Stereocontrolled synthesis of a nonracemic vitamin B12 A-B semicorrin

Article abstract of DOI:10.1021/ja9700515

The first synthesis of a vitamin B₁₂ A-B semicorrin 44 is described. Both A and B rings were prepared from the same precursor, enamide 40, which is obtained by a sequence of sigmatropic rearrangements and a biomimetic oxylactonization. The coup

Full text of DOI:10.1021/ja9700515

5512
J. Am. Chem. Soc. 1997, 119, 5512-5518
Stereocontrolled Synthesis of a Nonracemic Vitamin B12
A-B-Semicorrin
Johann Mulzer,*,† Benjamin List,‡ and Jan W. Bats‡
Contribution from the Institut fu¨r Organische Chemie der UniVersita¨t Wien, Wa¨hringerstrasse 38,
A-1090 Wien, Austria, and Institut fu¨r Organische Chemie der Johann Wolfgang
Goethe-UniVersita¨t, Marie Curie Strasse 11, D-60439 Frankfurt am Main, Germany
ReceiVed January 6, 1997X
Abstract: The first synthesis of a vitamin B12 A-B-semicorrin 44 is described. Both A and B rings were prepared
from the same precursor, enamide 40, which is obtained by a sequence of sigmatropic rearrangements and a biomimetic
oxylactonization. The coupling has been achieved via Eschenmoser sulfide contraction. A-B-semicorrin 44 allows
a new approach toward vitamin B12 and other uroporphinoids.
Vitamin B12 (1) belongs to the family of the uroporphinoid
cofactors, the so-called “pigments of life”,1,2 which includes such
vital substances as chlorophyll a (4), used by plants in
photosynthesis, and heme (7), the red blood pigment which is
essential for oxygen transport. Other members of this family
are siroheme (6), which has been discovered in sulfite and nitrite
reductases of bacteria and plants, and the nickel-containing
factor F 430 (5), the prosthetic group for the coenzyme M
reductase of primitive methanogenic bacteria (Figure 2).3
The cobalamins (1), methylcobalamin (2), and coenzyme B12
(3) (Figure 1) contain a reduced tetrapyrrole, the corrin macro-
cycle, which is less symmetric than porphyrin and characterized
by the direct junction of rings A and D. The ligand is decorated
with methyl, acetamide, and propionamide substituents. This
creates the situation in which nine of the 10 sp3 carbons are
stereogenic centers, with three of them being quaternary.
After the brilliant and extensive studies by R. B. Woodward
and A. Eschenmoser, culminating in the first two total syntheses4
of 1 and in the discovery of the Woodward-Hoffmann rules,5
no further synthesis has been achieved, despite promising
approaches by Stevens and Jacobi.6 In this paper, we wish to
disclose our own work in this area, which led to the first
synthesis of a northern (A-B) vitamin B12 semicorrin.
Figure 1. Vitamin B12 and its coenzymatic forms.
Results and Discussion
Strategy and Retrosynthetic Analysis. The A-B Strategy.
It is known from the work of Bernauer et al.7 that cobyric acid
(8), a corrinoid natural product and biosynthetic intermediate
† Universita¨t Wien.
‡ Universita¨t Frankfurt.
X Abstract published in AdVance ACS Abstracts, June 1, 1997.
(1) Zagalak, B., Friedrich, W., Eds. Vitamin B12; Proceedings of the 3rd
European Symposium on Vitamin B12 and Intrinsic Factor; Walter de
Gruyter: Berlin, 1979.
(2) Battersby, A. R. Science 1994, 264, 1551-1557.
(3) Montforts, F.-P.; Gerlach, B.; Ho¨per, F. Chem. ReV. 1994, 94, 327-
347 and references therein.
(4) (a) Woodward, R. B. Pure Appl. Chem. 1968, 17, 519. (b)
Woodward, R. B. ibid. 1971, 25, 283. (c) Woodward, R. B. ibid. 1973,
33, 145. (d) Eschenmoser, A.; Winter, C. E Science 1977, 196, 1410-
1420. For a brilliant review, see: Nicolaou, K. C.; Sorensen, E. J. Classics
in Total Synthesis; VCH: Weinheim, Germany, 1996; pp 99-136.
(5) (a) Woodward, R. B. Spec. Publ. Chem. Soc. 1967, 21, 217. (b)
Woodward, R. B.; Hoffmann R. Angew. Chem., Int. Ed. Engl. 1969, 8,
781.
Figure 2. Uroporphinoid cofactors: “the pigments of life”.
(6) (a) Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.;
Takeda, T.; Waldner, A.; Williard, P. G.; Zutter, U. J. Am. Chem. Soc.
1986, 108, 1039-1049 and references therein. (b) Jacobi, P. A.; Brielmann,
H. L.; Hauck, S. I. J. Org. Chem. 1996, 61, 5013-5023.
of 1, can be transformed into the vitamin. In view of the
structural similarities of the A-B part in 1, 6, and 5, we use a
convergent and flexible A-B + C-D strategy, which could
S0002-7863(97)00051-6 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Nonracemic Vitamin B12 A-B-Semicorrin
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5513
Scheme 1
Scheme 2
Scheme 3. Eschenmoser’s Synthesis of Ring A and B
Fragments
give access to all of these compounds by only varying the C-D
portion. Furthermore, Eschenmoser’s photoinduced A-D-
secocorrin cyclization4d,8 is perfectly suited to solve the “zero-
linkage problem”, i.e. the direct junction of rings A and D in 1.
This leads to the A-D-secocorrin 9 as a precursor. Further
bond disconnection between rings B and C gives A-B-
semicorrin 10. Interestingly semicorrin 11 has been used to
synthesize model isobacteriochlorin 12.9 Analogously, 10 could
be used in a synthesis of 6, besides the synthesis of 9 and 8
(Scheme 1).
Retrosynthetic Analysis of 10. Both rings, A and B, contain
a quaternary stereogenic center, bearing an acetate and a methyl
group vicinal to a tertiary stereogenic center with a propionate
side chain. They should therefore be accessible from the same
intermediate, namely enamide 14. This reduces the synthesis
of semicorrin 10 to a synthesis of enamide 14 and its dimer-
ization (Scheme 2).
Interestingly, such an approach could have also been realized
Via Eschenmoser’s synthesis of the ring fragments A and B as
outlined in Scheme 3.4d
Although this has never been attempted, the A and B rings
could in principle be connected by means of a sulfide contraction
between enamide 18 and thioamide 19 (Vide infra). However,
under the acidic conditions which are required in the oxidative
precoupling to the sulfide, it is likely that the methyl ester in
18 exerts a neighbouring group effect and recyclizes to lactone
17 via an acyl iminium intermediate. Moreover, the Eschen-
moser approach has three additional drawbacks: (a) it includes
optical resolution on the stage of carboxylic acid rac-15, which
implies a considerable loss of material; (b) the two stereogenic
centers in 18 and 19 are configurationally not independent, as
they are generated by the initiating Diels-Alder reaction; (c)
the side chains in 18 and 19 are not easily variable with respect
to chain length and functionalization.
Therefore, we decided to use a different approach to ring A
and B fragments which is based on lactic acid as the source of
chirality and utilizes sigmatropic rearrangements to establish
the crucial tertiary and quaternary stereogenic centers (Scheme
4). In this way, the sequence is more flexible, predictable with
respect to absolute configurations and optical purity, and does
(7) (a) Friedrich, W.; Gross, G.; Bernauer, K.; Zeller, P. HelV. Chim.
Acta 1960, 43, 704. (b) Friedrich, W. 2. Europa¨isches Symposium u¨ber
Vitamin B12u. Intrinsic Factor 2.-5, August 1961; Enke Verlag: Stuttgart,
Germany, 1962; pp 8ff.
(8) (a) Yamada, Y.; Milijkovic, D.; Wehrli, P.; Golding, B.; Lo¨linger,
P.; Keese, R.; Mu¨ller, K.; Eschenmoser, A. Angew. Chem. 1969, 81, 301-
306.
(9) (a) Ofner, S.; Rasetti, V.; Zehnder, B.; Eschenmoser, A. HelV. Chim.
Acta 1981, 64, 1431. (b) Montforts, F.-P.; Ofner, S.; Rasetti, V.;
Eschenmoser, A.; Woggon, W. D.; Jones, K.; Battersby, A. R. Angew. Chem.
1979, 91, 752.

5514 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Mulzer et al.
Scheme 4
Scheme 6
Scheme 7
Scheme 5
functionalized analogues of 23 and, hence, semicorrin 10. As
semicorrins have found widespread applications as chiral
catalysts,14 this is of interest also beyond the synthesis of 1.
We have shown that tetrasubstituted homoallylic alcohols can
be formed (E)-stereoselectively Via [2,3]-Wittig-Still sigma-
tropic rearrangement15 from trisubstituted allylic alcohols.13c
Thus, alcohol 23 was converted to the stannylmethyl ether 24
on treatment with potassium hydride and tri-n-butyl (iodo-
methyl)stannane.16 Tin-lithium exchange of stannylmethyl
ether 24 with n-butyllithium and subsequent [2,3]-Wittig-Still
rearrangement at low temperature furnished the tetrasubstituted
homoallylic alcohol (E)-25 with an E/Z ratio > 100:1. The
double-bond configuration was assigned by NOEDS measure-
ment on the minor isomer (Z)-25. The stereochemical outcome
of this reaction can be explaned with transition state TS2, where
allylic 1,3-strain interactions are minimized (Scheme 6). A
related transition state has recently been proposed by Kallmerten
in the synthesis of trisubstituted olefins.17
not require optical resolution. It also overcomes the problem
of reactive side chain functionalities, as they are introduced as
protected alcohols. Hence, enamide 14 could be prepared from
allyl diol 16 Via [3,3]-Claisen rearrangement for the construction
of the quaternary center and a [2,3]-Wittig rearrangement for
the tertiary center. Allyl diol 16 in turn could be elaborated
from enone 22.
Synthesis. For the synthesis of enone 22, we used a novel
one-pot three-component synthesis of R,â-unsaturated ketones
which has been developed in our laboratories.10 Thus, treatment
of the known lactic ester derivative 2011 with diethyl 1-(lithio-
ethyl)phosphonate and then with water and aldehyde 21 (from
1,4-butanediol Via monotritylation and Swern oxidation, see
Supporting Information) gave enone 22 in 58% yield, as a
single diastereomer (1H and 13C NMR). Presumably, this new
Corey-Kwiatkowski12 Horner-Wadsworth-Emmons tandem
reaction, which creates two carbon-carbon bonds in one
operation, proceeds Via a â-keto phosphonate carbanion. Treat-
ment of enone 22 with methyl magnesium chloride at low
temperature gave exclusively the anti-allylic alcohol 23 (from
NOEDS of an acetonide) in high yield. The high selectivity
can be interpreted in terms of the chelate Cram model (TS1)
(Scheme 5).13
Alcohol (E)-25 was converted to 27,18 which underwent a
highly effective and stereoselective Eschenmoser Claisen rear-
rangement19 under mild conditions, to give the γ,δ-unsaturated
amide 28 as a single diastereomer.20 The stereochemical
outcome of this reaction can be interpreted in terms of a chairlike
transition state TS3 (Scheme 8), in which allylic 1,3-strain
interactions are minimized.17a Interestingly this reaction was
originally designed by Eschenmoser for the creation of exactly
the same quaternary stereogenic center in an intended vitamin
B12 synthesis but was not used in the final synthesis. To our
disappointment neither amide 28 nor ether 29 could be oxidized
to the desired ketone 30, presumably a result from the sterical
Quite obviously, this connective assemblage of alcohol 23
from simple components (R-hydroxy ester + aldehyde +
Grignard reagent) allows the formation of a wide variety of
(14) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339.
(15) Still, W. C.; Mitra, A.; J. Am. Chem. Soc. 1978, 100, 1927.
(16) Seyferth, D.; Andrews, S. B. J. Organometal. Chem. 1971, 30, 151-
166. Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481-1487.
(17) (a) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1869. (b)
Wittman, M. D.; Kallmerten, J. J. Org. Chem. 1988, 53, 4631-4635.
(18) (a) Kozikowski, A. P.; Wu, J.-P. Tetrahedron Lett. 1987, 28, 5125-
5128. (b) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
(10) Mulzer, J.; Martin, H. J.; List, B. Tetrahedron Lett. 1996, 37, 9177-
9178.
(11) Burke, S. D.; Lee, K. C.; Santafianos, D. Tetrahedron Lett. 1991,
32, 3957-3960.
(12) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654.
(13) (a) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74,
5828-5835. (b) Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980,
21, 1031. (c) Mulzer, J.; List, B. Tetrahedron Lett. 1994, 35, 9021-9024.
(19) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HelV. Chim.
Acta 1964, 47, 2425.
(20) Assigned from NOEDS measurements.

Synthesis of Nonracemic Vitamin B12 A-B-Semicorrin
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5515
Scheme 8
Scheme 11
Scheme 9
Scheme 12
Scheme 10
yield from lactone 34. The absolute and relative configurations
of the stereogenic centers in 36 were determined by single-
crystal X-ray diffraction (Figure 3, Supporting Information).
After deprotection (TBAF) and in situ oxidation (PDC) of
ketone 36, keto acid 37 was obtained (Scheme 11). To introduce
nitrogen, 37 was dehydrated to the corresponding enol lactone.24
This is usually achieved under harsh conditions (for example,
H2SO4, Ac2O, HOAc).25 Much to our surprise, we found this
transformation to proceed quite readily on treating acid 37 with
MsCl and Hu¨nig’s base. At 0 °C enol lactone 38 is quantita-
tiVely formed within minutes. The reaction presumably proceeds
Via the mixed anhydride.
From 38, enamide 40 was then prepared with ammonia26 and
by dehydrating the intermediate keto amide 39 in vacuo. Amide
40, which is both the precursor for rings A and B, is sensitive
to moisture and is rehydrolyzed to 39. Therefore it was not
isolated and used directly for the next steps.
Dimerization of Enamide 40 Wia Sulfide Contraction. The
sulfide contraction was originally developed by Eschenmoser
during the synthesis of vitamin B1227,4a because the more obvious
imino ether enamine condensation, which proved to be very
successful in model studies, failed with vitamin B12 intermedi-
ates (Scheme 12). In principle, both reactions represent aza
analogous Claisen condensations, the sulfide contraction being
an intramolecular version.
For the synthesis of ring A precursor 42, the exocyclic double
bond in enamide 40 was first protected as cyano lactam,26,28
which was in situ treated with Lawesson’s reagent,26 to furnish
thio lactam 42 in 88% yield from keto amide 39 (Scheme 13).
Thio lactam 42 was produced as a mixture of diastereomers
(6:1, NMR) in favor of the (2R)-isomer, which was confirmed
by NOEDS of the final product. According to the protocol
developed by Eschenmoser et al.,27 treatment of a mixture of
enamide 40 and thio lactam 42 with benzoyl peroxide gave the
stable sulfide 43 which was isolated in 56% yield. This reaction
is presumably initiated by the formation of disufide (42)2, which
shielding of the adjacent quaternary center. A new route had
to be found (Scheme 7).
On considering the biosynthesis of vitamin B12,21 we noticed
that nature has to solve a similar problem (Scheme 9). The
crucial ring contraction step, from precorrin-3A (31) to precor-
rin-6A (33) is initiated by an oxygenase (CobG) converting 31
into precorrin-3B ()3×) (32), which chemically represents an
olefin oxy-lactonization. This gave us the idea to mimic the
CobG step by converting amide 28 to the corresponding hydroxy
lactone Via an epoxidation reaction.22
Indeed, treatment of amide 28 with m-chloroperbenzoic acid
furnished hydroxy lactone 34 as a mixture of diastereomers (2:
1, structural assignment by NOEDS of the isolated isomers) in
high yield (Scheme 10). Reduction (LAH), tritylation of the
primary alcohol function of the resulting triol (35),23 and in situ
glycol cleavage with Pb(OAc)4 gave ketone 36 in 72% overall
(21) Review on the biosynthesis of vitamin B12: Blanche, B.; Cameron,
B.; Crouzet, J.; Debussche, L.; Thibaut, D.; Vuilhorgne, M.; Leeper, F. J.;
Battersby, A. R. Angew. Chem. 1995, 107, 421-452. The oxidative
sequence shown in Scheme 9 was first described by: Spencer, J. B.;
Stolowich, N. J.; Roessner, C. A.; Min, C.; Scott, A. I. J. Am. Chem. Soc.
1993, 115, 11610-11611. The configuration at C-20 (tertiary alcohol) of
precorrin-3x was assigned by: J. B.; Stolowich, N. J.; Wang, J.; Spencer,
J. B.; Santander, P. J.; Roessner, C. A.; Scott, A. I. J. Am. Chem. Soc.
1996, 118, 1657-1662.
(22) Ichikawa, Y.-i.; Miwa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1985,
58, 3309-3311.
(23) Mulzer, J.; Kirstein, H. M.; Buschmann, J.; Luger, P. J. Am. Chem.
Soc. 1991, 113, 910-923.
(24) Amos, R. A.; Katzenellenbogen, J. A. J. Org. Chem. 1978, 43, 560-
564 and references therein.
(25) Shaw, E. J. Am. Chem. Soc. 1946, 68, 2510.
(26) Struve, D. Dissertation, Universita¨t Bremen, 1994.
(27) Fischli, F.; Eschenmoser, A. Angew. Chem. 1967, 79, 865.
(28) Wehrli, P. Dissertation, ETH-Zu¨rich, Austria, 1967.

5516 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Mulzer et al.
Scheme 13
and a novel, very mild procedure for the enol lactonization of
keto acids have been developed during this investigation. The
oxidation of the side chains to carboxylates has been reported.6b
With substantial quantities of 44 at hand, we feel in a good
position to complete total syntheses of siroheme (6), cobyric
acid (8), and finally vitamin B12 (1).
Experimental Section
(2R,3S,4E)-2-(((4-Methoxybenzyl)oxy)methoxy)-3,4-dimethyl-8-
(trityloxy)oct-4-en-3-ol (23). A cooled (-78 °C) solution of 9.30 g
(16.47 mmol) of enone 22 in 50 mL of dry THF under argon was treated
with 10 mL (30.00 mmol) of methyl magnesium chloride (3 M in THF).
After 30 min, 3 mL of saturated aqueous NH4Cl were added and the
mixture was warmed to room temperature (rt), dried (MgSO4), filtered,
and concentrated. Column chromatography (10:1 hexane/EtOAc) gave
Scheme 14
9.23 g (96%) of allylic alcohol 23 as a clear oil: [R]20 ) -17.7° (c
D
1
1.15, CHCl3); IR (thin film) 3567, 1491, 1449 cm-1; H NMR (250
MHz, CDCl3) δ 0.97 (d, J ) 6.3, 3H), 1.30 (s, 3H), 1.53 (d, J ) 1.0,
3H), 1.70 (m, 2H), 2.13 (m, 2H), 3.05 (t, J ) 6.5, 2H), 3.72 (q, J )
6.3, 1H), 3.80 (s, 3H), 4.54 (d, J ) 11.4, 1H), 4.59 (d, J ) 11.4, 1H),
4.75 (d, J ) 7.1, 1H), 4.82 (d, J ) 7.1, 1H), 5.55 (dt, J ) 1.0, 7.2,
1H), 6.88 (m, 2H), 7.17-7.21 (m, 11H), 7.38-7.46 (m, 6H); 13C NMR
(63 MHz, CDCl3) δ 13.02, 14.27, 24.36, 25.55, 29.86, 55.16, 63.04,
69.35, 77.36, 86.24, 93.26, 113.80, 123.80, 126.73, 127.61, 128.59,
129.40, 129.66, 137.06, 144.37, 159.22; EIMS m/z 330 (1), 243 (100),
121 (45). Anal. Calcd for C38H44O5: C, 78.54; H, 7.64. Found: C,
78.50; H, 7.74.
(2R,3S,4E)-2-(((4-Methoxybenzyl)oxy)methoxy)-3,4-dimethyl-3-
(tri-n-butylstannyl)methoxy-8-(trityloxy)oct-4-ene (24). Potassium
hydride (1.51 g, 37.69 mmol, prewashed three times with 8 mL of dry
pentane), vigorously stirred in a separate flask with 20 mL of dry THF,
was transferred through a transfer needle to an ice cold solution of the
alcohol 23 (8.74 g, 15.06 mmol) in 80 mL of dry THF. of Dry DMPU
(7.8 mL), and after 20 min, (iodomethyl)tri-n-butyltin (16.22 g, 37.69
mmol) in 30 mL of dry THF were added. After 6 h at rt, the mixture
was cooled to 0 °C and carefully treated under argon with water and
ice. The organic layer was washed with water, and the combined
aqueous layers were extracted with hexane. The combined organic
layers were dried (MgSO4), filtered, and concentrated. Purification by
silica gel chromatography (40:1 hexane/EtOAc) afforded 10.23 g (77%)
of ether 24: [R]20D ) -5.8° (c 3.54, CHCl3); IR (thin film) 2954, 1491,
1449 cm-1; 1H NMR (250 MHz, CDCl3) δ 0.80-0.92 (m, 15H), 1.13
(d, J ) 6.3, 3H), 1.17 (s, 3H), 1.29 (mc, 6H), 1.43-1.53 (m, 6H), 1.55
(s, 3H), 1.70 (mc, 2H), 2.11-2.20 (m, 2H), 3.06 (d, J ) 9.5, 1H), 3.08
(t, J ) 6.5, 2H), 3.36 (d, J ) 9.5, 1H), 3.68 (q, J ) 6.3, 1H), 3.77 (s,
3H), 4.40 (d, J ) 11.4, 1H), 4.49 (d, J ) 11.4, 1H), 4.53 (d, J ) 7.2,
1H), 4.62 (d, J ) 7.2, 1H), 5.38 (t, J ) 6.2, 1H), 6.81-6.87 (m, 2H),
7.13-7.31 (m, 11H), 7.41-7.46 (m, 6H); 13C NMR (63 MHz, CDCl3)
δ -6.28, 8.79, 12.39, 13.73, 14.44, 15.17, 25.19, 27.33, 29.16, 30.05,
50.35, 55.21, 63.31, 68.79, 76.14, 83.16, 86.30, 93.40, 113.76, 126.79,
127.66, 128.65, 129.33, 130.16, 136.76, 144.42, 159.08; EIMS m/z 827
([M - Bu]+, 3), 689 (1), 371 (6), 291 (12), 243 (100), 121 (32). Anal.
Calcd for C51H72O5Sn: C, 69.31; H, 8.21. Found: C, 69.38; H, 8.18.
(2S,3E,5R)- and (2R,3Z,5R)-5-(((4-Methoxybenzyl)oxy)methoxy)-
3,4-dimethyl-2-(3-(trityloxy)propyl)hex-3-en-1-ol (25). A cold (-95
°C) solution of 9.94 g (11.27 mmol) of ether 24 in 70 mL of dry THF
was treated with 21.2 mL of n-BuLi (1.6 M in hexane, 33.85 mmol).
After 2 h, the mixture was warmed to -50 °C and treated with 5 mL
of saturated aqueous NH4Cl and 100 mL of diethyl ether. The mixture
was dried (MgSO4), filtered, and concentrated. Purification by silica
gel chromatography (5:1 hexane/EtOAc) afforded 6.20 g (10.43 mmol,
92%) of olefin (E)-25 and 61 mg (0.10 mmol, 0.9%) of (Z)-25, both
is cleaved by a nucleophilic attack from enamide 40. Thereby
thiolactam 42 is regenerated and can be oxidized with benzoyl
peroxide again. On being heated in benzene (sealed tube, 120
°C, 70 h), 43 was converted into A-B-semicorrin 44 in 90%
yield, as a mixture of four diastereomers (ca. 36:6:6:1, NMR
and HPLC analysis), probably arising from an epimerization
(6:1) at C-3, during the sulfide contraction.4d Diastereomerically
pure 44 was obtained in 67% yield after HPLC separation. The
structural assignment of A-B-semicorrin 44 is based on high-
field NMR (600 MHz ROESY, NOESY, COSY 90, 13C-1H-
COSY), IR and MS spectroscopy, and combustion analysis. An
obvious synthesis of siroheme from 44 is suggested in Scheme
14, which is based on the Eschenmoser synthesis of model
isobachteriochlorin 12.9
Conclusion. In this paper, we describe the first synthesis of
a vitamin B12 A-B-semicorrin (44). By starting from (R)-
isobutyl lactate, this synthesis requires only 16 isolated inter-
mediates. The total yield is 7%. Key steps are a sequence of
sigmatropic rearrangements, including a [2,3]-Wittig-Still
rearrangement for the construction of the tertiary stereogenic
centers and a [3,3]-Claisen-Eschenmoser rearrangement for the
quaternary centers. Furthermore, we made use of a biomimetic
oxylactonization process. The sulfide contraction was used for
the final coupling reaction between a B ring enamide (40) and
an A ring thio lactam (42), which has been prepared in a one-
pot procedure from a ring A enamide. The tandem Corey-
Kwiatkowski/Horner-Wadsworth-Emmons reaction,10 a new
and highly diastereoselective synthesis of tetrasubstituted olefins,13c
as clear oils. Data for (E)-25: [R]20 ) +70.5° (c 0.20, CHCl3); IR
D
1
(thin film) 3455, 1613, 1449 cm-1; H NMR (250 MHz, CDCl3) δ
1.21 (d, J ) 6.5, 3H), 1.23-1.53 (m, 4H), 1.55 (s, 6H), 2.83 (mc, 1H),
3.02 (mc, 2H), 3.46 (mc, 2H), 3.64 (s, 1H), 3.74 (s, 3H), 4.45 (d, J )
12.1, 1H), 4.49 (d, J ) 6.7, 1H), 4.60 (d, J ) 6.7, 1H), 4.61 (d, J )
12.1, 1H), 4.83 (q, J ) 6.5, 1H), 6.80-6.86 (m, 2H), 7.16-7.29 (m,
11H), 7.39-7.43 (m, 6H); 13C NMR (63 MHz, CDCl3) δ 11.23, 11.52,
19.16, 25.05, 27.65, 44.12, 55.07, 63.32, 64.67, 68.77, 69.95, 86.20,
91.00, 113.64, 126.70, 127.58, 128.52, 129.31, 130.04, 130.68, 133.32,

Synthesis of Nonracemic Vitamin B12 A-B-Semicorrin
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5517
144.25, 159.02; EIMS m/z 594 (M+, <0.1), 243 (100), 121 (87). Anal.
Calcd for C39H46O5: C, 78.76; H, 7.79. Found: C, 78.50; H, 7.86.
Data for (Z)-25: [R]20D ) +45.6° (c 1.00, CHCl3); 1H NMR (250 MHz,
CDCl3) δ 1.31 (d, J ) 6.5, 3H), 1.20-1.75 (m, 4H), 1.61 (d, J ) 0.9,
3H), 1.72 (d, J ) 0.9, 3H), 2.90-3.19 (mc, 3H), 3.50 (mc, 2H), 3.78
(s, 3H), 4.54 (d, J ) 11.7, 1H), 4.60 (d, J ) 6.8, 1H), 4.65 (d, J ) 6.8,
1H), 4.68 (d, J ) 11.7, 1H), 4.95 (q, J ) 6.5, 1H), 6.85-6.91 (m, 2H),
7.22-7.37 (m, 11H), 7.44-7.52 (m, 6H); 13C NMR (63 MHz, CDCl3)
δ 12.82, 20.1125.91, 27.90, 43.46, 55.12, 63.73, 64.64, 68.68, 69.24,
86.26, 90.87, 113.66, 126.75, 127.63128.62, 129.18, 130.19, 131.44,
134.06, 144.39, 158.97. Anal. Calcd for C39H46O5: C, 78.76; H, 7.79.
Found: C, 78.61; H, 7.94.
concentrated. The residue was dissolved in 60 mL of CH2Cl2 and
treated with 1.72 g (3.87 mmol) of Pb(OAc)4. After 5 min, 2 g of
solid Na2CO3 was added and the mixture was stirred for 30 min, filtered,
and concentrated. Purification by silica gel chromatography (10:1
hexane/EtOAc) gave 3.10 g (98%) of ketone 36 as crystals: mp 93-
95 °C (THF); [R]20 ) -6.9° (c 0.77, CHCl3); IR (KBr pellet) 2928,
D
1
1702 cm-1; H NMR (250 MHz, CDCl3) δ 0.00 (s, 6H), 0.88 (mc,
14H), 1.00-2.00 (m, 5H), 2.00 (s, 3H), 2.82-3.18 (m, 4H), 3.36-
3.56 (m, 2H), 7.12-7.68 (m, 30H); 13C NMR (63 MHz, CDCl3) δ
-5.77, 15.31, 18.25, 23.36, 25.87, 26.61, 29.25, 37.12, 47.22, 51.79,
60.00, 63.22, 63.66, 86.36, 86.98, 126.86, 127.71, 128.57, 128.62,
144.08, 144.35, 212.80; EIMS m/z 573 (M+ - Tr, 0.1), 243 (100).
Anal. Calcd for C55H64O4Si: C, 80.84; H, 7.89. Found: C, 80.62; H,
7.85.
[3S,3(1S),4E]-3-[1-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(tri-
tyloxy)butyl]-3,4-dimethylhex-4-enoic acid Dimethyl Amide (28). A
solution of allyl alcohol 26 (4.38 g, 7.84 mmol) in 200 mL of toluene
was treated at 110 °C with 7.67 mL (6.97 g, 47.04 mmol) of
dimethylacetamide dimethyl acetal (90%) in 10 mL of toluene. During
the following 4 h, a mild argon stream was introduced into the solution
through a glass capillary to remove methanol. The solution was
concentrated and purified by silica gel chromatography (3:1 hexane/
Crystal Structure Determination of 36. Crystals of 36, grown
from THF, are monoclinic, space group P21 with a ) 9.3738(8) Å, b
) 13.007(2) Å, c ) 21.668(3) Å, â ) 100.856(8)°, V ) 2595(1) Å2,
Z ) 2, and Fcalc ) 1.138 g/cm3 at rt. A colorless, transparent crystal
of dimensions 0.09 × 0.32 × 0.37 mm3 was measured on an Enraf-
Nonius CAD4 diffractometer with graphite monochromated Cu KR
radiation. A total of 5255 reflections, corresponding to hemisphere of
reciprocal space, were collected up to 2θ ) 110°. A total of 5113
reflections with I > 0 were used. Three standard reflections, remea-
sured every 5500 s, decreased 3% during data collection. The data
were rescaled with respect to the standards. An empirical absorption
correction based on ψ-scan gave a relative transmission factor from
0.86 to 1.00. The structure was determined by direct methods using
program SHELXS. A difference Fourier synthesis revealed a com-
pletely disordered THF molecule per asymmetric unit. H atoms were
placed at calculated positions and were not refined. The non-H atoms
were refined with anisotropic thermal parameters on F values using
weighting scheme w(F) ) 4F2/{σ2(F2) + (0.03F2)2}. Refinement
converged at R(F) ) 0.064, wR(F) ) 0.073, S ) 2.44. The final
difference density was less than 0.44 e/Å3. A refinement including
the Flack x-parameter gave x ) -0.03(5) and confirmed the absolute
configuration of the structure (see Figure 3, Supporting Information).
EtOAc) to give 4.82 g (98%) of amide 28 as clear, viscous oil: [R]20
D
) -2.2° (c 1.00, CHCl3); IR (thin film) 1647, 1449 cm-1; H NMR
1
(250 MHz, CDCl3) δ 0.01 (s, 6H), 0.87 (s, 9H), 1.16 (s, 3H), 1.50
(mc, 2H), 1.56 (mc, 1H), 1.58 (s, 3H), 1.62 (d, J ) 5.5, 3H), 1.92 (mc,
1H), 2.40 (d, J ) 12.3, 1H), 2.52 (d, J ) 12.3, 1H), 2.87 (s, 3H), 2.92
(s, 3H), 3.08 (mc, 2H), 3.50 (mc, 2H), 5.28 (q, J ) 5.5, 1H), 7.16-
7.34 (m, 9H), 7.39-7.60 (m, 6H); 13C NMR (63 MHz, CDCl3) δ -5.75,
-5.66, 13.23, 13.70, 18.06, 19.78, 23.84, 25.82, 29.45, 35.30, 37.87,
39.31, 45.37, 46.67, 62.92, 63.75, 86.16, 118.52, 126.70, 127.58, 128.59,
139.59, 144.43, 171.60; EIMS m/z 627 (M+, 1), 570 (12), 368 (20),
243 (100). Anal. Calcd for C40H57O3NSi: C, 76.51; H, 9.15; N, 2.23.
Found: C, 76.44; H, 9.11; N, 2.22.
[4S,4(1S),5S,5(1R)]- and [4S,4(1S),5R,5(1S)]-4-[1-(((tert-Butyldi-
methylsilyl)oxy)methyl)-4-(trityloxy)butyl]-5-(1-hydroxyethyl)-4,5-
dimethyldihydrofuran-2-one (34a,b). Amide 28 (4.52 g, 7.19 mmol)
and 3.37 g (23.73 mmol) of Na2HPO4 in 80 mL of CH2Cl2 were treated
with 5.86 g (23.73 mmol) of m-CPBA in portions. After 4 h, the
mixture was washed twice with saturated aqueous NaHCO3 and with
water. The aqueous layers were extracted with CH2Cl2, and the
combined organic layers were dried (MgSO4), filtered, and concentrated.
Purification by silica gel chromatography (10:1 hexane/EtOAc) afforded
2.74 g of a major diastereomer which crystallizes from hexane and
1.37 g of a minor diastereomer as amorphous solid. The total yield of
both diastereomers (dr: 2:1) is 4.11 g (93%). Data for the major
(3S,4S)-4-Methyl-5-methylene-4-(2-(trityloxy)ethyl)-3-(3-(trityl-
oxy)propyl)dihydrofuran-2-one (38) and (3S,4S)-5-Hydroxy-4,5-
dimethyl-4-(2-(trityloxy)ethyl)-3-(3-(trityloxy)propyl)pyrrolidin-2-
one (39). To a cold (0 °C) solution of 2.37 g (3.30 mmol) of acid 37
in 60 mL of CH2Cl2 was added 4.51 mL (3.40 g, 26.43 mmol) of
i-Pr2NEt and 1.03 mL (1.52 g, 13.20 mmol) of MsCl. After 2-3 min
the mixture was filtered through silica gel. The product crystallizes
very readily from many common solvents (e.g., from diethyl ether/
hexane). Enol lactone 38 (2.30 g (>99%)) as fine white crystals can
be obtained. Usually the residue from the above filtration was used
for the next step without purification, by dissolving in 65 mL of THF
and 40 mL of ethanol and adding this solution to liquid ammonia (700
mL). After 36 h nearly the entire ammonia has evaporated. The residue
was concentrated and chromatographed (1:1 hexane/EtOAc) to yield
2.15 g (91%) of keto amide 39 as a solid. (Note: This material is not
stable on storage.) Enol lactone 38: mp 133-135 °C; [R]20D ) -16.0°
(c 0.75, CHCl3); IR (KBr pellet) 1799, 1669 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.07 (s, 3H), 1.46-1.60 (m, 3H), 1.79-1.94 (m, 3H), 2.47
(dd, J ) 7.7 and 6.3, 1H), 2.99-3.08 (m, 2H), 3.20 (mc, 2H), 4.06 (d,
J ) 2.9, 1H), 4.56 (d, J ) 2.9, 1H), 7.18-7.30 (m, 18H), 7.36-7.43
(m, 12H); 13C NMR (63 MHz, CDCl3) δ 23.13, 27.84, 38.50, 44.65,
44.66, 47.43, 59.91, 63.29, 86.39, 86.90, 87.18, 126.72, 126.84, 127.58,
127.66, 128.47, 128.57, 143.85, 144.27, 163.03, 175.58. Anal. Calcd
for C49H46O4: C, 84.21; H, 6.63. Found: C, 84.06; H, 6.86. Keto
diastereomer lactone (34a): mp 124 °C (hexane); [R]20 ) -17.7° (c
D
1
1.31, CHCl3); H NMR (250 MHz, CDCl3) δ 0.05 (s, 3H), 0.06 (s,
3H), 0.87 (s, 9H), 1.03 (s, 3H), 1.22 (d, J ) 6.3, 3H), 1.32 (mc, 1H),
1.33 (s, 3H), 1.55 (mc, 1H), 1.80 (mc, 2H), 2.13 (d, J ) 17.3, 1H),
2.58 (d, J ) 17.3, 1H), 2.99-3.11 (m, 2H), 3.22 (s, 1H), 3.62 (mc,
2H), 3.96 (q, J ) 6.3, 1H), 7.16-7.31 (m, 9H), 7.37-7.42 (m, 6H);
13C NMR (63 MHz, CDCl3) δ -5.78, 15.13, 15.26, 17.99, 18.14, 18.98,
25.80, 28.64, 42.90, 43.09, 48.11, 62.75, 63.28, 65.71, 67.13, 86.32,
91.95, 126.82, 127.65, 128.46, 144.02, 174.88. Anal. Calcd for
C38H52O5Si: C, 73.98; H, 8.50. Found: C, 73.42; H, 8.64. Data for
the minor diastereomer lactone (34b): 1H NMR (250 MHz, CDCl3) δ
0.03 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H), 1.15 (s, 3H), 1.21 (d, J ) 6.3,
3H), 1.24 (s, 3H), 1.42-1.48 (mc, 3H), 1.76-1.83 (m, 1H), 2.20 (d, J
) 17.1, 1H), 2.41 (d, J ) 17.1, 1H), 3.07 (mc, 2H), 3.67 (m, 1H), 3.84
(mc, 2H), 4.03 (mc, 1H), 7.16-7.30 (m, 9H), 7.36-7.41 (m, 6H); 13
C
NMR (63 MHz, CDCl3) δ -5.57, 14.61, 17.56, 18.00, 18.36, 25.31,
25.71, 28.46, 44.52, 45.91, 48.46, 62.32, 63.87, 67.72, 86.45, 91.33,
126.90, 127.69, 128.49, 143.99, 174.47. Data for a mixture of both
diastereomers: IR (KBr pellet) 1774, 1756 cm-1; EIMS m/z 616 (M+,
<0.1), 243 (100).
(3S,4S]-4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methyl-7-(tri-
tyloxy)-3-(2-(trityloxy)ethyl)heptan-2-one (36). Triol 35 (2.40 g, 3.87
mmol) as a mixture of diastereomers was dissolved in 40 mL of
pyridine, and a catalytic amount of DMAP and 4.30 g (15.49 mmol)
of Ph3CCl were added. After 2 d at rt, a small amount of water and
40 mL of ethanol were added. The mixture was concentrated, treated
with 25 mL of hexane, and filtered, and the residue was washed with
hexane. This hexane solution was dried (MgSO4), filtered, and
amide 39: [R]20 ) +11.5° (c 0.60, CHCl3); IR (KBr pellet) 3387,
D
1687 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.76 (s, 3H), 1.25 (s, 3H),
1.20-1.40 (m, 1H), 1.50-1.70 (m, 2H), 1.73-1.81 (m, 1H), 1.85-
2.10 (m, 2H), 2.41 (mc, 1H), 2.99-3.10 (m, 2H), 3.19-3.38 (m, 2H),
3.84 (s, 1H), 5.71 (s, 1H), 7.21-7.33 (m, 18H), 7.34-7.44 (m, 12H);
13C NMR (63 MHz, CDCl3) δ 14.13, 22.96, 23.55, 48.12, 48.33, 60.34,
63.15, 86.29, 88.04, 88.62, 126.78, 126.90, 127.65, 127.73, 128.51,
128.63, 144.34, 144.37, 178.76. Anal. Calcd for C49H49NO4: C, 82.21;
H, 6.90; N, 1.96. Found: C, 81.21; H,6.95; N, 1.88.
(3S,4S)-4-Methyl-5-methylene-4-(2-(trityloxy)ethyl)-3-(3-(trityl-
oxy)propyl)pyrrolidin-2-one (40), (2R,3S,4S)-2,3-Dimethyl-5-oxo-
3-(2-(trityloxy)ethyl)-4-(3-(trityloxy)propyl)pyrrolidine-2-carboni-

5518 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Mulzer et al.
trile, and (2R,3S,4S)-2,3-Dimethyl-5-thioxo-3-(2-(trityloxy)ethyl)-
4-(3-(trityloxy)propyl)pyrrolidine-2-carbonitrile (42). Keto amide
39 (1933 mg, 2.70 mmol) was melted at 1 mbar and 110 °C and kept
under these conditions for 1 h. Spectroscopically pure enamide 40
(1884 mg, >99%) was thus obtained. (Note: This amide is moisture
sensitive and gives keto amide 39 on storage.) The above enamide
(40) (796 mg, 1.14 mmol) was dissolved in 8 mL of THF and treated
with a mixture of KCN (222 mg, 3.42 mmol) and KHCO3 (342 mg,
3.42 mmol) and dissolved in 8 mL of water and 16 mL of isopropanol.
After being stirred at 55 °C for 24 h, the mixture was poured into
CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were dried (MgSO4), filtered, and
concentrated to give 827 mg (>99%) of cyano lactam 41. This was
dissolved in 10 mL of dry THF and treated with Lawesson’s reagent
(593 mg, 1.60 mmol). After 45 min at 60 °C, the mixture was poured
into diethyl ether and saturated aqueous NaHCO3; the aqueous layer
was extracted with diethyl ether, and the combined organic layers were
dried (MgSO4), filtered, and concentrated. Purification by silica gel
chromatography (5:1 hexane/EtOAc) afforded 744 mg (88%) of thio
lactam 42 as a solid. Enamide 40: IR (KBr pellet) 1709, 1677, 1654
cm-1; 1H NMR (250 MHz, CDCl3) δ 1.07 (s, 3H), 1.40-1.70 (m, 3H),
1.75-1.97 (m, 3H), 2.30 (mc, 1H), 2.90-3.10 (m, 2H), 3.17 (mc, 2H),
3.89 (d, J ) 1.9, 1H), 4.15 (d, J ) 1.9, 1H), 7.15-7.35 (m, 18H),
7.35-7.47 (m, 12H), 7.52 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 22.88,
23.51, 28.35, 39.68, 44.06, 48.67, 60.21, 63.58, 84.00, 86.23, 86.93,
126.72, 126.84, 127.58, 127.66, 128.47, 128.57, 143.85, 144.27, 162.51,
177.91. Cyano lactam 41 [(2R:2S) ) 6:1 mixture of diastereomers]:
[R]20D ) -10.7° (c 1.20, CHCl3); IR (KBr pellet) 1709 cm-1; 1H NMR
(400 MHz, CDCl3) δ 0.74 (s, 3H), 1.25-1.38 (m, 1H), 1.31 (s, 3H),
1.66 (mc, 1H), 1.92-1.97 (m, 1H), 2.08 (mc, 1H), 2.19 (mc, 1H), 2.30
(dd, J ) 3.5, 9.3, 1H), 3.04 (mc, 2H), 3,14 (mc, 1H), 6.06 (s, 1H),
7.17-7.36 (m, 18H), 7.41-7.45 (m, 12H); 13C NMR (63 MHz, CDCl3)
δ 14.09, 21.24, 21.70, 28.62, 37.43, 48.45, 51.55, 59.15, 59.84, 63.23,
86.46, 87.50, 120.17, 126.89, 127.09, 127.75, 127.89, 128.58, 128.68,
143,76, 144,36, 176.91. Anal. Calcd for C50H48N2O3: C, 82.84; H,
6.67, N, 3.86. Found: C, 82.34; H, 7.03; N, 3.52. Thio lactam 42
45.29, 48.37, 51.61, 59.99, 60.35, 62.87, 63.36, 73.00, 83.65, 86.11,
86.36, 86.93, 87.04, 119.69, 126.61, 126.78, 127.47, 127.59, 128.37,
128.42, 128.45, 143.68, 143.76, 143.99, 144.14, 152.02, 176.88, 178.40.
Anal. Calcd for C99H93N3O5S: C, 82.75; H, 6.52; N, 2.92. Found:
C, 82.49; H, 6.89; N, 2.67.
[2R,3S,4S,5(2Z,3S,4S)]-2,3-Dimethyl-5-[(3-methyl-5-oxo-3-(2-(tri-
tyloxy)ethyl)-4-(3-(trityloxy)propyl)pyrrolidin-2-ylidene)methyl]-3-
(2-(trityloxy)ethyl)-4-(3-(trityloxy)propyl)-3,4-dihydro-2H-pyrrole-
2-carbonitrile (44). A solution of 200 mg (139 µmol) of sulfide 43
and triethyl phosphite (0.148 mL, 142 mg, 850 µmol) in 2 mL of dry
benzene was degassed and heated to 120 °C for 72 h in a sealed tube.
The mixture was concentrated and chromatographed on aluminium
oxide (activity III-IV, linear gradient of 10-20% EtOAc/hexane) to
give 177 mg (90%) of A-B-semicorrin 44 as a mixture of diastereo-
isomers (ca. 36:6:6:1). Diastereomerically pure material was obtained
by HPLC (Nuc 50-10, 10:1:2 hexane/MeOAc/diethyl ether, +20%
hexane, 10 mL/min). The pure A-B-semicorrin 44 (130 mg, 67%)
was thus obtained as an amorphous solid: [R]20 ) +17.3° (c 0.26,
D
CHCl3); IR (KBr pellet) 1738, 1638, 1545 cm-1; 1H NMR (600 MHz,
with ROESY, NOESY, COSY 90, 13C-1H-COSY, C6D6) δ 0.34 (s,
3H, C2-Me), 0.87 (s, 3H, C7-Me), 1.18 (s, 3H, C1-Me), 1.18 (mc, 1H,
C3′-Ha), 1.34 (mc, 2H, C3′′-Ha, C8′-Ha), 1.54 (mc, 2H, C3′-Hb, C8′-Hb),
1.67 (mc, 2H, C8′′-Ha, C3′′-Hb), 1.78 (mc, 2H, C7′-H2), 2.00 (mc, 1H,
C2′-Ha), 2.25 (mc, 1H, C8′′-Hb), 2.34 (mc, 1H, C2′-Hb), 2.51 (dd, J )
5.8 and 8.5, 1H, C8-H), 2.61 (dd, J ) 4.1 and 7.9, 1H, C3-H), 3.02
(mc, 1H, C3′′′-Ha), 3.10-3.28 (m, 6H, C2′′-Ha, C3′′′-Hb, C7′′-H2, C8′′′
-
H2), 3.34 (mc, 1H, C2′′-Hb), 5.05 (s, 1H, C5-H), 7.00-7.20 (m, 36H,
Ar-H), 7.48-7.60 (m, 24H, Ar-H), 11.24 (s, br, 1H, N-H); 13C NMR
(63 MHz, C6D6) δ 14.28 (C2-Me), 22.65 (C1-Me), 23.60 (C3′), 23.82
(C8′), 23.91 (C7-Me), 29.05 (C8′′), 30.60 (C3′′), 38.44 (C2′), 39.47 (C7′),
45.50 (C2), 47.60 (C8), 50.69 (C7), 59.44 (C3), 60.48 (C7′′), 60.93 (C2′′),
63.57 (C3′′′), 64.18 (C8′′′), 72.94 (C1), 86.91, 87.04, 87.67, 87.71, 87.87
(C5), 120.61 (C1-CN), 126.85, 126.99, 127.03, 127.10, 127.71, 127.81,
127.86, 128.48, 128.58, 128.68, 144.31, 144.61, 144.82, 145.03, 162.95
(C6), 177.69 (C4), 178.36 (C9); FDMS m/z 1403 (M+, 15), 1377 (M+
- CN, 100), 1134 (M+ - Tr - CN, 15), 243 (96); [+]-FAB
(m-nitrobenzyl alcohol, CsI, xenon) m/z 1537 (M+ + Cs, 0.3), 243
(100). Anal. Calcd for C99H93N3O5‚4H2O: C, 80.51; H, 6.89; N, 2.85.
Found: C, 80.62; H, 7.20; N, 2.61.
[(2R:2S) ) 6:1 mixture of diastereomers]: [R]20 ) +3.4° (c 0.85,
D
1
CHCl3); IR (KBr pellet) 1596 cm-1; H NMR (250 MHz, CDCl3) δ
0.59 (s, 3H), 1.25 (s, 3H), 1.24-1.41 (m, 1H), 1.57-190 (m, 3H),
2.01-2.33 (m, 2H), 2.40-2.50 (m, 1H), 2.93-3.12 (m, 4H), 7.09-
7.29 (m, 18H), 7.30-7.45 (m, 12H), 8.28 (s, 1H); 13C NMR (63 MHz,
CDCl3) δ 13.35, 20.41, 23.45, 29.25, 36.74, 51.06, 59.58, 61.07, 63.06,
64.01, 86.41, 87.47, 126.81, 127.02, 127.67, 127.83, 128.46, 128.57,
143.54, 144.25. Anal. Calcd for C50H48N2O2S: C, 81.05; H, 6.53; N,
3.78. Found: C, 81.22; H, 6.43; N, 3.51.
Acknowledgment. This work is taken from the Ph.D. Thesis
of B.L., Johann Wolfgang Goethe-Universita¨t, 1997. The
crystallography was performed by J.W.B. Financial support by
the Deutsche Forschungsgemeinschaft and Schering AG, Berlin,
is gratefully acknowledged. We thank Professor Eschenmoser
and Professor Montforts for helpful discussions and for provid-
ing us with unpublished experimental details. B.L. thanks the
City of Berlin for a NaFo¨G stipendium. We thank Dr. G.
Zimmermann (NMR), Dr. A. Scha¨fer (NMR), Dr. G. Du¨rner
(HPLC), M. Christoph (analyses), and J. del Corte for technical
assistance. Mass spectra were obtained from the Max-Planck-
Institut fu¨r Polymerforschung, Mainz, and from the Institut fu¨r
Organische Chemie der FU, Berlin. Dedicated to Professor E.
Winterfeldt on the occasion of his 65th birthday.
[2R,3S,4S,5(2Z,3S,4S)]-2,3-Dimethyl-5-[(3-methyl-5-oxo-3-(2-(tri-
tyloxy)ethyl)-4-(3-(trityloxy)propyl)pyrrolidin-2-ylidene)methane-
sulfonyl]-3-(2-(trityloxy)ethyl)-4-(3-(trityloxy)propyl)-3,4-dihydro-
2H-pyrrole-2-carbonitrile (43). A solution of thio lactam 42 (1740
mg, 1.00 mmol) in 5 mL of dry benzene was added to freshly prepared
enamide 40 (1047 mg, 1.50 mmol). At 0 °C benzoyl peroxide (415
mg, 1.20 mmol) was added. The mixture was stirred in the dark and
under argon for 24 h and poured into a mixture of diethyl ether and
saturated aqueous NaHCO3. The organic layer was dried (MgSO4),
filtered, and concentrated. Purification by silica gel chromatography
(linear gradient of 10-20% EtOAc/hexane) afforded 804 mg (56%)
of sulfide 43 as a solid. [R]20 ) +4.8° (c 1.05, CHCl3); IR (KBr
D
pellet) 1716, 1646, 1566 cm-1; 1H NMR (600 MHz, CDCl3) δ 0.64 (s,
3H), 1.09 (s, 3H), 1.21 (s, 3H), 1.22-1.55 (m, 6H), 1.76-1.95 (m,
5H), 2.13 (mc, 1H), 2.40 (mc, 1H), 2.70 (dd, J ) 4.5 and 8.4, 1H),
2.95-3.11 (m, 5H), 3.12-3.28 (m, 3H), 5,14 (s, 1H), 7.04 (s, 1H),
7.13-7.34 (m, 36H), 7.36-7.48 (m, 24H); 13C NMR (63 MHz, CDCl3)
δ 15.03, 22.14, 22.93, 23.04, 23.24, 28.14, 29.34, 31.34, 37.82, 39.12,
Supporting Information Available: Preparation and ana-
lytical data of compounds 20, 21, 22, 26, 27, 29, 35, and 37
and crystal data of ketone 36 (31 pages). See any current
masthead page for ordering and internet access instructions.
JA9700515