.38
(1H, m), 4.60 and 4.90 (2H, AB, J ) 10 Hz), 5.29 (1H, d, J )
9 Hz), 5.51 (2H, m), 6.46 (1H, dd, J ) 15, 11 Hz), 6.72 (1H, s),
6.76 (1H, s).
P r ep a r a t ion of Ca r b a m a t e 20. p-Nitrophenyl chloro-
formate (50 mg, 0.25 mmol, 9.2 equiv) in CH2Cl2 (0.5 mL) was
added to a solution of 18 (19 mg, 0.027 mmol) in CH2Cl2 (1
mL) and pyridine (1 mL) at 0 °C. After 24 h at rt, a saturated
methanolic solution of ammonia (5 mL) was added. The
mixture was stirred for 14 h at rt. After concentration in
vacuo, the residue was dissolved in ether (40 mL). After
standard workup the solid material that was obtained was
chromatographed (SiO2, eluent pentane/ether 1:1) to give to
the carbamate 20 (15 mg, 75%), C37H57ClN2O6SiS2. EIMS: M+
752, m/ z 737 (M - 15)+, 695 (M - 57)+, 691 [M - (H2NCO2H)]+,
559 [M - (132+18)]+. 1H NMR (250 MHz, CDCl3) δ for the
major conformer: -0.05 (3H, s), 0.00 (3H, s), 0.88 (9H), 0.93
(3H, d, J ) 6 Hz), 1.46 (3H, s, CH3), 1.89 (3H, d, J ) 1 Hz),
3.14 (3H, s), 3.33 (3H, s), 3.91 (3H, s), 6.40 (1H, dd, J ) 15, 11
Hz), 6.67 (1H, s), 6.70 (1H, s).
3-O-(ter t-Bu tyldim eth ylsilyl)-4,5-deoxym aytan sin ol (21).
CaCO3 (30 mg, 033 mmol) and HgCl2 (30 mg, 0.11 mmol) were
added to a solution of 20 (14 mg, 0.0186 mmol) in CH3CN/
H2O (3 mL, 5/1). This mixture was stirred for 18 h at rt. The
addition of diisopropylethylamine (0.1 mL) was followed after
30 min by that of an aqueous solution of Na2S (2%, 1 mL),
giving a black precipitate. After 30 min, dilution with AcOEt,
filtration through a Celite pad, and standard workup gave,
after filtration (silica gel), an impure cyclic carbamate (8 mg),
which was desilylated without further purification.
Ack n ow led gm en t. We thank Dr. Wright and Pro-
fessor A. Sneeden for providing us with samples of
maytansine and Mr. J . F. Gallard and Mrs. M. T. Martin
for the registration and interpretation of HMBC experi-
ments, and Professor P. Potier is acknowledged for his
encouragement.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for 3,
4, 7-20, 22, and 1 (18 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
4-Deoxym a yta n sin ol (22). Aqueous HF (48%, 70 µL) was
added to a solution of 21 (8 mg, 0.012 mmol). This mixture
was stirred for 2 h at rt, neutralized with solid Na2CO3, and
diluted with AcOEt (20 mL). The organic phase was washed
(22) Finch, A.; Pearn, J . Tetrahedron 1964, 20, 173-176.
J O960363A